Sample records for pharmacokinetics tissue distribution

  1. Pharmacokinetics of warfarin in rats: role of serum protein binding and tissue distribution

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cheung, W.K.

    The purpose of this study was to explore the role of serum protein binding and tissue distribution in the non-linear pharmacokinetics of warfarin in rats. The first phase of the research was an attempt to elucidate the causes of intersubject differences in serum protein binding of warfarin in rats. It was found that the distribution of S-warfarin between blood and liver, kidneys, muscle, or fatty tissue was non-linear. Based on the tissue distribution data obtained, a physiologically-based pharmacokinetic model was developed to describe the time course of S-warfarin concentrations in the serum and tissues of rats. The proposed model wasmore » able to display the dose-dependent pharmacokinetics of warfarin in rats. Namely a lower clearance and a smaller apparent volume of distribution with increasing dose, which appear to be due to the presence of capacity-limited, high-affinity binding sites for warfarin in various tissues. To determine if the binding of warfarin to the high-affinity binding sites in the liver of rats is reversible, concentrations of S-warfarin in the liver and serum of rats were monitored for a very long time after an intravenous injection of a 1 mg/kg dose. In another study in rats, non-radioactive warfarin was found to be able to displace tissue-bound C/sup 14/-warfarin which was administered about 200 hours before the i.v. injection of the non-radioactive warfarin, showing that the binding of warfarin to the high-affinity binding sites in the body is persistent and reversible.« less

  2. Pharmacokinetics, Tissue Distribution, and Anti-Lipogenic/Adipogenic Effects of Allyl-Isothiocyanate Metabolites

    PubMed Central

    Ahn, Jiyun; Chung, Woo-Jae; Jang, Young Jin; Seong, Ki-Seung; Moon, Jae-Hak; Ha, Tae Youl; Jung, Chang Hwa

    2015-01-01

    Allyl-isothiocyanate (AITC) is an organosulfur phytochemical found in abundance in common cruciferous vegetables such as mustard, wasabi, and cabbage. Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function of AITC metabolites is still largely unknown. In this study, we evaluated the inhibitory effects of AITC metabolites on lipid accumulation in vitro and elucidated the pharmacokinetics and tissue distribution of AITC metabolites in rats. We found that AITC metabolites generally conjugate with glutathione (GSH) or N-acetylcysteine (NAC) and are distributed in most organs and tissues. Pharmacokinetic analysis showed a rapid uptake and complete metabolism of AITC following oral administration to rats. Although AITC has been reported to exhibit anti-tumor activity in bladder cancer, the potential bioactivity of its metabolites has not been explored. We found that GSH-AITC and NAC-AITC effectively inhibit adipogenic differentiation of 3T3-L1 preadipocytes and suppress expression of PPAR-γ, C/EBPα, and FAS, which are up-regulated during adipogenesis. GSH-AITC and NAC-AITC also suppressed oleic acid-induced lipid accumulation and lipogenesis in hepatocytes. Our findings suggest that AITC is almost completely metabolized in the liver and rapidly excreted in urine through the mercapturic acid pathway following administration in rats. AITC metabolites may exert anti-obesity effects through suppression of adipogenesis or lipogenesis. PMID:26317351

  3. Pharmacokinetics, Tissue Distribution, and Anti-Lipogenic/Adipogenic Effects of Allyl-Isothiocyanate Metabolites.

    PubMed

    Kim, Yang-Ji; Lee, Da-Hye; Ahn, Jiyun; Chung, Woo-Jae; Jang, Young Jin; Seong, Ki-Seung; Moon, Jae-Hak; Ha, Tae Youl; Jung, Chang Hwa

    2015-01-01

    Allyl-isothiocyanate (AITC) is an organosulfur phytochemical found in abundance in common cruciferous vegetables such as mustard, wasabi, and cabbage. Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function of AITC metabolites is still largely unknown. In this study, we evaluated the inhibitory effects of AITC metabolites on lipid accumulation in vitro and elucidated the pharmacokinetics and tissue distribution of AITC metabolites in rats. We found that AITC metabolites generally conjugate with glutathione (GSH) or N-acetylcysteine (NAC) and are distributed in most organs and tissues. Pharmacokinetic analysis showed a rapid uptake and complete metabolism of AITC following oral administration to rats. Although AITC has been reported to exhibit anti-tumor activity in bladder cancer, the potential bioactivity of its metabolites has not been explored. We found that GSH-AITC and NAC-AITC effectively inhibit adipogenic differentiation of 3T3-L1 preadipocytes and suppress expression of PPAR-γ, C/EBPα, and FAS, which are up-regulated during adipogenesis. GSH-AITC and NAC-AITC also suppressed oleic acid-induced lipid accumulation and lipogenesis in hepatocytes. Our findings suggest that AITC is almost completely metabolized in the liver and rapidly excreted in urine through the mercapturic acid pathway following administration in rats. AITC metabolites may exert anti-obesity effects through suppression of adipogenesis or lipogenesis.

  4. Pharmacokinetics and Tissue Distribution Study of Chlorogenic Acid from Lonicerae Japonicae Flos Following Oral Administrations in Rats

    PubMed Central

    Zhou, Yulu; Zhou, Ting; Pei, Qi; Liu, Shikun; Yuan, Hong

    2014-01-01

    Chlorogenic acid (ChA) is proposed as the major bioactive compounds of Lonicerae Japonicae Flos (LJF). Forty-two Wistar rats were randomly divided into seven groups to investigate the pharmacokinetics and tissue distribution of ChA, via oral administration of LJF extract, using ibuprofen as internal standard, employing a high performance liquid chromatography in conjunction with tandem mass spectrometry. Analytes were extracted from plasma samples and tissue homogenate by liquid–liquid extraction with acetonitrile, separated on a C 18 column by linear gradient elution, and detected by electrospray ionization mass spectrometry in negative selected multiple reaction monitoring mode. Our results successfully demonstrate that the method has satisfactory selectivity, linearity, extraction recovery, matrix effect, precision, accuracy, and stability. Using noncompartment model to study pharmacokinetics, profile revealed that ChA was rapidly absorbed and eliminated. Tissue study indicated that the highest level was observed in liver, followed by kidney, lung, heart, and spleen. In conclusion, this method was suitable for the study on pharmacokinetics and tissue distribution of ChA after oral administration. PMID:25140190

  5. Pharmacokinetics, tissue distribution, and excretion of zinc oxide nanoparticles

    PubMed Central

    Baek, Miri; Chung, Hae-Eun; Yu, Jin; Lee, Jung-A; Kim, Tae-Hyun; Oh, Jae-Min; Lee, Won-Jae; Paek, Seung-Min; Lee, Jong Kwon; Jeong, Jayoung; Choy, Jin-Ho; Choi, Soo-Jin

    2012-01-01

    Background This study explored the pharmacokinetics, tissue distribution, and excretion profile of zinc oxide (ZnO) nanoparticles with respect to their particle size in rats. Methods Two ZnO nanoparticles of different size (20 nm and 70 nm) were orally administered to male and female rats, respectively. The area under the plasma concentration-time curve, tissue distribution, excretion, and the fate of the nanoparticles in organs were analyzed. Results The plasma zinc concentration of both sizes of ZnO nanoparticles increased during the 24 hours after administration in a dose-dependent manner. They were mainly distributed to organs such as the liver, lung, and kidney within 72 hours without any significant difference being found according to particle size or rat gender. Elimination kinetics showed that a small amount of ZnO nanoparticles was excreted via the urine, while most of nanoparticles were excreted via the feces. Transmission electron microscopy and x-ray absorption spectroscopy studies in the tissues showed no noticeable ZnO nanoparticles, while new Zn-S bonds were observed in tissues. Conclusion ZnO nanoparticles of different size were not easily absorbed into the bloodstream via the gastrointestinal tract after a single oral dose. The liver, lung, and kidney could be possible target organs for accumulation and toxicity of ZnO nanoparticles was independent of particle size or gender. ZnO nanoparticles appear to be absorbed in the organs in an ionic form rather than in a particulate form due to newly formed Zn-S bonds. The nanoparticles were mainly excreted via the feces, and smaller particles were cleared more rapidly than the larger ones. ZnO nanoparticles at a concentration below 300 mg/kg were distributed in tissues and excreted within 24 hours. These findings provide crucial information on possible acute and chronic toxicity of ZnO nanoparticles in potential target organs. PMID:22811602

  6. Synthetic microRNA cassette dosing: pharmacokinetics, tissue distribution and bioactivity.

    PubMed

    Wang, Hongyan; Chiu, Ming; Xie, Zhiliang; Chiu, Michael; Liu, Zhongfa; Chen, Ping; Liu, Shujun; Byrd, John C; Muthusamy, Natarajan; Garzon, Ramiro; Croce, Carlo M; Marcucci, Guido; Chan, Kenneth K

    2012-06-04

    MicroRNAs (miRs) are deregulated in cancer and leukemia. Restoring aberrantly downregulated tumor suppressor miRs or antagonizing overexpressed oncogenic miRs in malignant cells by synthetic RNA oligonucleotides represents a potentially novel therapeutic approach in cancer and leukemia. However, given the complex networking and concurrent deregulation of miRs in malignant cells, an effective approach may require concurrent targeting of multiple miRs. Cassette dosing involves simultaneous administration of a mixture of oligonucleotides from the same or different structural classes. However, information on cassette dosing pharmacokinetics, tissue distribution and bioactivity of synthetic miRs is lacking. In this study, three synthetic 2'-methoxyphosphorothioate-miRs (2'-MeOPSmiR16-1, 2'-MeOPSmiR29b and 2'-MeOPSantagomiR155) were administered iv to C57BL/6 mice as a mixture, each at 7.5 mg/kg. Analysis of concentrations of individual miR in plasma and major organ tissues (bone marrow, spleen, liver, brain, heart, kidney and lung) was performed. The mRNA and protein levels of miR's biotargets were monitored sequentially after dosing up to 24 h. Our results demonstrated that these synthetic miRs retain their different individual pharmacokinetic properties and all display three-compartmental pharmacokinetics. 2'-MeOPSmiR16-1 has the longest plasma gamma half-life of 2508 min and lowest total body clearance of 0.0054 L/min·kg, whereas 2'-MeOPSmiR29b has the shortest gamma half-life of 510.6 min and highest total body clearance of 0.042 L/min·kg. The tissue concentrations of all three 2'-MeOPS-modified miR(s)/antagomiR were measurable from 5 min to at least 24 h after dosing, indicating that these concurrently delivered oligonucleotides can reach organ tissues. Importantly, there were biological activities of the concurrently administered miRs which persisted, as shown by the downregulation of specific targets in tested tissues, albeit with variations. Brain was one of

  7. Pharmacokinetics of Antiretrovirals in Mucosal Tissue

    PubMed Central

    Cottrell, M.L.; Srinivas, N.; Kashuba, A.D.M.

    2015-01-01

    Introduction In the absence of an HIV vaccine or cure, antiretroviral (ARV) based prevention strategies are being investigated to reduce HIV incidence. These prevention strategies depend on achieving effective drug concentrations at the site HIV exposure which is most commonly the mucosal tissues of the lower gastrointestinal tract and the female genital tract. Areas covered This article collates all known data regarding drug exposure in these vulnerable mucosal tissues, and reviews important mechanisms of ARV drug distribution. Research papers and abstracts describing antiretroviral pharmacokinetics in the female genital tract and lower gastrointestinal mucosal tissues available in MEDLINE® or presented at scientific conferences prior to December 2014 are reviewed in detail. Important influences on ARV mucosal tissue distribution, including protein binding, active drug transport, and endogenous hormones, are also reviewed. Expert opinion ARVs exhibit highly variable pharmacokinetics in mucosal tissues. In general, antiretroviral exposure is higher in the lower gastrointestinal tract compared to the female genital tract, but concentrations required for protective efficacy are largely unknown. The expected site of HIV exposure represents an important consideration when designing and optimizing antiretroviral based prevention strategies. PMID:25797064

  8. Pharmacokinetics, tissue distribution, and metabolism of nitrofurantoin in the channel catfish (Ictalurus punctatus)

    USGS Publications Warehouse

    Stehly, G.R.; Plakas, S.M.

    1993-01-01

    The pharmacokinetics, tissue distribution, and metabolism of the drug nitrofurantoin were examined in the channel catfish (Ictalurus punctatus) after intravascular or oral dosing. Mean plasma concentrations of nitrofurantoin after intravascular administration at 1 and 10 mg/kg of body weight were best fit to two- and three-compartment pharmacokinetic models, respectively. Nitrofurantoin was rapidly eliminated from the plasma after intravascular dosing; at 1 and 10 mg/kg, the terminal half-lives were 23 and 46 min, respectively. After oral dosing at 1 mg/kg, peak plasma concentrations (0.06 mu g/ml) occurred at 2 h; the bioavailability was 17%. Residues of nitrofurantoin and its metabolites in the tissues were initially eliminated rapidly but persisted at the later sampling times. Residue concentrations were highest in the plasma and excretory tissues. Approximately 21% and 4% of the oral dose were eliminated in the urine and bile, respectively. Parent nitrofurantoin was the major radiolabelled compound found in the urine; however, the percentage of total residues composed of metabolites increased with time. Biliary residues consisted mostly of nitrofurantoin metabolites. High-performance liquid chromatography revealed the presence of at least five metabolites in the urine and bile.

  9. Estimation of the minimum permeability coefficient in rats for perfusion-limited tissue distribution in whole-body physiologically-based pharmacokinetics.

    PubMed

    Jeong, Yoo-Seong; Yim, Chang-Soon; Ryu, Heon-Min; Noh, Chi-Kyoung; Song, Yoo-Kyung; Chung, Suk-Jae

    2017-06-01

    The objective of the current study was to determine the minimum permeability coefficient, P, needed for perfusion-limited distribution in PBPK. Two expanded kinetic models, containing both permeability and perfusion terms for the rate of tissue distribution, were considered: The resulting equations could be simplified to perfusion-limited distribution depending on tissue permeability. Integration plot analyses were carried out with theophylline in 11 typical tissues to determine their apparent distributional clearances and the model-dependent permeabilities of the tissues. Effective surface areas were calculated for 11 tissues from the tissue permeabilities of theophylline and its PAMPA P. Tissue permeabilities of other drugs were then estimated from their PAMPA P and the effective surface area of the tissues. The differences between the observed and predicted concentrations, as expressed by the sum of squared log differences with the present models were at least comparable to or less than the values obtained using the traditional perfusion-limited distribution model for 24 compounds with diverse PAMPA P values. These observations suggest that the use of a combination of the proposed models, PAMPA P and the effective surface area can be used to reasonably predict the pharmacokinetics of 22 out of 24 model compounds, and is potentially applicable to calculating the kinetics for other drugs. Assuming that the fractional distribution parameter of 80% of the perfusion rate is a reasonable threshold for perfusion-limited distribution in PBPK, our theoretical prediction indicates that the pharmacokinetics of drugs having an apparent PAMPA P of 1×10 -6 cm/s or more will follow the traditional perfusion-limited distribution in PBPK for major tissues in the body. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Pharmacokinetics and tissue distribution of psammaplin A, a novel anticancer agent, in mice.

    PubMed

    Kim, Hak Jae; Kim, Tae Hwan; Seo, Won Sik; Yoo, Sun Dong; Kim, Il Han; Joo, Sang Hoon; Shin, Soyoung; Park, Eun-Seok; Ma, Eun Sook; Shin, Beom Soo

    2012-10-01

    This study reports the pharmacokinetics and tissue distribution of a novel histone deacetylase and DNA methyltransferase inhibitor, psammaplin A (PsA), in mice. PsA concentrations were determined by a validated LC-MS/MS assay method (LLOQ 2 ng/mL). Following intravenous injection at a dose of 10 mg/kg in mice, PsA was rapidly eliminated, with the average half-life (t(1/2, λn)) of 9.9 ± 1.4 min and the systemic clearance (CL(s)) of 925.1 ± 570.1 mL/min. The in vitro stability of PsA was determined in different tissue homogenates. The average degradation t(1/2) of PsA in blood, liver, kidney and lung was found relatively short (≤ 12.8 min). Concerning the in vivo tissue distribution characteristics, PsA was found to be highly distributed to lung tissues, with the lung-to-serum partition coefficients (K(p)) ranging from 49.9 to 60.2. In contrast, PsA concentrations in other tissues were either comparable with or less than serum concentrations. The high and specific lung targeting characteristics indicates that PsA has the potential to be developed as a lung cancer treatment agent.

  11. Comparative pharmacokinetic and tissue distribution profiles of four major bioactive components in normal and hepatic fibrosis rats after oral administration of Fuzheng Huayu recipe.

    PubMed

    Yang, Tao; Liu, Shan; Wang, Chang-Hong; Tao, Yan-Yan; Zhou, Hua; Liu, Cheng-Hai

    2015-10-10

    Fuzheng Huayu recipe (FZHY) is a herbal product for the treatment of liver fibrosis approved by the Chinese State Food and Drug Administration (SFDA), but its pharmacokinetics and tissue distribution had not been investigated. In this study, the liver fibrotic model was induced with intraperitoneal injection of dimethylnitrosamine (DMN), and FZHY was given orally to the model and normal rats. The plasma pharmacokinetics and tissue distribution profiles of four major bioactive components from FZHY were analyzed in the normal and fibrotic rat groups using an ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. Results revealed that the bioavailabilities of danshensu (DSS), salvianolic acid B (SAB) and rosmarinic acid (ROS) in liver fibrotic rats increased 1.49, 3.31 and 2.37-fold, respectively, compared to normal rats. There was no obvious difference in the pharmacokinetics of amygdalin (AMY) between the normal and fibrotic rats. The tissue distribution of DSS, SAB, and AMY trended to be mostly in the kidney and lung. The distribution of DSS, SAB, and AMY in liver tissue of the model rats was significantly decreased compared to the normal rats. Significant differences in the pharmacokinetics and tissue distribution profiles of DSS, ROS, SAB and AMY were observed in rats with hepatic fibrosis after oral administration of FZHY. These results provide a meaningful basis for developing a clinical dosage regimen in the treatment of hepatic fibrosis by FZHY. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Bioavailability, Pharmacokinetics and Tissue Distribution of P57AS3 (P57) from Hoodia gordonii Mouse Model

    USDA-ARS?s Scientific Manuscript database

    P57AS3, an oxypregnane steroidal glycoside (P57) is known to be responsible for the diet suppressing activity of Hoodia gordonii, a dietary supplement used for weight loss. In this study, bioavailability, pharmacokinetics and tissue distribution of P57 was determined in CD1 female mice after adminis...

  13. Comparative study of pharmacokinetics and tissue distribution of osthole in rats after oral administration of pure osthole and Libanotis buchtormensis supercritical extract.

    PubMed

    Shi, Juan; Fu, Qiang; Chen, Wang; Yang, Hai-Ping; Liu, Jing; Wang, Xiao-Meng; He, Xu

    2013-01-09

    Libanotis buchtormensis is the source of an important traditional medicine from Shaanxi province of China used in the treatment of many illnesses. Libanotis buchtormensis supercritical extract (LBSE) has analgesic, sedative and anti-inflammatory qualities. Osthole is one of the major bioactive components of LBSE; it is known for its significant anti-tumor, analgesic, and anti-inflammatory properties, it also alleviates hyperglycemia. The purpose of the present study was to compare the pharmacokinetics and tissue distribution of osthole in Sprague-Dawley (SD) rats after oral administration of pure osthole and LBSE. The two preparations were administered at the same osthole dose (approximately 130 mg/kg). The results should provide some guidance for the clinical applications of Libanotis buchtormensis. Comparative pharmacokinetics and tissue distribution of osthole in SD rats after oral administration of pure osthole and LBSE were analyzed using reversed-phase high-performance liquid chromatography (RP-HPLC). All pharmacokinetic data were analyzed using 3P97 software. Samples of blood and internal organs (heart, liver, spleen, lungs and kidney) were collected and pretreated according to the experimental schedule. After pretreatment, plasma and tissue samples were extracted using ether-ethyl acetate mixture (3:1, v/v). The concentration of osthole in the plasma and tissues were determined using the RP-HPLC method. The procedure described in this paper shows good precision and stability and is suitable for the osthole assays in biological samples. We found that the average plasma concentration-time profile of osthole after oral administration of osthole and LBSE showed a single peak. There were also clear differences between plasma concentrations of osthole after oral administration of pure osthole and LBSE. Non-osthole ingredients in LBSE showed some pharmacokinetic interactions with osthole and hence decreased its absorption levels (p<0.05). Our results show

  14. Simultaneous determination of bioactive components of Radix Angelicae Sinensis-Radix Paeoniae Alba herb couple in rat plasma and tissues by UPLC-MS/MS and its application to pharmacokinetics and tissue distribution.

    PubMed

    Luo, Niancui; Li, Zhenhao; Qian, Dawei; Qian, Yefei; Guo, Jianming; Duan, Jin-Ao; Zhu, Min

    2014-07-15

    A highly sensitive and rapid ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been developed and validated for simultaneous quantification of seven components in rat plasma and five components in rat tissues after oral administration of the extracts of different combination Radix Angelicae Sinensis-Radix Paeoniae Alba herb couple and has been applied to compare the different pharmacokinetics and tissue distribution properties of these bioactive components. The extracts of Radix Angelicae Sinensis (RAS), Radix Paeoniae Alba (RPA) and Radix Angelicae Sinensis-Radix Paeoniae Alba herb couple (RRHC) were orally administrated to rats, respectively. The concentrations of ferulic acid, caffeic acid, vanillic acid, ligustilide, paeoniflorin, albiflorin and oxypaeoniflorin in rat plasma and the concentrations of ferulic acid, vanillic acid, paeoniflorin, albiflorin and oxypaeoniflorin in tissues were determined by UPLC-MS/MS. The plasma samples were pretreated by protein precipitation with methanol and the tissue samples were homogenated with water and pretreated by protein precipitation with methanol. Chromatographic separation was performed on a C18 column using 0.1% formic acid-acetonitrile as mobile phase for gradient elution. A triple quadrupole (TQ) tandem mass spectrometry equipped with an electrospray ionization source was used as detector operating both in positive and negative ionization mode and operated by multiple-reaction monitoring (MRM) scanning. Noncompartmental pharmacokinetic parameters were calculated by DAS 2.0 program. The differences between each group were compared by SPSS 16.0 with Independent-Samples T-test. The pharmacokinetic parameters (such as Cmax, Tmax, T1/2, AUC0-T, MRT0-T, Vz/F or CLz/F) of all the detected components between the single herb (RAS or RPA) and herb pair (RRHP) showed significant differences (P<0.05). It indicated that the compatibility of RAS and RPA could alter the pharmacokinetics features

  15. Comparative pharmacokinetics and tissue distribution profiles of lignan components in normal and hepatic fibrosis rats after oral administration of Fuzheng Huayu recipe.

    PubMed

    Yang, Tao; Liu, Shan; Zheng, Tian-Hui; Tao, Yan-Yan; Liu, Cheng-Hai

    2015-05-26

    Fuzheng Huayu recipe (FZHY) is formulated on the basis of Chinese medicine theory in treating liver fibrosis. To illuminate the influence of the pathological state of liver fibrosis on the pharmacokinetics and tissue distribution profiles of lignan components from FZHY. Male Wistar rats were randomly divided into normal group and Hepatic fibrosis group (induced by dimethylnitrosamine). Six lignan components were detected and quantified by ultrahigh performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)in the plasma and tissue of normal and hepatic fibrosis rats. A rapid, sensitive and convenient UHPLC-MS/MS method has been developed for the simultaneous determination of six lignan components in different rat biological samples successfully. After oral administration of FZHY at a dose of 15g/kg, the pharmacokinetic behaviors of schizandrin A (SIA), schizandrin B (SIB), schizandrin C (SIC), schisandrol A (SOA), Schisandrol B (SOB) and schisantherin A (STA) have been significantly changed in hepatic fibrosis rats compared with the normal rats, and their AUC(0-t) values were increased by 235.09%, 388.44%, 223.30%, 669.30%, 295.08% and 267.63% orderly (P<0.05). Tissue distribution results showed the amount of SIA, SIB, SOA and SOB were significant increased in heart, lung, spleen and kidney of hepatic fibrosis rats compared with normal rats at most of the time point (P<0.05). Meanwhile, the result also reveals that the hepatic fibrosis could delay the peak time of lignans in liver. The results proved that the established UHPLC-MS/MS method could be applied to the comparative study on pharmacokinetics and tissue distribution of lignan components in normal and hepatic fibrosis rats. The hepatic fibrosis could alter the pharmacokinetics and tissue distribution properties of lignan components in rats after administration of FZHY. The results might be helpful for guide the clinical application of this medicine. Copyright © 2015 Elsevier Ireland Ltd. All

  16. Pharmacokinetics and tissue distribution study of Praeruptorin D from Radix peucedani in rats by high-performance liquid chromatography (HPLC).

    PubMed

    Liang, Taigang; Yue, Wenyan; Du, Xue; Ren, Luhui; Li, Qingshan

    2012-01-01

    Praeruptorin D (PD), a major pyranocoumarin isolated from Radix Peucedani, exhibited antitumor and anti-inflammatory activities. The aim of this study was to investigate the pharmacokinetics and tissue distribution of PD in rats following intravenous (i.v.) administration. The levels of PD in plasma and tissues were measured by a simple and sensitive reversed-phase high-performance liquid chromatography (HPLC) method. The biosamples were treated by liquid-liquid extraction (LLE) with methyl tert-butyl ether (MTBE) and osthole was used as the internal standard (IS). The chromatographic separation was accomplished on a reversed-phase C(18) column using methanol-water (75:25, v/v) as mobile phase at a flow rate of 0.8 mL/min and ultraviolet detection wave length was set at 323 nm. The results demonstrate that this method has excellent specificity, linearity, precision, accuracy and recovery. The pharmacokinetic study found that PD fitted well into a two-compartment model with a fast distribution phase and a relative slow elimination phase. Tissue distribution showed that the highest concentration was observed in the lung, followed by heart, liver and kidney. Furthermore, PD can also be detected in the brain, which indicated that PD could cross the blood-brain barrier after i.v. administration.

  17. Multiscale Modeling of Antibody-Drug Conjugates: Connecting Tissue and Cellular Distribution to Whole Animal Pharmacokinetics and Potential Implications for Efficacy.

    PubMed

    Cilliers, Cornelius; Guo, Hans; Liao, Jianshan; Christodolu, Nikolas; Thurber, Greg M

    2016-09-01

    Antibody-drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from nonspecific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody-drug conjugate Kadcyla in HER2-positive mouse xenografts. This model is able to capture the impact of the drug-antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs.

  18. Multiscale Modeling of Antibody Drug Conjugates: Connecting tissue and cellular distribution to whole animal pharmacokinetics and potential implications for efficacy

    PubMed Central

    Cilliers, Cornelius; Guo, Hans; Liao, Jianshan; Christodolu, Nikolas; Thurber, Greg M.

    2016-01-01

    Antibody drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from non-specific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody drug conjugate Kadcyla in HER2 positive mouse xenografts. This model is able to capture the impact of the drug antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs. PMID:27287046

  19. In vivo pharmacokinetic and tissue distribution investigation of sustained-release cisplatin implants in the normal esophageal submucosa of 12 beagle dogs.

    PubMed

    Yin, Jia-Xue; Wei, Zhi; Xu, Jian-Jian; Sun, Zi-Qin

    2015-09-01

    The aim of this study was to clarify the pharmacokinetic, tissue distribution, hematologic, and histopathologic characteristics of sustained-release cisplatin from implants [CDDP-nanoparticle (NP) implants]. Eighteen dogs (six hybrids and twelve beagles) were divided into three groups. In Group A, the six hybrid dogs were intravenously administered 20 mg CDDP via a hind limb vein. In Groups B and C, CDDP-NP implants containing CDDP doses of 40 and 60 mg, respectively, were embedded into the esophageal submucosa of beagles via painless gastroscopy with an endoscopic booster. Graphite frameless atomic absorption spectrophotometry was used to measure total platinum in plasma and tissues at various timepoints. In addition, free platinum levels in Group B were determined using inductively coupled plasma mass spectrometry. Toxicologic evaluation was also conducted. Pharmacokinetic results indicated that the CDDP-NP implant could achieve a smooth pharmacokinetic curve, with the plasma invalid concentration reached after almost 480 h, which is approximately ten times longer than that of standard CDDP (48 h). The peak time, peak concentration, clearance, elimination half-life, area under the curve, volume of distribution at steady state, and mean residence time of Groups B and C were 494 and 211, 0.39 and 0.42, 0.044 and 0.059, 80.11 and 87.70, 44 and 49, 38.8 and 57.9, and 12.29 and 12.39 times those of Group A, respectively (all P < 0.05). The ratio of free/total platinum concentration was 2.0-3.1% in plasma, 14.2% in liver tissue, and 14.3% in kidney tissue. Tissue distribution studies showed that the highest platinum concentrations were found in the esophagus, followed by the kidney and liver. Compared with pre-implantation (day 0), there were no significant differences in most hematological indicators in Groups B and C (P > 0.05). Furthermore, histopathologic examination of the kidneys of dogs from Group C revealed no significant kidney damage. Unlike the intravenous

  20. Abcb1 in Pigs: Molecular cloning, tissues distribution, functional analysis, and its effect on pharmacokinetics of enrofloxacin

    PubMed Central

    Guo, Tingting; Huang, Jinhu; Zhang, Hongyu; Dong, Lingling; Guo, Dawei; Guo, Li; He, Fang; Bhutto, Zohaib Ahmed; Wang, Liping

    2016-01-01

    P-glycoprotein (P-gp) is one of the best-known ATP-dependent efflux transporters, contributing to differences in pharmacokinetics and drug-drug interactions. Until now, studies on pig P-gp have been scarce. In our studies, the full-length porcine P-gp cDNA was cloned and expressed in a Madin-Darby Canine Kidney (MDCK) cell line. P-gp expression was then determined in tissues and its role in the pharmacokinetics of oral enrofloxacin in pigs was studied. The coding region of pig Abcb1 gene was 3,861 bp, encoding 1,286 amino acid residues (Mw = 141,966). Phylogenetic analysis indicated a close evolutionary relationship between porcine P-gp and those of cow and sheep. Pig P-gp was successfully stably overexpressed in MDCK cells and had efflux activity for rhodamine 123, a substrate of P-gp. Tissue distribution analysis indicated that P-gp was highly expressed in brain capillaries, small intestine, and liver. In MDCK-pAbcb1 cells, enrofloxacin was transported by P-gp with net efflux ratio of 2.48 and the efflux function was blocked by P-gp inhibitor verapamil. High expression of P-gp in the small intestine could modify the pharmacokinetics of orally administrated enrofloxacin by increasing the Cmax, AUC and Ka, which was demonstrated using verapamil, an inhibitor of P-gp. PMID:27572343

  1. A novel liquid chromatography Orbitrap mass spectrometry method with full scan for simultaneous determination of multiple bioactive constituents of Shenkang injection in rat tissues: Application to tissue distribution and pharmacokinetic studies.

    PubMed

    Yang, Jie; Sun, Zhi; Li, Duolu; Duan, Fei; Li, Zhuolun; Lu, Jingli; Shi, Yingying; Xu, Tanye; Zhang, Xiaojian

    2018-06-07

    Shenkang injection is a traditional Chinese formula with good curative effect on chronic renal failure. In this paper, a novel, rapid and sensitive ultra high performance liquid chromatography coupled with Q Exactive hybrid quadrupole orbitrap high resolution accurate mass spectrometry was developed and validated for simultaneous determination of seven bioactive constituents of Shenkang injection in rat plasma and tissues after intravenous administration. Acetonitrile was used as protein precipitation agent in biological samples dispose with carbamazepine as internal standard. The chromatographic separation was carried out on a C 18 column with a gradient mobile phase consisting of acetonitrile and water (containing 0.1% formic acid). The MS analysis was performed in the full scan positive and negative ion mode. The lower limits of quantification for the seven analytes in rat plasma and tissues were 0.1-10 ng/mL. The validated method was successfully applied to tissue distribution and pharmacokinetic studies of Shenkang injection after intravenous administration. The results of the tissue distribution study showed that the high concentration of seven constituents were primarily in the kidney tract. This is the first time to report the application of Q-Orbitrap with full scan mass spectrometry in tissue distribution and pharmacokinetic studies of Shenkang injection. This article is protected by copyright. All rights reserved.

  2. Pharmacokinetics and tissue distribution of furanodiene W/O/W multiple emulsions in rats by a fast and sensitive HPLC-APCI-MS/MS method.

    PubMed

    Zhang, Li-Feng; Lu, Tao-Tao; Zhang, Shu-Qiu; Lin, Wen-Han; Li, Qing-Shan

    2013-12-01

    A sensitive and specific HPLC-APCI-MS/MS method was developed and validated for the quantification of furanodiene, a natural antitumor compound in rat plasma and tissues. W/O/W multiple emulsions of furanodiene, identified through microscope-observation and eosin staining method, were prepared with a two-step-procedure. Pharmacokinetics and tissue distribution were studied in rats after oral, intraperitoneal and intravenous injection with the dose of 5, 10 and 50 mg/kg, respectively. The assay achieved a good sensitivity and specificity for the determination of furanodiene in biological samples. The results showed that the concentration-time curves of furanodiene in rats after intravenous injection were fitted to a two-compartment model and the linear pharmacokinetic characteristic. The highest concentration in rat tissue was observed in the spleen, followed by heart, liver, lung, kidney, small intestine and brain. Comparing with the low concentration in plasma, furanodiene could be detected in various tissue samples after oral or intraperitoneal injection which indicated furanodiene had good and rapid tissue uptake. The results suggested that the wide tissue distribution of furanodiene could conduce to the therapeutic effects, but the short biological half-life limited its further application as an antitumor agent. The results are helpful for the structure modification of furanodiene as an antitumor candidate.

  3. Preclinical Pharmacokinetics, Tissue Distribution, and Plasma Protein Binding of Sodium (±)-5-Bromo-2-(α-Hydroxypentyl) Benzoate (BZP), an Innovative Potent Anti-ischemic Stroke Agent.

    PubMed

    Tian, Xin; Li, Hong-Meng; Wei, Jing-Yao; Liu, Bing-Jie; Zhang, Yu-Hai; Wang, Gao-Ju; Chang, Jun-Biao; Qiao, Hai-Ling

    2016-01-01

    Sodium (±)-5-bromo-2-(α-hydroxypentyl) benzoate (BZP) is a potential cardiovascular drug and exerts potent neuroprotective effect against transient and long-term ischemic stroke in rats. BZP could convert into 3-butyl-6-bromo-1(3H)-isobenzofuranone (Br-NBP) in vitro and in vivo. However, the pharmacokinetic profiles of BZP and Br-NBP still have not been evaluated. For the purpose of investigating the pharmacokinetic profiles, tissue distribution, and plasma protein binding of BZP and Br-NBP, a rapid, sensitive, and specific method based on liquid chromatography coupled to mass spectrometry (LC-MS/MS) has been developed for determination of BZP and Br-NBP in biological samples. The results indicated that BZP and Br-NBP showed a short elimination half-life, and pharmacokinetic profile in rats (3, 6, and 12 mg/kg; i.v.) and beagle dogs (1, 2, and 4 mg/kg; i.v.gtt) were obtained after single dosing of BZP. After multiple dosing of BZP, there was no significant accumulation of BZP and Br-NBP in the plasma of rats and beagle dogs. Following i.v. single dose (6 mg/kg) of BZP to rats, BZP and Br-NBP were distributed rapidly into all tissues examined, with the highest concentrations of BZP and Br-NBP in lung and kidney, respectively. The brain distribution of Br-NBP in middle cerebral artery occlusion (MCAO) rats was more than in normal rats (P < 0.05). The plasma protein binding degree of BZP at three concentrations (8000, 20,000, and 80,000 ng/mL) from rat, beagle dog, and human plasma were 98.1-98.7, 88.9-92.7, and 74.8-83.7% respectively. In conclusion, both BZP and Br-NBP showed short half-life, good dose-linear pharmacokinetic profile, wide tissue distribution, and different degree protein binding to various species plasma. This was the first preclinical pharmacokinetic investigation of BZP and Br-NBP in both rats and beagle dogs, which provided vital guidance for further preclinical research and the subsequent clinical trials.

  4. Determination of a novel anticancer c-Met inhibitor LS-177 in rat plasma and tissues with a validated UPLC-MS/MS method: application to pharmacokinetics and tissue distribution study.

    PubMed

    Ju, Ping; Liu, Zhenzhen; Jiang, Yu; Zhao, Simin; Zhang, Lunhui; Zhang, Yuanyuan; Gu, Liqiang; Tang, Xing; Bi, Kaishun; Chen, Xiaohui

    2015-07-01

    LS-177 is a novel small-molecule kinase inhibitor employed to interrupt the c-Met signaling pathway. A rapid and sensitive ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determination of LS-177 in rat plasma and tissues. The biosamples were extracted by liquid-liquid extraction with methyl tert-butyl ether and separated on a C18 column (50 × 4.6 mm, 2.6 µm) using a gradient elution mobile phase consisting of acetonitrile-0.1% formic acid water. Under the optimal conditions, the selectivity of the method was satisfactory with no endogenous interference. The intraday and interday precisions (relative standard deviation) were <10.5% and the accuracy (relative error) was from -12.5 to 12.5% at all quality control levels. Excellent recovery and negligible matrix effects were observed. Stability studies showed that LS-177 was stable during the preparation and analytical processes. The UPLC-MS/MS method was successfully applied to pharmacokinetic and tissue distribution studies. The results indicated that there was no significant drug accumulation after multiple-dose oral administration of LS-177. The tissue distribution study exhibited significant higher uptakes of LS-177 in stomach, intestine, lung and liver among all of the tissues. The results in pharmacokinetics and tissue distribution may provide a meaningful basis for clinical application. Copyright © 2014 John Wiley & Sons, Ltd.

  5. Pharmacokinetics and tissue distribution study of schisandrin B in rats by ultra-fast liquid chromatography with tandem mass spectrometry.

    PubMed

    Zhu, Heyun; Zhang, Xiurong; Guan, Jiao; Cui, Baiji; Zhao, Longshan; Zhao, Xu

    2013-05-05

    A rapid, sensitive and high throughput ultra-fast liquid chromatography with tandem mass spectrometry (UFLC-MS/MS) method was established and validated for the determination of schisandrin B in rat plasma and various tissues (including heart, liver, spleen, lung, and kidney). The biological samples were prepared by protein precipitation, and the separation was achieved on a shim-pack XR-ODS C18 column (75 mm × 3.0 mm, 2.2 μm) with a mobile phase consisting of methanol-0.1% formic acid water (85:15, v/v) at a flow rate of 0.4 mL/min. The MS/MS detection was performed on an API 3200 QTRAP mass spectrometry equipped with electrospray ionization (ESI) source using multiple reactions monitoring (MRM) mode by monitoring the fragmentation of m/z 401.2→300.2 for schisandrin B and m/z 271.2→203.1 for imperatorin (internal standard, IS). The calibration curve was linear in the range of 1-500 ng/mL for plasma and tissue homogenates (r ≥ 0.9927). The lower limit of quantification (LLOQ) was 1 ng/mL. The validated method was successfully applied to the pharmacokinetics and tissue distribution study of schisandrin B after oral administration to rats. The pharmacokinetic curve showed double peaks after oral administration, which demonstrated that a hepatoenteral circulation may exist. Tissue distribution showed the highest level was observed in liver, then in kidney, which indicated schisandrin B was mainly accumulated in liver and renal excretion might be a main elimination route. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Silymarin in liposomes and ethosomes: pharmacokinetics and tissue distribution in free-moving rats by high-performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Chang, Li-Wen; Hou, Mei-Ling; Tsai, Tung-Hu

    2014-12-03

    The aim of this study was to prepare silymarin formulations (silymarin entrapped in liposomes and ethosomes, formulations referred to as LSM and ESM, respectively) to improve oral bioavailability of silymarin and evaluate its tissue distribution by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in free-moving rats. Silibinin is the major active constituent of silymarin, which is the main component to be analyzed. A rapid, sensitive, and repeatable LC-MS/MS method was developed and validated in terms of precision, accuracy, and extraction recovery. Furthermore, the established method was applied to study the pharmacokinetics and tissue distribution of silymarin in rats. The size, ζ potential, and drug release of the formulations were characterized. These results showed that the LSM and ESM encapsulated formulations of silymarin may provide more efficient tissue distribution and increased oral bioavailability, thus improving its therapeutic bioactive properties in the body.

  7. Pharmacokinetics, bioavailability, tissue distribution and excretion of tangeretin in rat.

    PubMed

    Hung, Wei-Lun; Chang, Wei-Shan; Lu, Wen-Chien; Wei, Guor-Jien; Wang, Yu; Ho, Chi-Tang; Hwang, Lucy Sun

    2018-04-01

    Tangeretin, 4',5,6,7,8-pentamethoxyflavone, is one of the major polymethoxyflavones (PMFs) existing in citrus fruits, particularly in the peels of sweet oranges and mandarins. Tangeretin has been reported to possess several beneficial bioactivities including anti-inflammatory, anti-proliferative and neuroprotective effects. To achieve a thorough understanding of the biological actions of tangeretin in vivo, our current study is designed to investigate the pharmacokinetics, bioavailability, distribution and excretion of tangeretin in rats. After oral administration of 50 mg/kg bw tangeretin to rats, the C max , T max and t 1/2 were 0.87 ± 0.33 μg/mL, 340.00 ± 48.99 min and 342.43 ± 71.27 min, respectively. Based on the area under the curves (AUC) of oral and intravenous administration of tangeretin, calculated absolute oral bioavailability was 27.11%. During tissue distribution, maximum concentrations of tangeretin in the vital organs occurred at 4 or 8 h after oral administration. The highest accumulation of tangeretin was found in the kidney, lung and liver, followed by spleen and heart. In the gastrointestinal tract, maximum concentrations of tangeretin in the stomach and small intestine were found at 4 h, while in the cecum, colon and rectum, tangeretin reached the maximum concentrations at 12 h. Tangeretin excreted in the urine and feces was recovered within 48 h after oral administration, concentrations were only 0.0026% and 7.54%, respectively. These results suggest that tangeretin was mainly eliminated as metabolites. In conclusion, our study provides useful information regarding absorption, distribution, as well as excretion of tangeretin, which will provide a good base for studying the mechanism of its biological effects. Copyright © 2017. Published by Elsevier B.V.

  8. Application of a liquid chromatography-tandem mass spectrometry method to the pharmacokinetics, tissue distribution and excretion studies of Dactylicapnos scandens in rats.

    PubMed

    Guo, Changchuan; Jiang, Yan; Li, Li; Hong, Lan; Wang, Yuqing; Shen, Qian; Lou, Yan; Hu, Haihong; Zhou, Hui; Yu, Lushan; Jiang, Huidi; Zeng, Su

    2013-02-23

    The herbal ingredients of isocorydine and protopine were isolated from Dactylicapnos scandens. This study was aimed at developing a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method to quantify isocorydine and protopine in rat plasma and tissues for pharmacokinetic, tissue distribution and excretion studies. Biological samples were processed with ethyl acetate extraction, and corydaline was chosen as the internal standard (IS). The analytes were separated by a C(18) column and detected with a triple quadrupole mass spectrometer using positive ion ESI in the multiple reaction monitoring (MRM) mode. The MS/MS ion transitions monitored were m/z 342.0→278.9 for isocorydine, 354.1→188.0 for protopine and 370.0→192.0 for IS, respectively. Excellent linearity was observed over the concentration range between 10 and 3000 ng/mL for isocorydine and 10-300 ng/mL for protopine. The lower limit of quantification (LLOQ) was 10 ng/mL for both isocorydine and protopine. This novel method was rapid, accurate, high sensitive and high selective. It was successfully applied to the pharmacokinetic, tissue distribution and excretion studies of D. scandens. These preclinical data of D. scandens would be useful for the clinical reference. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Pharmacokinetic, bioavailability and tissue distribution study of MP3950, a new gastroprokinetic candidate compound, in rat using UPLC-MS/MS.

    PubMed

    Zhao, Yu; Zhao, Min; Jiang, Qi; Qin, Feng; Wang, Chengying; Xiong, Zhili; Wang, Shaojie; He, Zhonggui; Guo, Xingjie; Zhao, Longshan

    2018-06-02

    MP3950 is being developed as a gastroprokinetic candidate compound. To illustrate the pharmacokinetic profiles, absolute bioavailability after intravenous administration and oral administration with MP3950 as well as tissue distribution in vivo, an UPLC-MS/MS approach which was rapid and selective was developed to determine MP3950 in plasma and tissue of rat. Sample pre-treatment of plasma sample was one-step protein precipitation. 0.1% formic acid containing 5 mmol/L ammonium acetate-methanol(55/45,v/v) was used for isocratic elution on a Waters ACQUITY UPLC® BEH C18 (50 mm × 2.1 mm, 1.7 μm) to achieve the separation. The analysis was performed in MRM mode via positive ESI mode. LLOQ of the method was 10 ng/mL, and the linearity up to 10,000 ng/mL. The intra-day precision (relative standard deviation, RSD) was 4.0-9.0% and the inter-day precision was 4.2-10.6%. The accuracy (relative error, RE) was -1.2-2.4%. Tissue samples were collected from the brain, heart, liver, spleen, lung, kidney, stomach, duodenum, small intestine, large intestine, appendix and skeletal muscle. The same liquid chromatographic and mass spectrometric conditions were used, and it's proven that this method was feasible to analyze the MP3950 in tissues with good precision and accuracy over the range from 10 to 5000 ng·mL -1 . It was found that the concentration of MP3950 is higher in digestive system. The tissue distribution, pharmacokinetic and bioavailability of MP3950 in rats were carried out by the method for the first time, which can provide enough information for the further development and investigation of MP3950. Copyright © 2018. Published by Elsevier B.V.

  10. Validated UPLC-MS/MS method for quantification of seven compounds in rat plasma and tissues: Application to pharmacokinetic and tissue distribution studies in rats after oral administration of extract of Eclipta prostrata L.

    PubMed

    Du, Guangyan; Fu, Lingling; Jia, Jun; Pang, Xu; Yu, Haiyang; Zhang, Youcai; Fan, Guanwei; Gao, Xiumei; Han, Lifeng

    2018-06-01

    A rapid, sensitive and specific ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method was developed to investigate the pharmacokinetics and tissue distribution of Eclipta prostrata extract. Rats were orally administrated the 70% ethanol extract of E. prostrata, and their plasma as well as various organs were collected. The concentrations of seven main compounds, ecliptasaponin IV, ecliptasaponin A, apigenin, 3'-hydroxybiochanin A, luteolin, luteolin-7-O-glucoside and wedelolactone, were quantified by UPLC-MS/MS through multiple reactions monitoring method. The precisions (RSD) of the analytes were all <15.00%. The extraction recoveries ranged from 74.65 to 107.45% with RSD ≤ 15.36%. The matrix effects ranged from 78.00 to 118.06% with RSD ≤ 15.04%. To conclude, the present pharmacokinetic and tissue distribution studies provided useful information for the clinical usage of Eclipta prostrata L. Copyright © 2018 John Wiley & Sons, Ltd.

  11. Pharmacokinetics and tissue distribution study in mice of triptolide-loaded lipid emulsion and accumulation effect on pancreas.

    PubMed

    Li, Xue; Mao, Yuling; Li, Kai; Shi, Tianyu; Yao, Huimin; Yao, Jianhua; Wang, Shujun

    2016-05-01

    Triptolide (TP) shows strong anti-tumor activities on various cancer cells, especially on pancreatic cancer. TP inhibits HSP70 expression leading to cell death in pancreatic cancer cells and induces cell death by apoptotic and autophagic pathways. In order to increase the therapeutic index of TP, a novel intravenous TP-loaded delivery system, TP-loaded lipid emulsion (TP-LE), has been developed to treat solid tumor. In the present study, the preparation and characterization of TP-LE were described. The pharmacokinetics and tissue distribution study of TP-LE in mice were also evaluated. Results demonstrated that TP-LE had an average particle size of 154.6 nm, entrapment efficiency (EE%) of 87%, zeta potential of -0.903 mV and autoclaved stability. The pharmacokinetic study showed that blood concentrations of both TP-LE and TP reached a maximum at the end of intravenous administration (1.25 mg/kg) and declined rapidly within the first 10 min with a mean residence time (MRT) of about 10 min. In the tissue distribution study, a preferential accumulation and longer residence time of drug in pancreas were found in TP-LE. The AUC0-60min of TP-LE in pancreas was 2.19 times in comparison to free TP, suggesting that the use of TP-LE conferred improvements in biodistribution, accumulation and therapeutic efficacy in pancreas. Moreover, the concentrations of TP-LE in heart, lung and kidney were lower than that of the TP group, indicating the potential for reduced toxicity of TP-LE. Together, all the results show that TP-LE appears to be a promising formulation for using TP in treating cancer, and more specifically pancreatic cancer.

  12. Gender differences in pharmacokinetics and tissue distribution of 3 perfluoroalkyl and polyfluoroalkyl substances in rats.

    PubMed

    Kim, Sook-Jin; Heo, Seo-Hee; Lee, Dong-Seok; Hwang, In Gyun; Lee, Yong-Bok; Cho, Hea-Young

    2016-11-01

    The aim of this study was to confirm and investigate the gender differences in pharmacokinetic (PK) characteristics and tissue distribution of 3 perfluoroalkyl and polyfluoroalkyl substances (PFASs) consisted of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexane sulfonic acid (PFHxS) in both male and female rats. For this study, a simultaneous determination method of the 3 PFASs in rat plasma and tissues was developed and validated using a UPLC-MS/MS system. The PK parameters after a single oral or intravenous administration of the 3 PFASs in both rats were calculated using WinNonlin ® software. The mean half-life of the 3 PFASs in female and male rats was in the range of 0.15-0.19 and 1.6-1.8 days for PFOA, 23.5-24.8 and 26.4-28.7 days for PFOS, and 0.9-1.7 and 20.7-26.9 days for PFHxS, respectively. The 3 PFASs were highly distributed in the liver and kidney. These results suggest that there are gender differences in the PKs for PFOA and PFHxS in rats, whereas the PFOS represented no significant gender differences except the Kp value of liver. The validated simultaneous determination method of the 3 PFASs was also within the accepted criteria of the international guidance. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings.

    PubMed

    Li, Jie; Li, Xin; Ren, Yu-Shan; Lv, Yuan-Yuan; Zhang, Jun-Sheng; Xu, Xiao-Li; Wang, Xian-Zhen; Yao, Jing-Chun; Zhang, Gui-Min; Liu, Zhong

    2017-01-01

    Although arctigenin ( AG ) has diverse bioactivities, such as anti-oxidant, anti-inflammatory, anti-cancer, immunoregulatory and neuroprotective activities, its pharmacokinetics have not been systematically evaluated. The purpose of this work was to identify the pharmacokinetic properties of AG via various experiments in vivo and in vitro . In this research, rats and beagle dogs were used to investigate the PK (pharmacokinetics, PK) profiles of AG with different drug-delivery manners, including intravenous (i.v), hypodermic injection (i.h), and sublingual (s.l) administration. The data shows that AG exhibited a strong absorption capacity in both rats and beagle dogs (absorption rate < 1 h), a high absorption degree (absolute bioavailability > 100%), and a strong elimination ability ( t 1/2 < 2 h). The tissue distributions of AG at different time points after i.h showed that the distribution of AG in rat tissues is rapid (2.5 h to reach the peak) and wide (detectable in almost all tissues and organs). The AG concentration in the intestine was the highest, followed by that in the heart, liver, pancreas, and kidney. In vitro , AG were incubated with human, monkey, beagle dog and rat liver microsomes. The concentrations of AG were detected by UPLC-MS/MS at different time points (from 0 min to 90 min). The percentages of AG remaining in four species' liver microsomes were human (62 ± 6.36%) > beagle dog (25.9 ± 3.24%) > rat (15.7 ± 9%) > monkey (3.69 ± 0.12%). This systematic investigation of pharmacokinetic profiles of arctigenin (AG) in vivo and in vitro is worthy of further exploration.

  14. Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings

    PubMed Central

    Li, Jie; Li, Xin; Ren, Yu-Shan; Lv, Yuan-Yuan; Zhang, Jun-Sheng; Xu, Xiao-Li; Wang, Xian-Zhen; Yao, Jing-Chun; Zhang, Gui-Min; Liu, Zhong

    2017-01-01

    Although arctigenin (AG) has diverse bioactivities, such as anti-oxidant, anti-inflammatory, anti-cancer, immunoregulatory and neuroprotective activities, its pharmacokinetics have not been systematically evaluated. The purpose of this work was to identify the pharmacokinetic properties of AG via various experiments in vivo and in vitro. In this research, rats and beagle dogs were used to investigate the PK (pharmacokinetics, PK) profiles of AG with different drug-delivery manners, including intravenous (i.v), hypodermic injection (i.h), and sublingual (s.l) administration. The data shows that AG exhibited a strong absorption capacity in both rats and beagle dogs (absorption rate < 1 h), a high absorption degree (absolute bioavailability > 100%), and a strong elimination ability (t1/2 < 2 h). The tissue distributions of AG at different time points after i.h showed that the distribution of AG in rat tissues is rapid (2.5 h to reach the peak) and wide (detectable in almost all tissues and organs). The AG concentration in the intestine was the highest, followed by that in the heart, liver, pancreas, and kidney. In vitro, AG were incubated with human, monkey, beagle dog and rat liver microsomes. The concentrations of AG were detected by UPLC-MS/MS at different time points (from 0 min to 90 min). The percentages of AG remaining in four species’ liver microsomes were human (62 ± 6.36%) > beagle dog (25.9 ± 3.24%) > rat (15.7 ± 9%) > monkey (3.69 ± 0.12%). This systematic investigation of pharmacokinetic profiles of arctigenin (AG) in vivo and in vitro is worthy of further exploration. PMID:28659807

  15. Pharmacokinetics and tissue distribution of five active ingredients of Eucommiae cortex in normal and ovariectomized mice by UHPLC-MS/MS.

    PubMed

    An, Jing; Hu, Fangdi; Wang, Changhong; Zhang, Zijia; Yang, Li; Wang, Zhengtao

    2016-09-01

    1. Pinoresinol di-O-β-d-glucopyranoside (PDG), geniposide (GE), geniposidic acid (GA), aucubin (AN) and chlorogenic acid (CA) are the representative active ingredients in Eucommiae cortex (EC), which may be estrogenic. 2. The ultra high-performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous determination of the five ingredients showed good linearity, low limits of quantification and high extraction recoveries, as well as acceptable precision, accuracy and stability in mice plasma and tissue samples (liver, spleen, kidney and uterus). It was successfully applied to the comparative study on pharmacokinetics and tissue distribution of PDG, GE, GA, AN and CA between normal and ovariectomized (OVX) mice. 3. The results indicated that except CA, the plasma and tissue concentrations of PDG, GE, GA in OVX mice were all greater than those in normal mice. AN could only be detected in the plasma and liver homogenate of normal mice, which was poorly absorbed in OVX mice and low in other measured tissues. PDG, GE and GA seem to be better absorbed in OVX mice than in normal mice proved by the remarkable increased value of AUC0-∞ and Cmax. It is beneficial that PDG, GE, GA have better plasma absorption and tissue distribution in pathological state.

  16. Pharmacokinetics and tissue distribution of enrofloxacin after single intramuscular injection in Pacific white shrimp.

    PubMed

    Fang, X; Zhou, J; Liu, X

    2018-02-01

    The pharmacokinetic properties and tissue distribution of enrofloxacin (EF) were investigated after single intramuscular (i.m.) dose of 10 mg/kg body weight (b.w.) in Pacific white shrimp at 22 to 25°C. EF and its metabolite ciprofloxacin (CF) were determined by high-performance liquid chromatography. After i.m. administration, EF was absorbed quickly, and the peak of EF concentration (C max ) reached at first time point in hemolymph. The volume of distribution V d(area) of EF was 3.84 L/kg, indicating that the distribution of EF was good. The area under the concentration-time curve (AUC) of EF was 90.1 and 274.2 μg hr/ml in muscle and hepatopancreas, respectively, which was higher than 75.8 μg hr/ml in hemolymph. The EF elimination was slow in muscle and hepatopancreas with the half-life (T 1/2β ) of 52.3 and 75.8 hr, respectively. CF, the mainly metabolite of EF, was detected in hemolymph, muscle and hepatopancreas. The C max was 0.030, 0.013 and 0.218 μg/ml, respectively. Based on a minimum inhibitory concentration (MIC) of 0.006-0.032 μg/ml for susceptible strains, EF i.m. injected at a dose 10 mg/kg could be efficacious against common pathogenic bacteria of Pacific white shrimp. © 2017 John Wiley & Sons Ltd.

  17. The model of drugs distribution dynamics in biological tissue

    NASA Astrophysics Data System (ADS)

    Ginevskij, D. A.; Izhevskij, P. V.; Sheino, I. N.

    2017-09-01

    The dose distribution by Neutron Capture Therapy follows the distribution of 10B in the tissue. The modern models of pharmacokinetics of drugs describe the processes occurring in conditioned "chambers" (blood-organ-tumor), but fail to describe the spatial distribution of the drug in the tumor and in normal tissue. The mathematical model of the spatial distribution dynamics of drugs in the tissue, depending on the concentration of the drug in the blood, was developed. The modeling method is the representation of the biological structure in the form of a randomly inhomogeneous medium in which the 10B distribution occurs. The parameters of the model, which cannot be determined rigorously in the experiment, are taken as the quantities subject to the laws of the unconnected random processes. The estimates of 10B distribution preparations in the tumor and healthy tissue, inside/outside the cells, are obtained.

  18. HPLC method for the pharmacokinetics and tissue distribution of taspine solution and taspine liposome after intravenous administrations to mice.

    PubMed

    Lu, Wen; He, Lang Chong; Zeng, Xian-Ming

    2008-01-07

    Taspine is a bioactive aporphine alkaloid, which has many potent pharmacological effects. A simple, rapid HPLC method to quantify taspine in mouse plasma and tissue homogenates containing either taspine solution or liposome was developed and validated. Sample preparation was achieved by liquid-liquid extraction with acetoacetate. Taspine was separated on a C(18) reversed phase HPLC column, and quantified by its absorbance at 245 nm. The pharmacokinetics and tissue distribution after intravenous administrations of taspine liposome (L-Ta) and taspine solution (Ta) to ICR mice were then compared. The area under the plasma concentration-time curve (AUC) was higher for L-Ta than for Ta. In contrast, the total body clearance (CL), apparent volume of distribution V(c) and plasma half-life for the distribution (t(1/2 alpha)) and elimination phase (t(1/2 beta)) were lower for L-Ta, in comparison to the respective parameter of Ta. The AUC values were higher in the lung than in other organs for both L-Ta and Ta. The AUC in the spleen, kidney and liver of L-Ta were higher than those of Ta. However, the heart and brain AUC of Ta was higher than that of L-Ta. It can thus be concluded that incorporation into liposomes prolonged taspine retention within the systemic circulation, increased its distribution to the spleen and liver but reduced its distribution to the heart and brain.

  19. Comparisons of pharmacokinetic and tissue distribution profile of four major bioactive components after oral administration of Xiang-Fu-Si-Wu Decoction effective fraction in normal and dysmenorrheal symptom rats.

    PubMed

    Liu, Pei; Li, Wei; Li, Zhen-hao; Qian, Da-wei; Guo, Jian-ming; Shang, Er-xin; Su, Shu-lan; Tang, Yu-ping; Duan, Jin-ao

    2014-07-03

    Xiang-Fu-Si-Wu Decoction (XFSWD) has been widely used to treat primary dysmenorrhea in clinical practice for hundreds of years and shown great efficacy. One fraction of XFSWD, which was an elution product by macroporous adsorption resin from aqueous extract solution with 60% ethanol (XFSWE), showed great analgesic effect. The present study was conducted to investigate the possible pharmacokinetic and tissue distribution profiles of four major bioactive constituents (berberine, protopine, tetrahydrocoptisine and tetrahydropalmatine) after oral administration of XFSWE in dysmenorrheal symptom rats, and to compare the difference between normal and dysmenorrheal symptom rats. Estradiol benzoate and oxytocin were used to produce dysmenorrheal symptom rat model. The experimental period was seven days. At the final day of experimental period, both normal and dysmenorrheal symptom rats were orally administrated with XFSWE, and then the blood and tissues samples were collected at different time points. Berberine, protopine, tetrahydrocoptisine and tetrahydropalmatine in blood and tissue samples were determined by LC-MS/MS. Pharmacokinetic parameters were calculated from the plasma concentration-time data using non-compartmental methods. The differences of pharmacokinetic parameters among groups were tested by one-way analysis of variance (ANOVA). There were statistically significant differences (P<0.05) in Cmax, Tmax, AUC(0-t), AUC(0-∞), MRT(0-t), MRT(0-∞) and CL/F between normal and dysmenorrheal symptom rats that orally administered with same dosage of XFSWE. In tissue distribution study, the results showed that the overall trend was C(Spleen)>C(Liver)>C(Kidney)>C(Uterus)>C(Heart)>C(Lung)>C(Ovary)>C(Brain)>C(Thymus), C(M-60 min)>C(M-120 min)>C(M-30 min)>C(C-60 min)>C(C-120 min)>C(C-30 min). The contents of protopine in liver, spleen and uterus were more than that in other tissues of dysmenorrheal symptom rats. Compared to normal rats, partial contents of the compounds

  20. Pharmacodynamic and pharmacokinetic studies and prostatic tissue distribution of fosfomycin tromethamine in bacterial prostatitis or normal rats.

    PubMed

    Fan, L; Shang, X; Zhu, J; Ma, B; Zhang, Q

    2018-05-02

    In this study, we assessed the therapeutic effects of fosfomycin tromethamine (FT) in a bacterial prostatitis (BP) rat model. The BP model was induced by Escherichia coli and was demonstrated after 7 days microbiologically and histologically. Then, 25 BP rats selected were randomly divided into five treatment groups: model group, positive group, FT-3 day group, FT-7 day group and FT-14 day group. Ventral lobes of prostate from all animals were removed, and the serum samples were collected at the end of the experiments. Microbiological cultures and histological findings of the prostate samples demonstrated reduced bacterial growth and improved inflammatory responses in FT-treatment groups compared with the model group, indicating that FT against prostatic infection induced by E. coli showed good antibacterial effects. Moreover, plasma pharmacokinetics and prostatic distribution of fosfomycin were studied and compared in BP and normal rats. The concentrations of fosfomycin in samples were analysed by liquid chromatography-tandem mass spectrometry. There were no differences in plasma pharmacokinetic parameters between two groups. But significantly higher penetration of fosfomycin into prostatic tissues was found in BP rats. We therefore suggested that FT had a good therapeutic effect on BP and it might be used in curing masculine reproductive system diseases. © 2018 Blackwell Verlag GmbH.

  1. The in vivo pharmacokinetics, tissue distribution and excretion investigation of mesaconine in rats and its in vitro intestinal absorption study using UPLC-MS/MS.

    PubMed

    Liu, Xiuxiu; Tang, Minghai; Liu, Taohong; Wang, Chunyan; Tang, Qiaoxin; Xiao, Yaxin; Yang, Ruixin; Chao, Ruobing

    2017-12-27

    1. Mesaconine, an ingredient from Aconitum carmichaelii Debx., has been proven to have cardiac effect. For further development and better pharmacological elucidation, the in vivo process and intestinal absorptive behavior of mesaconine should be investigated comprehensively. 2. An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitation of mesaconine in rat plasma, tissue homogenates, urine and feces to investigate the in vivo pharmacokinetic profiles, tissue distribution and excretion. The intestinal absorptive behavior of mesaconine was investigated using in vitro everted rat gut sac model. 3. Mesaconine was well distributed in tissues and a mass of unchanged form was detected in feces. It was difficultly absorbed into blood circulatory system after oral administration. The insufficient oral bioavailability of mesaconine may be mainly attributed to its low intestinal permeability due to a lack of lipophilicity. The absorption of mesaconine in rat's intestine is a first-order process with the passive diffusion mechanism.

  2. Distribution, pharmacokinetics and primary metabolism model of tramadol in zebrafish.

    PubMed

    Zhuo, Huiqin; Jin, Hongwei; Peng, Huifang; Huang, Heqing

    2016-12-01

    The current study aimed to develop a rapid, robust and adequately sensitive method for simultaneous determination of the concentration of tramadol and its active metabolites in zebrafish. The pharmacokinetic and elimination pattern of tramadol and its major phase I metabolites following oral or intramuscular administration in zebrafish tissues was achieved using electrospray ionization‑quadrupole‑time of flight/mass spectrometry (ESI‑Q‑TOF/MS) and gas chromatography/mass spectrometry (GC‑MS). Following administration, the metabolisms were detected in the brain, eyes, muscle and gill tissues within 1 h. Two tramadol metabolites, O‑ and N‑desmethyltramadol, were detected in brain tissue, with N‑desmethyltramadol detected at a higher level. Following GC‑MS detection the curve indicated an initial rapid phase, corresponding to the detection of the tramadol within 1 min, and reached peak value in the brain at 5 min. Faster drug clearance was detected in low‑dose groups, and concentration had dropped around the to initial level (1.11 µg) at 20 min, but was detectable for up to 3 h. However, it took 80 min to fall back to the initial value (1.73 µg) in the high‑dose groups, and tramadol was detectable for up to 4 h. This study developed and validated a simple and high throughput analytical procedure to determine the distribution and pharmacokinetic profiles of tramadol, and its primary metabolites in tissues of zebrafish.

  3. Multichannel imaging to quantify four classes of pharmacokinetic distribution in tumors.

    PubMed

    Bhatnagar, Sumit; Deschenes, Emily; Liao, Jianshan; Cilliers, Cornelius; Thurber, Greg M

    2014-10-01

    Low and heterogeneous delivery of drugs and imaging agents to tumors results in decreased efficacy and poor imaging results. Systemic delivery involves a complex interplay of drug properties and physiological factors, and heterogeneity in the tumor microenvironment makes predicting and overcoming these limitations exceptionally difficult. Theoretical models have indicated that there are four different classes of pharmacokinetic behavior in tissue, depending on the fundamental steps in distribution. In order to study these limiting behaviors, we used multichannel fluorescence microscopy and stitching of high-resolution images to examine the distribution of four agents in the same tumor microenvironment. A validated generic partial differential equation model with a graphical user interface was used to select fluorescent agents exhibiting these four classes of behavior, and the imaging results agreed with predictions. BODIPY-FL exhibited higher concentrations in tissue with high blood flow, cetuximab gave perivascular distribution limited by permeability, high plasma protein and target binding resulted in diffusion-limited distribution for Hoechst 33342, and Integrisense 680 was limited by the number of binding sites in the tissue. Together, the probes and simulations can be used to investigate distribution in other tumor models, predict tumor drug distribution profiles, and design and interpret in vivo experiments. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  4. Multichannel imaging to quantify four classes of pharmacokinetic distribution in tumors

    PubMed Central

    Bhatnagar, Sumit; Deschenes, Emily; Liao, Jianshan; Cilliers, Cornelius; Thurber, Greg M.

    2014-01-01

    Low and heterogeneous delivery of drugs and imaging agents to tumors results in decreased efficacy and poor imaging results. Systemic delivery involves a complex interplay of drug properties and physiological factors, and heterogeneity in the tumor microenvironment makes predicting and overcoming these limitations exceptionally difficult. Theoretical models have indicated that there are four different classes of pharmacokinetic behavior in tissue, depending on the fundamental steps in distribution. In order to study these limiting behaviors, we used multichannel fluorescence microscopy and stitching of high-resolution images to examine the distribution of four agents in the same tumor microenvironment. A validated generic partial differential equation model with a graphical user interface was used to select fluorescent agents exhibiting these four classes of behavior, and the imaging results agreed with predictions. BODIPY-FL exhibited higher concentrations in tissue with high blood flow, cetuximab gave perivascular distribution limited by permeability, high plasma protein and target binding resulted in diffusion-limited distribution for Hoechst 33342, and Integrisense 680 was limited by the number of binding sites in the tissue. Together, the probes and simulations can be used to investigate distribution in other tumor models, predict tumor drug distribution profiles, and design and interpret in vivo experiments. PMID:25048378

  5. First plasma and tissue pharmacokinetic study of the YSNSG cyclopeptide, a new integrin antagonist, using microdialysis.

    PubMed

    Slimano, Florian; Djerada, Zoubir; Bouchene, Salim; Van Gulick, Laurence; Brassart-Pasco, Sylvie; Dukic, Sylvain

    2017-07-15

    The YSNSG peptide is a synthetic peptide targeting α v β 3 integrin. This peptide exhibits promising activity in vitro and in vivo against melanoma. To determine pharmacokinetic parameters and predictive active doses in the central nervous system (CNS) and subcutaneous tissue (SC), we conducted microdialysis coupled with pharmacokinetic modeling and Monte Carlo simulation. After a recovery period of surgical procedures, a microdialysis probe was inserted in the caudate and in subcutaneous tissue. Plasma samples and dialysates collected 5h after YSNSG intravenous administration (10mg/kg) were analyzed by UPLC-MS/MS. A nonlinear mixed-effect modeling approach implemented in Monolix® 2016R1 was performed. Model selection and evaluation were based on the usual diagnostic plot, precision and information criteria. The primary plasma and tissue pharmacokinetic parameters were comparable with those of other integrin antagonists, such as cilengitide or ATN-161. Tissue/plasma and brain/plasma area under the curve (AUC) ratio were 66.2±21.6% and 3.6±4.7%, respectively. Two models of 2-compartments with an additional microdialysis compartment, parameterized as rate constants (k for elimination, k12/k21 and k13/k31 for distribution) and volumes (central V1 and peripheral microdialysis compartment V3) with zero-order input were selected to describe the dialysate concentrations in CNS and SC. The inter-individual variability (IIV) was described by exponential terms, and residual variability was described by a combined additive and proportional error model. Individual AUC (plasma and tissues) values were derived for each animal using the Empirical-Bayes-Estimates of the individual parameters. The regimens needed to achieve an in vitro predetermined target concentration in tissues were studied by Monte Carlo simulations using Monolix® 2016R1. YSNSG pharmacokinetic parameters show promising results in terms of subcutaneous disposition. Further investigations into such

  6. Distribution of the anticancer drugs doxorubicin, mitoxantrone and topotecan in tumors and normal tissues.

    PubMed

    Patel, Krupa J; Trédan, Olivier; Tannock, Ian F

    2013-07-01

    Pharmacokinetic analyses estimate the mean concentration of drug within a given tissue as a function of time, but do not give information about the spatial distribution of drugs within that tissue. Here, we compare the time-dependent spatial distribution of three anticancer drugs within tumors, heart, kidney, liver and brain. Mice bearing various xenografts were treated with doxorubicin, mitoxantrone or topotecan. At various times after injection, tumors and samples of heart, kidney, liver and brain were excised. Within solid tumors, the distribution of doxorubicin, mitoxantrone and topotecan was limited to perivascular regions at 10 min after administration and the distance from blood vessels at which drug intensity fell to half was ~25-75 μm. Although drug distribution improved after 3 and 24 h, there remained a significant decrease in drug fluorescence with increasing distance from tumor blood vessels. Drug distribution was relatively uniform in the heart, kidney and liver with substantially greater perivascular drug uptake than in tumors. There was significantly higher total drug fluorescence in the liver than in tumors after 10 min, 3 and 24 h. Little to no drug fluorescence was observed in the brain. There are marked differences in the spatial distributions of three anticancer drugs within tumor tissue and normal tissues over time, with greater exposure to most normal tissues and limited drug distribution to many cells in tumors. Studies of the spatial distribution of drugs are required to complement pharmacokinetic data in order to better understand and predict drug effects and toxicities.

  7. Pharmacokinetics, tissue distribution and identification of putative metabolites of JI-101 - a novel triple kinase inhibitor in rats.

    PubMed

    Gurav, S D; Gilibili, R R; Jeniffer, S; Mohd, Z; Giri, S; Govindarajan, R; Srinivas, N R; Mullangi, R

    2012-01-01

    JI-101, chemically 1-[1-(2-amino-pyridin-4-ylmethyl)-1H-indol-4-yl]-3-(5-bromo-2-methoxy-phenyl)-urea hydrochloride, is a novel orally active kinase inhibitor, which has shown potent in vitro and in vivo anticancer activity against a variety of cancer cell lines and xenografts. It is currently entering Phase II clinical development for the treatment of solid tumors. The aim of the study is to assess the metabolic stability of JI-101 in various pre-clinical and human liver microsomes, to identify the major CYPs (cytochrome β450) involved in the metabolism of JI-101 and identification of putative metabolites. We have also studied the pharmacokinetics, tissue distribution and excretion of JI-101 in Sprague Dawley rats. JI-101 was found to be stable in various liver microsomes tested. JI-101 is highly permeable and not a substrate for P-gp (permeability glycoprotein). JI-101 excreted through bile along with its mono- and di-hydroxy metabolites. Following oral administration, JI-101 was rapidly absorbed, reaching Cmax within 2 h. The t½ of JI-101 with intravenous and oral route was found to be 1.75 ± 0.79 and 2.66 ± 0.13 h, respectively. The Cl and Vd by intravenous route for JI-101 were found to be 13.0 ± 2.62 mL/min/kg and 2.11 ± 1.42 L/kg, respectively. The tissue distribution of JI-101 was extensive with rapid and preferred uptake into lung tissue. Overall, the oral bioavailability of JI-101 is 55% and the primary route of elimination for JI-101 is feces. © Georg Thieme Verlag KG Stuttgart · New York.

  8. Plasma pharmacokinetics, tissue disposition, excretion and metabolism of vinorelbine in mice as determined by high performance liquid chromatography.

    PubMed

    van Tellingen, O; Kuijpers, A V; Beijnen, J H; Nooijen, W J; Bult, A

    1993-01-01

    We have investigated the pharmacokinetics of the investigational semi-synthetic vinca alkaloid vinorelbine (navelbine, NVB). The analyses have been performed by using a sensitive and selective method based on ion-exchange normal phase high-performance liquid chromatography with fluorescence detection combined with liquid-liquid extraction for sample clean-up. Pharmacokinetic studies were performed in male FVB mice receiving 12 mg/kg NVB through intravenous injection. The results have been compared to those obtained for vinblastine (VBL). The plasma pharmacokinetics of NVB can be described by a three compartment model. The elimination half-life is significantly longer and the plasma AUC values higher for NVB compared to VBL. This is reflected in tissues, where, 24 hr after drug administration, the concentration of NVB is 5 to 10-fold higher compared to VBL. Qualitatively, the tissue distribution and retention of the drugs is very similar. The drug concentrations in most tissues decline parallel with the circulating plasma levels, whereas prolonged retention is found in tissues of lymphatic and testicular origin. Deacetylation yielding deacetylnavelbine (DNVB) is the primary metabolic route for NVB. This cytotoxic metabolite accounts for a substantial part of the overall disposition of drug. Only 58% of the administered dose is excreted in the urine (17%) and faeces (41%) as NVB or DNVB. No other metabolites have been detected.

  9. Pharmacokinetics, Metabolism, Distribution and Permeability of Nanomedicine.

    PubMed

    Ravindran, Selvan; Suthar, Jitendra Kumar; Rokade, Rutuja; Deshpande, Pooja; Singh, Pooja; Pratinidhi, Ashutosh; Khambadkhar, Rajeshree; Utekar, Srushti

    2018-01-01

    Medical application of nanotechnology is termed as Nanomedicine and is widely used in healthcare industries. Nanotechnology has helped Physicians, Scientists and Technologists to understand the changes in cellular levels to develop nanomedicines and address the challenges faced by the healthcare sectors. Nanoparticles with less than 1nm in size have been used as drug delivery and gene delivery systems to accelerate the drug action in humans. Size of nanomaterials is akin to that of biomolecules and expected to have better interactions. Hence, its utility for various biomedical applications is explored. Pharmacokinetics, metabolism, permeability, distribution and elimination studies of nanoparticles are essential to understand its potency, toxicity threshold and confirm its safe use in humans. Reports were available for toxicity studies on nanoparticles, but work on metabolism, pharmacokinetics, distribution and permeability of nanomedicine is limited. Hence, the main focus of this review article is about metabolism, pharmacokinetics, permeability and biodistribution of nanomaterials used in nanomedicine. Nanomedicine is increasingly becoming important in the treatment of diseases and diagnosis. Size of the particle plays an important role. As the particle size decreases its effect to cure the disease increases. Pharmacokinetics, bioavailability, half-life, metabolism, biodistribution and permeability of nanomedicine were found to be better than that of microsized drugs. In vitro and In vivo ADME (Absorption, Distribution, Metabolism and Excretion) studies are mandatory for pharmaceutical organic drugs. Similarly, nanomaterials should be subjected to both in vitro and in vivo ADME studies. Thus, nanomedicine can assist in the development of safe personalized medicine in humans. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Pharmacokinetics of Rhodamine 110 and Its Organ Distribution in Rats.

    PubMed

    Jiang, Shiau-Han; Cheng, Yung-Yi; Huo, Teh-Ia; Tsai, Tung-Hu

    2017-09-06

    Rhodamine dyes have been banned as food additives due to their potential tumorigenicity. Rhodamine 110 is illegal as a food additive, although its pharmacokinetics have not been characterized, and no accurate bioanalytical methods are available to quantify rhodamine 110. The aim of this study was to develop and validate a fast, stable, and sensitive method to quantify rhodamine 110 using high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) to assess its pharmacokinetics and organ distribution in awake rats. Rhodamine 110 exhibited linear pharmacokinetics and slow elimination after oral administration. Furthermore, its oral bioavailability was approximately 34-35%. The distribution in the liver and kidney suggests that these organs are primarily responsible for rhodamine 110 metabolism and elimination. Our investigation describes the pharmacokinetics and a quantification method for rhodamine 110, improving our understanding of the food safety of rhodamine dyes.

  11. Application of liquid chromatography-tandem mass spectrometry to study the effect of docetaxel on pharmacokinetics and tissue distribution of apatinib in mice.

    PubMed

    Feng, Siqi; Zhang, Jingwei; Wang, Ying; Sun, Runbin; Feng, Dong; Peng, Ying; Yang, Na; Zhang, Yue; Gao, Haoxue; Gu, Huilin; Wang, Guangji; Aa, Jiye; Zhou, Fang

    2018-04-15

    Apatinib, a highly selective small-molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), has attracted many attentions due to its anticancer activity in various malignancies containing non-small-cell lung cancer (NSCLC). Our previous preclinical study confirmed the enhanced anti-tumor efficacy of combined treatment between apatinib and docetaxel for NSCLC. However, the effects of docetaxel on pharmacokinetics and tissue distribution of apatinib are not clear. In present study, a reliable HPLC-MS/MS method was established for determination of apatinib. This method had a good linearity in the range of 1-5000 ng/mL, and the recovery and matrix effect were 100.1-103.5%, 77.6-83.5%, respectively. Plasma exposure level of apatinib and the values of C max , AUC 0-12h , T 1/2 , and MRT were not affected by multi-dose of docetaxel. The tissue distributions (kidney, heart, lung, spleen) of apatinib in combined treatment group were lower at 0.25 h but higher at 2 h, and that in intestine and liver were not significantly changed compared with control group. However, pre-treatment with docetaxel had no significant effect on AUC 0-4h of apatinib in tissues in mice. In conclusion, plasma and tissues exposure levels of apatinib were not affected by long-termed treatment with docetaxel, indicating that docetaxel is less likely to increase the side effect of apatinib such as hypertension, hand-foot syndrome and so on. Copyright © 2018. Published by Elsevier B.V.

  12. Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics, and distribution

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Vuillemenot, Brian R., E-mail: bvuillemenot@bmrn.com; Kennedy, Derek; Reed, Randall P.

    CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mildmore » increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV

  13. Pharmacokinetics of tilmicosin in equine tissues and plasma.

    PubMed

    Clark, C; Dowling, P M; Ross, S; Woodbury, M; Boison, J O

    2008-02-01

    The macrolide antibiotic tilmicosin has potential for treating bacterial respiratory tract infections in horses. A pharmacokinetic study evaluated the disposition of tilmicosin in the horse after oral (4 mg/kg) or subcutaneous (s.c.) (10 mg/kg) administration. Tilmicosin was not detected in equine plasma or tissues after oral administration at this dose. With s.c. injection, tilmicosin concentrations reached a maximum concentration of approximately 200 ng/mL in the plasma of the horses. Tilmicosin concentrations in plasma persisted with a mean residence time (MRT) of 19 h. Maximum tissue residue concentrations (C(max)) of tilmicosin measured in equine lung, kidney, liver and muscle tissues after s.c. administration were 2784, 4877, 1398, and 881 ng/g, respectively. The MRT of tilmicosin in these tissues was approximately 27 h. Subcutaneous administration of tilmicosin resulted in severe reactions at the injection sites.

  14. Checking distributional assumptions for pharmacokinetic summary statistics based on simulations with compartmental models.

    PubMed

    Shen, Meiyu; Russek-Cohen, Estelle; Slud, Eric V

    2016-08-12

    Bioequivalence (BE) studies are an essential part of the evaluation of generic drugs. The most common in vivo BE study design is the two-period two-treatment crossover design. AUC (area under the concentration-time curve) and Cmax (maximum concentration) are obtained from the observed concentration-time profiles for each subject from each treatment under each sequence. In the BE evaluation of pharmacokinetic crossover studies, the normality of the univariate response variable, e.g. log(AUC) 1 or log(Cmax), is often assumed in the literature without much evidence. Therefore, we investigate the distributional assumption of the normality of response variables, log(AUC) and log(Cmax), by simulating concentration-time profiles from two-stage pharmacokinetic models (commonly used in pharmacokinetic research) for a wide range of pharmacokinetic parameters and measurement error structures. Our simulations show that, under reasonable distributional assumptions on the pharmacokinetic parameters, log(AUC) has heavy tails and log(Cmax) is skewed. Sensitivity analyses are conducted to investigate how the distribution of the standardized log(AUC) (or the standardized log(Cmax)) for a large number of simulated subjects deviates from normality if distributions of errors in the pharmacokinetic model for plasma concentrations deviate from normality and if the plasma concentration can be described by different compartmental models.

  15. Pharmacokinetic and pharmacometabolomic study of pirfenidone in normal mouse tissues using high mass resolution MALDI-FTICR-mass spectrometry imaging.

    PubMed

    Sun, Na; Fernandez, Isis E; Wei, Mian; Wu, Yin; Aichler, Michaela; Eickelberg, Oliver; Walch, Axel

    2016-02-01

    Given the importance of pirfenidone as the first worldwide-approved drug for idiopathic pulmonary fibrosis treatment, its pharmacodynamic properties and the metabolic response to pirfenidone treatment have not been fully elucidated. The aim of the present study was to get molecular insights of pirfenidone-related pharmacometabolomic response using MALDI-FTICR-MSI. Quantitative MALDI-FTICR-MSI was carried out for determining the pharmacokinetic properties of pirfenidone and its related metabolites 5-hydroxymethyl pirfenidone and 5-carboxy pirfenidone in lung, liver and kidney. To monitor the effect of pirfenidone administration on endogenous cell metabolism, additional in situ endogenous metabolite imaging was performed in lung tissue sections. While pirfenidone is highly abundant and delocalized across the whole micro-regions of lung, kidney and liver, 5-hydroxymethyl pirfenidone and 5-carboxy pirfenidone demonstrate heterogeneous distribution patterns in lung and kidney. In situ endogenous metabolite imaging study of lung tissue indicates no significant effects of pirfenidone on metabolic pathways. Remarkably, we found 129 discriminative m/z values which represent clear differences between control and treated lungs, the majority of which are currently unknown. PCA analysis and heatmap view can accurately distinguish control and treated groups. This is the first pharmacokinetic study to investigate the tissue distribution of orally administered pirfenidone and its related metabolites simultaneously in organs without labeling. The combination of pharmametabolome with histological features provides detailed mapping of drug effects on metabolism as response of healthy lung tissue to pirfenidone treatment.

  16. Penetration and pharmacokinetics of non-steroidal anti-inflammatory drugs in rat prostate tissue.

    PubMed

    Yellepeddi, Venkata K; Radhakrishnan, Jayashree; Radhakrishnan, Rajan

    2018-02-01

    Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) involves inflammation of the prostate and affects the quality of life of men of all ages. It is well reported in clinical studies that the treatment for CP/CPPS using nonsteroidal anti-inflammatory drugs (NSAIDs) produced favorable outcomes. However, currently, there are no guidelines on choice of the NSAIDs for the treatment of CP/CPPS. Therefore, in the current research study, we evaluated the prostate tissue penetration of four NSAIDs in rats to provide guidance on choice of NSAIDs for the treatment of CP/CPPS. Male Sprague-Dawley rats were administered orally with four NSAIDs viz. celecoxib, diclofenac, ibuprofen, and naproxen at 500 mg/kg dose. The animals were then sacrificed at various time points, and their prostate tissues were harvested. The NSAIDs were then extracted from the prostate tissues using liquid extraction technique, and their concentration in prostate tissue was quantified using high-performance liquid chromatography (HPLC). The prostate tissue penetration and related pharmacokinetic parameters were evaluated by non-compartmental analysis. The HPLC method for quantifying NSAIDs in prostate tissue resulted in single, sharp peaks without any interference and all validation parameters were within limits. Celecoxib showed the highest area under the curve (AUC) [146.50 ± 2.75 μg/mL*h] of all NSAID's. A two-factor analysis of variance (ANOVA) with replication indicated an overall statistically significant difference in the pharmacokinetic parameters for celecoxib, diclofenac, ibuprofen, and naproxen. This study for the first time reported the relative prostate tissue penetration of four NSAIDs. The pharmacokinetic data indicated that celecoxib has the highest penetration and retention in rat prostate tissues. Therefore, celecoxib may be considered as a better choice for the treatment CP/CPPS involving NSAIDs. © 2017 Wiley Periodicals, Inc.

  17. Sunitinib-ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain, liver, and kidney in male and female mice differently.

    PubMed

    Lau, Christine Li Ling; Chan, Sook Tyng; Selvaratanam, Manimegahlai; Khoo, Hui Wen; Lim, Adeline Yi Ling; Modamio, Pilar; Mariño, Eduardo L; Segarra, Ignacio

    2015-08-01

    Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC0→∞ decreased in plasma (P < 0.05), was higher in liver and brain (P < 0.001), and lower in kidney (P < 0.001) vs. male control mice. After ibuprofen coadministration, female mice showed lower AUC0→∞ in plasma (P < 0.01), brain, liver, and kidney (all P < 0.001). However, in male mice, AUC0→∞ remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P < 0.001). The tissue-to-plasma AUC0→∞ ratio was similar between male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6-fold higher liver-to-plasma ratio (P < 0.001) while remained unchanged in female mice and in kidney (male and female mice) but decreased 55% in brain (P < 0.05). The tissue-to-plasma partial AUC ratio, the drug tissue targeting index, and the tissue-plasma hysteresis-like plots also showed sex-based ibuprofen-sunitinib drug interaction differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender-based P450 and efflux/transporters differences. © 2015 Société Française de Pharmacologie et de Thérapeutique.

  18. Practical concept of pharmacokinetics/pharmacodynamics in the management of skin and soft tissue infections.

    PubMed

    Pea, Federico

    2016-04-01

    This article gives an overview of the practical concept of pharmacokinetic/pharmacodynamic principles useful for clinicians in the management of skin and soft tissue infections (SSTIs). Recent studies suggest that distinguishing between bacteriostatic or bactericidal activity when choosing an antimicrobial for the treatment of severe infections could probably be clinically irrelevant. Conversely, what could help clinicians in maximizing the therapeutic efficacy of the various drugs in routine practice is taking care of some pharmacokinetic/pharmacodynamic principles. Concentration-dependent agents may exhibit more rapid bacterial killing than observed with time-dependent agents. Serum concentrations may not always adequately predict tissue exposure in patients with SSTIs, and measuring concentrations at the infection site is preferable. Hydrophilic antimicrobials showed generally lower penetration rates than the lipophilic ones and might require alternative dosing approaches in the presence of severe sepsis or septic shock. Conversely, tissue penetration of lipophilic antimicrobials is often unaffected by the pathophysiological status. Real-time therapeutic drug monitoring may be a very helpful tool for optimizing therapy of severe infections. Taking care of pharmacokinetic/pharmacodynamic principles deriving from the most recent findings may help clinicians in maximizing treatment of SSTIs with antimicrobials in every situation.

  19. Pharmacokinetics and tissue elimination of flunixin in veal calves.

    PubMed

    Kissell, Lindsey W; Brinson, Patrick D; Gehring, Ronette; Tell, Lisa A; Wetzlich, Scott E; Baynes, Ronald E; Riviere, Jim E; Smith, Geof W

    2016-06-01

    OBJECTIVE To describe plasma pharmacokinetic parameters and tissue elimination of flunixin in veal calves. ANIMALS 20 unweaned Holstein calves between 3 and 6 weeks old. PROCEDURES Each calf received flunixin (2.2 mg/kg, IV, q 24 h) for 3 days. Blood samples were collected from all calves before the first dose and at predetermined times after the first and last doses. Beginning 24 hours after injection of the last dose, 4 calves were euthanized each day for 5 days. Plasma and tissue samples were analyzed by ultraperformance liquid chromatography. Pharmacokinetic parameters were calculated by compartmental and noncompartmental methods. RESULTS Mean ± SD plasma flunixin elimination half-life, residence time, and clearance were 1.32 ± 0.94 hours, 12.54 ± 10.96 hours, and 64.6 ± 40.7 mL/h/kg, respectively. Mean hepatic and muscle flunixin concentrations decreased to below FDA-established tolerance limits (0.125 and 0.025 μg/mL, respectively) for adult cattle by 3 and 2 days, respectively, after injection of the last dose of flunixin. Detectable flunixin concentrations were present in both the liver and muscle for at least 5 days after injection of the last dose. CONCLUSIONS AND CLINICAL RELEVANCE The labeled slaughter withdrawal interval for flunixin in adult cattle is 4 days. Because administration of flunixin to veal calves represents extralabel drug use, any detectable flunixin concentrations in edible tissues are considered a violation. Results indicated that a slaughter withdrawal interval of several weeks may be necessary to ensure that violative tissue residues of flunixin are not detected in veal calves treated with that drug.

  20. Multimodal assessment of spatial distribution of drug-tracer uptake by brain tissue after intra-arterial injections

    NASA Astrophysics Data System (ADS)

    Singh-Moon, Rajinder; Chaudhuri, Durba; Wang, Mei; Straubinger, Robert; Bigio, Irving J.; Joshi, Shailendra

    2014-02-01

    It is challenging to track the rapid changes in drug concentrations after intra-arterial (IA) administration to elucidate the pharmacokinetics of this method of drug delivery. Traditional pharmacokinetic parameters (such as protein binding) that are highly relevant to intravenous (IV) administration do not seem to apply to IA injections. Regional drug delivery is affected by the biomechanics of drug injection, resting blood flow, and local tissue extraction. In-vivo and ex-vivo, optical methods for spatial mapping of drug deposition can assist in visualizing drug distributions and aid in the screening of potential drugs and carrier candidates. We present a multimodal approach for the assessment of drug distribution in postmortem tissue specimens using diffuse reflectance spectroscopy, multispectral imaging, and confocal microscopy and demonstrate feasibility of distinguishing route of administration advantages of liposome-dye conjugate delivery. The results of this study suggest that insight on drug dynamics gained by this aggregated approach can be used to help screen and/or optimize potential drug candidates and drug delivery protocols.

  1. Microdialysis as a way to measure antibiotics concentration in tissues.

    PubMed

    Marchand, Sandrine; Chauzy, Alexia; Dahyot-Fizelier, Claire; Couet, William

    2016-09-01

    As for all other drugs, antibiotics must reach their pharmacodynamic target in order to exert their effect, but because infection may occur in various tissues the distribution of antibiotics has always been of particular concern. In this article, we will first critically review the various methodologies available to study antibiotics tissue distribution, including microdialysis, secondly we will show how basic pharmacokinetic concepts may help to predict or interpret antibiotics tissue distribution and third we will address the question of linking antibiotics tissue distribution with their antimicrobial effect, using modern pharmacokinetic-pharmacodynamic methods. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling.

    PubMed

    Vlot, Anna H C; de Witte, Wilhelmus E A; Danhof, Meindert; van der Graaf, Piet H; van Westen, Gerard J P; de Lange, Elizabeth C M

    2017-12-04

    Selectivity is an important attribute of effective and safe drugs, and prediction of in vivo target and tissue selectivity would likely improve drug development success rates. However, a lack of understanding of the underlying (pharmacological) mechanisms and availability of directly applicable predictive methods complicates the prediction of selectivity. We explore the value of combining physiologically based pharmacokinetic (PBPK) modeling with quantitative structure-activity relationship (QSAR) modeling to predict the influence of the target dissociation constant (K D ) and the target dissociation rate constant on target and tissue selectivity. The K D values of CB1 ligands in the ChEMBL database are predicted by QSAR random forest (RF) modeling for the CB1 receptor and known off-targets (TRPV1, mGlu5, 5-HT1a). Of these CB1 ligands, rimonabant, CP-55940, and Δ 8 -tetrahydrocanabinol, one of the active ingredients of cannabis, were selected for simulations of target occupancy for CB1, TRPV1, mGlu5, and 5-HT1a in three brain regions, to illustrate the principles of the combined PBPK-QSAR modeling. Our combined PBPK and target binding modeling demonstrated that the optimal values of the K D and k off for target and tissue selectivity were dependent on target concentration and tissue distribution kinetics. Interestingly, if the target concentration is high and the perfusion of the target site is low, the optimal K D value is often not the lowest K D value, suggesting that optimization towards high drug-target affinity can decrease the benefit-risk ratio. The presented integrative structure-pharmacokinetic-pharmacodynamic modeling provides an improved understanding of tissue and target selectivity.

  3. Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams, fetuses, and neonates with physiologically based pharmacokinetic modeling

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lin, Zhoumeng; Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602; Fisher, Jeffrey W.

    Atrazine (ATR) is a widely used chlorotriazine herbicide, a ubiquitous environmental contaminant, and a potential developmental toxicant. To quantitatively evaluate placental/lactational transfer and fetal/neonatal tissue dosimetry of ATR and its major metabolites, physiologically based pharmacokinetic models were developed for rat dams, fetuses and neonates. These models were calibrated using pharmacokinetic data from rat dams repeatedly exposed (oral gavage; 5 mg/kg) to ATR followed by model evaluation against other available rat data. Model simulations corresponded well to the majority of available experimental data and suggest that: (1) the fetus is exposed to both ATR and its major metabolite didealkylatrazine (DACT) atmore » levels similar to maternal plasma levels, (2) the neonate is exposed mostly to DACT at levels two-thirds lower than maternal plasma or fetal levels, while lactational exposure to ATR is minimal, and (3) gestational carryover of DACT greatly affects its neonatal dosimetry up until mid-lactation. To test the model's cross-species extrapolation capability, a pharmacokinetic study was conducted with pregnant C57BL/6 mice exposed (oral gavage; 5 mg/kg) to ATR from gestational day 12 to 18. By using mouse-specific parameters, the model predictions fitted well with the measured data, including placental ATR/DACT levels. However, fetal concentrations of DACT were overestimated by the model (10-fold). This overestimation suggests that only around 10% of the DACT that reaches the fetus is tissue-bound. These rodent models could be used in fetal/neonatal tissue dosimetry predictions to help design/interpret early life toxicity/pharmacokinetic studies with ATR and as a foundation for scaling to humans. - Highlights: • We developed PBPK models for atrazine in rat dams, fetuses, and neonates. • We conducted pharmacokinetic (PK) study with atrazine in pregnant mice. • Model predictions were in good agreement with experimental rat and mouse PK

  4. A COMPREHENSIVE INSIGHT ON OCULAR PHARMACOKINETICS

    PubMed Central

    Agrahari, Vibhuti; Mandal, Abhirup; Agrahari, Vivek; Trinh, Hoang My; Joseph, Mary; Ray, Animikh; Hadji, Hicheme; Mitra, Ranjana; Pal, Dhananjay; Mitra, Ashim K.

    2017-01-01

    Eye is a distinctive organ with protective anatomy and physiology. Several pharmacokinetics compartment model of ocular drug delivery has been developed for describing the absorption, distribution and elimination of ocular drugs in the eye. Determining pharmacokinetics parameters in ocular tissues is a major challenge because of the complex anatomy and dynamic physiological barrier of the eye. In this review, pharmacokinetics of these compartments exploring different drugs, delivery systems and routes of administration are discussed including factors affecting intraocular bioavailability. Factors such as pre-corneal fluid drainage, drug binding to tear proteins, systemic drug absorption, corneal factors, melanin binding, drug metabolism renders ocular delivery challenging and elaborated in this manuscript. Several compartment models are discussed those are developed in ocular drug delivery to study the pharmacokinetics parameters. There are several transporters present in both anterior and posterior segments of the eye which play a significant role in ocular pharmacokinetics and summarized briefly. Moreover, several ocular pharmacokinetics animal models and relevant studies are reviewed and discussed in addition to the pharmacokinetics of various ocular formulations. PMID:27798766

  5. Pharmacokinetics of flomoxef in mucosal tissue of the middle ear and mastoid following intravenous administration in humans.

    PubMed

    Saito, H; Kimura, T; Takeda, T; Kishimoto, S; Oguma, T; Shimamura, K

    1990-01-01

    The pharmacokinetics of flomoxef in serum and in the mucosal tissue of the middle ear and mastoid were studied in 9 patients undergoing tympanoplasties. All patients received 1 g of flomoxef intravenously. Flomoxef levels in serum and in mucosal tissue were determined by a bioassay method. The peak value of mean concentrations of flomoxef in the mucosal tissue was 30.3 +/- 11.7 micrograms/ml at 10 min after the administrations. Pharmacokinetic analyses showed that the concentration of flomoxef in the mucosal tissue was over 1.56 micrograms/ml (which is the MIC90 for the common pathogens of otitis media) for more than 2 h and decreased parallel with serum concentration with a half-life of about 40 min.

  6. Design of a dynamic optical tissue phantom to model extravasation pharmacokinetics

    NASA Astrophysics Data System (ADS)

    Zhang, Jane Y.; Ergin, Aysegul; Andken, Kerry Lee; Sheng, Chao; Bigio, Irving J.

    2010-02-01

    We describe an optical tissue phantom that enables the simulation of drug extravasation from microvessels and validates computational compartmental models of drug delivery. The phantom consists of a microdialysis tubing bundle to simulate the permeable blood vessels, immersed in either an aqueous suspension of titanium dioxide (TiO2) or a TiO2 mixed agarose scattering medium. Drug administration is represented by a dye circulated through this porous microdialysis tubing bundle. Optical pharmacokinetic (OP) methods are used to measure changes in the absorption coefficient of the scattering medium due to the arrival and diffusion of the dye. We have established particle sizedependent concentration profiles over time of phantom drug delivery by intravenous (IV) and intra-arterial (IA) routes. Additionally, pharmacokinetic compartmental models are implemented in computer simulations for the conditions studied within the phantom. The simulated concentration-time profiles agree well with measurements from the phantom. The results are encouraging for future optical pharmacokinetic method development, both physical and computational, to understand drug extravasation under various physiological conditions.

  7. Pharmacokinetic Studies of Oxathio-Heterocycle Fused Chalcones.

    PubMed

    Okoniewska, Krystyna; Konieczny, Marek T; Lemke, Krzysztof; Grabowski, Tomasz

    2017-02-01

    Chalcone constitutes one of the most used molecular frameworks in medicinal chemistry and its derivatives exhibit a broad spectrum of biological activities. Low absolute bioavailability, poor distribution, intensive metabolism and elimination of chalcones are the main problems in designing new drugs based on their structure. One of the fundamental steps in evaluation of drug candidates is a comparative analysis of pharmacokinetic parameters. The aim of the studies was the pharmacokinetic characterization of the selected oxathio-heterocycle fused chalcones. The pharmacokinetic parameters of 19 compounds were reported. The analyzed chalcones were examined after a single intravenous administration to forty 7-week-old mature male rats of Wistar stock. Pharmacokinetic analysis was performed independently using SHAM (slopes, highest, amounts, and moments) and the two-compartment model. Basic physiochemical parameters were calculated. The bioanalytical methods were validated in terms of repeatability, linearity, accuracy, precision, and selectivity. The pharmacokinetics of the examined group of chalcones are compatible with the two-compartment model. The physicochemical characteristics of this group are quite homogeneous. The kinetics of the examined chalcones are indicative of a distribution to the tissue compartment with the predominance of a rate constant from central to peripheral compartments (k 12 ) over the rate constant from peripheral to central compartments (k 21 ). The elimination from the central compartment (k 10 ) is higher than the transfer from the central compartment to the tissues (k 10  > k 12 ) in almost all examined cases. The presented group of compounds may form a starting point for studies into drugs treating autoimmune diseases of the gastro-intestinal tract.

  8. Pharmacokinetics and metabolism of benzene in Zymbal gland and other key target tissues after oral administration in rats.

    PubMed Central

    Low, L K; Meeks, J R; Norris, K J; Mehlman, M A; Mackerer, C R

    1989-01-01

    Solid tumors have been reported in the Zymbal gland, oral and nasal cavities, and mammary gland of Sprague-Dawley rats following chronic oral administration of benzene. The cause for the specificity of such lesions remains unclear, but it is possible that tissue-specific metabolism or pharmacokinetics of benzene is responsible. Metabolism and pharmacokinetic studies were carried out in our laboratory with 14C-benzene at oral doses of 0.15 to 500 mg/kg to ascertain tissue retention, metabolite profile, and elimination kinetics in target and nontarget organs and in blood. Findings from those studies indicate the following: a) the Zymbal gland is not a sink or a site of accumulation for benzene or its metabolites even after a single high dose (500 mg/kg) or after repeated oral administration; b) the metabolite profile is quantitatively different in target tissues (e.g., Zymbal gland, nasal cavity), nontarget tissues and blood; and (c) pharmacokinetic studies show that the elimination of radioactivity from the Zymbal gland is biphasic. PMID:2792043

  9. Pharmacokinetics and tissue distribution of parenterally administered human alpha-lymphotoxin in normal and meth-A tumor-bearing BALB/c mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Averbook, B.J.; Jeffes, E.B.; Yamamoto, R.S.

    1989-08-01

    These in vivo studies examine the pharmacokinetics of parenterally administered purified, native human alpha-lymphotoxin (LT) in normal and Meth-A bearing BALB/c mice. We found that the lytic activity of alpha-LT was inactivated within 5 h in the blood of both normal and tumor-bearing mice in vivo. However, LT bioactivity in vitro was not affected by incubation with fresh serum. Radioiodinated LT was rapidly sequestered in the kidneys of both normal and tumor-bearing animals. Systemically administered, radioiodinated LT did not selectively localize in tumor tissues.

  10. Effects of Phytochemical P-Glycoprotein Modulators on the Pharmacokinetics and Tissue Distribution of Doxorubicin in Mice.

    PubMed

    Kim, Tae Hwan; Shin, Soyoung; Yoo, Sun Dong; Shin, Beom Soo

    2018-02-07

    Pungent spice constituents such as piperine, capsaicin and [6]-gingerol consumed via daily diet or traditional Chinese medicine, have been reported to possess various pharmacological activities. These dietary phytochemicals have also been reported to inhibit P-glycoprotein (P-gp) in vitro and act as an alternative to synthetic P-gp modulators. However, the in vivo effects on P-gp inhibition are currently unknown. This study aimed to test the hypothesis that phytochemical P-gp inhibitors, i.e., piperine, capsaicin and [6]-gingerol, modulate the in vivo tissue distribution of doxorubicin, a representative P-gp substrate. Mice were divided into four groups and each group was pretreated with intraperitoneal injections of control vehicle, piperine, capsaicin, or [6]-gingerol and doxorubicin (1 mg/kg) was administered via the penile vein. The concentrations of the phytochemicals and doxorubicin in the plasma and tissues were determined by LC-MS/MS. The overall plasma concentration-time profiles of doxorubicin were not significantly affected by piperine, capsaicin, or [6]-gingerol. In contrast, doxorubicin accumulation was observed in tissues pretreated with piperine or capsaicin. The tissue to plasma partition coefficients, K p , for the liver and kidney were higher in the piperine-pretreated group, while the K p for kidney, brain and liver were higher in the capsaicin-pretreated group. [6]-Gingerol did not affect doxorubicin tissue distribution. The data demonstrated that the phytochemicals modulated doxorubicin tissue distribution, which suggested their potential to induce food-drug interactions and act as a strategy for the delivery of P-gp substrate drugs to target tissues and tumors.

  11. Ocular Distribution and Pharmacokinetics of Lifitegrast in Pigmented Rabbits and Mass Balance in Beagle Dogs.

    PubMed

    Chung, Jou-Ku; Spencer, Elizabeth; Hunt, Matthew; McCauley, Thomas; Welty, Devin

    Lifitegrast is approved in the United States for the treatment of dry eye disease (DED). We assessed lifitegrast's ocular distribution/pharmacokinetic profile in rabbits, and 14 C-lifitegrast mass balance/excretion in dogs. Female pigmented rabbits received a single topical ocular dose of lifitegrast (Formulation No. 1, n = 25; No. 2, n = 25) per eye twice daily (target, 1.75 mg/eye/dose). Blood/ocular tissues were collected on day 5. Beagle dogs received single intravenous (n = 10; target, 3 mg, 262 μCi/animal) and ocular (n = 8, target, 3 mg, 30 μCi/eye) doses of 14 C-lifitegrast (∼8 weeks between doses). Blood, excreta, and cage rinse/wipes were collected. Concentrations were measured by mass spectrometry/liquid scintillation counting. Pharmacokinetic analyses (noncompartmental) included maximum concentration (C max ), time to C max (t max ), and area under the concentration-time curve from 0 to 8 h (AUC 0-8 ). In rabbits, lifitegrast C max and AUC 0-8 were similar between formulations. C max was highest in ocular anterior segment tissues: 5,190-14,200 ng/g [conjunctiva (palpebral/bulbar), cornea, anterior sclera]. Posterior segment tissues had lower concentrations (0-826 ng/g). AUC 0-8 followed a similar trend. Plasma concentrations were low (C max <18 ng/mL). Tissue/plasma t max was ∼0.25-1 h. In dogs, after intravenous/ocular doses, 14 C-lifitegrast was eliminated primarily through feces. Excreted radioactivity was mainly unchanged lifitegrast. High exposure of lifitegrast in rabbit ocular anterior segment tissues and low exposure in posterior segment tissues/plasma suggests that lifitegrast reaches target tissues for DED treatment, with low potential for off-target systemic/ocular effects. Excretion of unchanged 14 C-lifitegrast suggests minimal drug metabolism in vivo. This is consistent with lifitegrast clinical trial efficacy/safety data.

  12. Pharmacokinetics, distribution, metabolism, and excretion of the dual reuptake inhibitor [(14)C]-nefopam in rats.

    PubMed

    Yu, Jian; Solon, Eric; Shen, Helen; Modi, Nishit B; Mittur, Aravind

    2016-11-01

    1. This study examined the pharmacokinetics, distribution, metabolism, and excretion of [(14)C] nefopam in rats after a single oral administration. Blood, plasma, and excreta were analyzed for total radioactivity, nefopam, and metabolites. Metabolites were profiled and identified. Radioactivity distribution was determined by quantitative whole-body autoradiography. 2. The pharmacokinetic profiles of total radioactivity and nefopam were similar in male and female rats. Radioactivity partitioned approximately equally between plasma and red blood cells. A majority of the radioactivity was excreted in urine within 24 hours and mass balance was achieved within 7 days. 3. Intact nefopam was a minor component in plasma and excreta. Numerous metabolites were identified in plasma and urine generated by multiple pathways including: hydroxylation/oxidation metabolites (M11, M22a and M22b, M16, M20), some of which were further glucuronidated (M6a to M6c, M7a to M7c, M8a and M8b, M3a to M3d); N-demethylation of nefopam to metabolite M21, which additionally undergoes single or multiple hydroxylations or sulfation (M9, M14, M23), with some of the hydroxylated metabolites further glucuronidated (M2a to M2d). 4. Total radioactivity rapidly distributed with highest concentrations found in the urinary bladder, stomach, liver, kidney medulla, small intestine, uveal tract, and kidney cortex without significant accumulation or persistence. Radioactivity reversibly associated with melanin-containing tissues.

  13. Comparisons of the pharmacokinetic and tissue distribution profiles of withanolide B after intragastric administration of the effective part of Datura metel L. in normal and psoriasis guinea pigs.

    PubMed

    Yang, Lianrong; Meng, Xin; Kuang, Haixue

    2018-04-15

    A simple, highly sensitive ultra-performance liquid chromatography- electrospray ionization-mass spectrometry (LC-ESI-MS) method has been developed to quantify of withanolide B and obakunone (IS) in guinea pig plasma and tissues, and to compare the pharmacokinetics and tissue distribution of withanolide B in normal and psoriasis guinea pigs. After mixing with IS, plasma and tissues were pretreated by protein precipitation with methanol. Chromatographic separation was performed on a C18 column using aqueous (0.1% formic acid) and acetonitrile (0.1% formic acid) solutions at 0.4 mL/min as the mobile phase. The gradient program was selected (0-4.0 min, 2-98% B; 4.0-4.5 min, 98-2% B; and 4.5-5 min, 2% B). Detection was performed on a 4000 QTRAP UPLC-ESI-MS/MS system from AB Sciex in the multiple reaction monitoring (MRM) mode. Withanolide B and obakunone (IS) were monitored under positive ionization conditions. The optimized mass transition ion-pairs (m/z) for quantitation were 455.1/109.4 for withanolide B and 455.1/161.1 for obakunone. Copyright © 2018. Published by Elsevier B.V.

  14. Ocular tissue distribution and pharmacokinetic study of a small 13kDa domain antibody after intravitreal, subconjuctival and eye drop administration in rabbits.

    PubMed

    Gough, Gerald; Szapacs, Matthew; Shah, Tejash; Clements, Peter; Struble, Craig; Wilson, Robert

    2018-02-01

    Domain antibodies (dAb's) comprise the smallest functional unit of human IgG and can be targeted to a range of different soluble cytokine and receptor targets in the eye. In particular their small size may offer advantage for ocular tissue penetration and distribution. To investigate this we used a 13kDa tool molecule to undertake a preliminary short term ocular tissue distribution and pharmacokinetic study in the rabbit eye. The dAb was administered by the intravitreal or subconjunctival route or, as topical eye drops for up to five days and dAb concentrations measured in vitreous, aqueous, conjunctiva, choroid-RPE, retina, iris, sclera, and ciliary body. The observed elimination half-live of the dAb (~3 days) in vitreous showed a similar elimination rate to that of a much larger (∼50kDa) Fab fragment whilst the half-life following subconjunctival administration was ∼24 h and, after eye drop dosing the dAb was detectable in aqueous and conjunctiva. These preliminary data show that the intravitreal half-life of dAb's are similar to much larger antibody fragments, offering the potential to deliver significantly more drug to target on a molar basis with a single intravitreal injection potentially enabling dosing frequencies of once a month or less. Subconjunctival injection may provide short duration therapeutic levels of dAb to the anterior and posterior chamber whilst topical eye drop delivery of dAbs may be useful in front-of-eye disease. These data indicate that small domain antibodies may have utility in ophthalmology. Further studies are warranted. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Plasma vs heart tissue concentration in humans - literature data analysis of drugs distribution.

    PubMed

    Tylutki, Zofia; Polak, Sebastian

    2015-03-12

    Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  16. Characterization, pharmacokinetics and tissue distribution of chlorogenic acid-loaded self-microemulsifying drug delivery system.

    PubMed

    Chen, Li; Liu, Chang-Shun; Chen, Qing-Zhen; Wang, Sen; Xiong, Yong-Ai; Jing, Jing; Lv, Jia-Jia

    2017-03-30

    The purpose of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) to improve the oral bioavailability of Chlorogenic acid (CA), an important bioactive compound from Lonicerae Japonicae Flos with poor permeability. SMEDDS was prepared and characterized by self-emulsifying rate, morphological observation, droplet size determination, stability, in vitro release, in vivo bioavailability and tissue distribution experiments. Results shown that the SMEDDS of CA has a high self-emulsifying rate (>98%) in the dissolution media, and its microemulsion exhibits small droplet size (16.37nm) and good stability. In vitro release test showed a complete release of CA from SMEDDS in 480min. After oral administration in mice, significantly enhanced bioavailability of CA was achieved through SMEDDS (249.4% relative to the CA suspension). Interestingly, SMEDDS significantly changed the tissue distribution of CA and showed a better targeting property to the kidney (2.79 of the relative intake efficiency). It is suggested that SMEDDS improves the oral bioavailability of CA may mainly through increasing its absorption and slowing the metabolism of absorbed CA via changing its distribution from the liver to the kidney. In conclusion, it is indicated that SMEDDS is a promising carrier for the oral delivery of CA. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Pharmacokinetics of amikacin in serum and in tissue contiguous with pressure sores in humans with spinal cord injury.

    PubMed Central

    Segal, J L; Brunnemann, S R; Eltorai, I M

    1990-01-01

    Pressure sores are a common occurrence in immobilized patients. They increase morbidity and mortality and impede rehabilitation. Antibiotics are routinely used to assist in effecting a cure when infection is present. Nevertheless, for patients with spinal cord injuries (SCI), strategies for effective therapy with antibiotics based on measurement of concentrations in tissue and pharmacokinetic behavior in extravascular spaces do not exist. By analyzing the concentration-time profile and protein binding of amikacin in the interstitial fluid (IF) in contact with pressure sores, we found that the disposition of amikacin in the tissue contiguous with pressure sores appears to be governed by simultaneous first-order and capacity-limited pharmacokinetic behavior. Amikacin disposition in IF proceeded without a simple relationship to amikacin concentrations in serum, and the time course in IF was not accurately simulated by linear models of amikacin pharmacokinetic behavior. Total amikacin clearance estimated from a pharmacokinetic model using simultaneous first-order and nonlinear intercompartmental transfer of amikacin was not significantly different from clearance calculated by us in a prior study of amikacin pharmacokinetic behavior in patients with SCI. In patients with SCI, optimal use of amikacin in the treatment of infected pressure sores is contingent upon accurate characterization of the pharmacokinetic behavior of this aminoglycoside in serum and in the IF in contact with these lesions. Only methods which quantitate amikacin concentration and protein binding in IF and incorporate a model that can simultaneously simulate nonlinear and linear disposition processes should be relied upon to influence therapeutic decision making. PMID:2386372

  18. Pharmacokinetic evaluation of tissue distribution of pirfenidone and its metabolites for idiopathic pulmonary fibrosis therapy.

    PubMed

    Togami, Kohei; Kanehira, Yukimune; Tada, Hitoshi

    2015-05-01

    Pirfenidone is the first and only clinically used anti-fibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). It was reported previously that pirfenidone metabolites (5-hydroxypirfenidone and 5-carboxypirfenidone) also have anti-fibrotic effects. The present study evaluated the distribution of pirfenidone and its metabolites in the lung, liver and kidney tissues in rats. The time course for the different concentrations of pirfenidone, 5-hydroxypirfenidone and 5-carboxypirfenidone in the lung tissue following oral administration (30 mg/kg) to rats was lower than that in plasma, and the area under the drug concentration-time curve (AUC) ratios of lung/plasma for pirfenidone, 5-hydroxypirfenidone and 5-carboxypirfenidone were 0.52, 0.40 and 0.61, respectively. In in vitro transport experiments, the basolateral-to-apical transport of pirfenidone and its metabolites through the model of lung epithelial cell (Calu-3) monolayers was not significantly different from their apical-to-basolateral transport. In binding experiments, the binding rate of these drugs to the lung tissue was lower than that to the plasma protein. These findings suggest that the low distribution of pirfenidone and its metabolites in the lungs was based on their low affinities with lung tissue and not the transport characteristics of lung epithelial cells. On the other hand, the AUC ratios of liver/plasma for pirfenidone and 5-carboxypirfenidone were 2.3 and 6.5 and the AUC ratios of kidney/plasma were 1.5 and 20, respectively. The binding rates to the liver and kidney tissues were higher than those to the plasma protein. These results suggest that high concentrations of these drugs were found in the liver and kidney tissues. Copyright © 2014 John Wiley & Sons, Ltd.

  19. Predicting volume of distribution with decision tree-based regression methods using predicted tissue:plasma partition coefficients.

    PubMed

    Freitas, Alex A; Limbu, Kriti; Ghafourian, Taravat

    2015-01-01

    Volume of distribution is an important pharmacokinetic property that indicates the extent of a drug's distribution in the body tissues. This paper addresses the problem of how to estimate the apparent volume of distribution at steady state (Vss) of chemical compounds in the human body using decision tree-based regression methods from the area of data mining (or machine learning). Hence, the pros and cons of several different types of decision tree-based regression methods have been discussed. The regression methods predict Vss using, as predictive features, both the compounds' molecular descriptors and the compounds' tissue:plasma partition coefficients (Kt:p) - often used in physiologically-based pharmacokinetics. Therefore, this work has assessed whether the data mining-based prediction of Vss can be made more accurate by using as input not only the compounds' molecular descriptors but also (a subset of) their predicted Kt:p values. Comparison of the models that used only molecular descriptors, in particular, the Bagging decision tree (mean fold error of 2.33), with those employing predicted Kt:p values in addition to the molecular descriptors, such as the Bagging decision tree using adipose Kt:p (mean fold error of 2.29), indicated that the use of predicted Kt:p values as descriptors may be beneficial for accurate prediction of Vss using decision trees if prior feature selection is applied. Decision tree based models presented in this work have an accuracy that is reasonable and similar to the accuracy of reported Vss inter-species extrapolations in the literature. The estimation of Vss for new compounds in drug discovery will benefit from methods that are able to integrate large and varied sources of data and flexible non-linear data mining methods such as decision trees, which can produce interpretable models. Graphical AbstractDecision trees for the prediction of tissue partition coefficient and volume of distribution of drugs.

  20. Cefazolin pharmacokinetics in cats under surgical conditions.

    PubMed

    Albarellos, Gabriela A; Montoya, Laura; Passini, Sabrina M; Lupi, Martín P; Lorenzini, Paula M; Landoni, María F

    2017-10-01

    Objectives The aim of this study was to determine the plasma pharmacokinetic profile, tissue concentrations and urine elimination of cefazolin in cats under surgical conditions after a single intravenous dose of 20 mg/kg. Methods Intravenous cefazolin (20 mg/kg) was administered to nine young mixed-breed cats 30 mins before they underwent surgical procedures (ovariectomy or orchiectomy). After antibiotic administration, samples from blood, some tissues and urine were taken. Cefazolin concentrations were determined in all biological matrices and pharmacokinetic parameters were estimated. Results Initial plasma concentrations were high (C p(0) , 134.80 ± 40.54 µg/ml), with fast and moderately wide distribution (distribution half-life [t ½(d) ] 0.16 ± 0.15 h; volume of distribution at steady state [V (d[ss]) ] 0.29 ± 0.10 l/kg) and rapid elimination (body clearance [Cl B ], 0.21 ± 0.06 l/h/kg; elimination half-life [t ½ ], 1.18 ± 0.27 h; mean residence time 1.42 ± 0.36 h). Thirty to 60 mins after intravenous administration, cefazolin tissue concentrations ranged from 9.24 µg/ml (subcutaneous tissue) to 26.44 µg/ml (ovary). The tissue/plasma concentration ratio ranged from 0.18 (muscle) to 0.58 (ovary). Cefazolin urine concentrations were high with 84.2% of the administered dose being eliminated in the first 6 h postadministration. Conclusions and relevance Cefazolin plasma concentrations remained above a minimum inhibitory concentration of ⩽2 µg/ml up to 4 h in all the studied cats. This suggests that a single intravenous dose of 20 mg/kg cefazolin would be adequate for perioperative prophylactic use in cats.

  1. A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Poulin, Patrick, E-mail: patrick-poulin@videotron.ca; Ekins, Sean; Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201

    A general toxicity of basic drugs is related to phospholipidosis in tissues. Therefore, it is essential to predict the tissue distribution of basic drugs to facilitate an initial estimate of that toxicity. The objective of the present study was to further assess the original prediction method that consisted of using the binding to red blood cells measured in vitro for the unbound drug (RBCu) as a surrogate for tissue distribution, by correlating it to unbound tissue:plasma partition coefficients (Kpu) of several tissues, and finally to predict volume of distribution at steady-state (V{sub ss}) in humans under in vivo conditions. Thismore » correlation method demonstrated inaccurate predictions of V{sub ss} for particular basic drugs that did not follow the original correlation principle. Therefore, the novelty of this study is to provide clarity on the actual hypotheses to identify i) the impact of pharmacological mode of action on the generic correlation of RBCu-Kpu, ii) additional mechanisms of tissue distribution for the outlier drugs, iii) molecular features and properties that differentiate compounds as outliers in the original correlation analysis in order to facilitate its applicability domain alongside the properties already used so far, and finally iv) to present a novel and refined correlation method that is superior to what has been previously published for the prediction of human V{sub ss} of basic drugs. Applying a refined correlation method after identifying outliers would facilitate the prediction of more accurate distribution parameters as key inputs used in physiologically based pharmacokinetic (PBPK) and phospholipidosis models.« less

  2. Pharmacokinetics and brain distribution of tetrahydropalmatine and tetrahydroberberine after oral administration of DA-9701, a new botanical gastroprokinetic agent, in rats.

    PubMed

    Jung, Ji Won; Kwon, Yong Sam; Jeong, Jin Seok; Son, Miwon; Kang, Hee Eun

    2015-01-01

    DA-9701, a new botanical gastroprokinetic agent, has potential for the management of delayed gastric emptying in Parkinson's disease if it has no central anti-dopaminergic activity. Therefore, we examined the pharmacokinetics of DA-9701 components having dopamine D2 receptor antagonizing activity, tetrahydropalmatine (THP) and tetrahydroberberine (THB), following various oral doses (80-328 mg/kg) of DA-9701. The distribution of THP and THB to the brain and/or other tissues was also evaluated after single or multiple oral administrations of DA-9701. Oral administration of DA-9701 yielded dose-proportional area under the plasma concentration-time curve (AUC0-8 h) and maximum plasma concentration (Cmax) values for THP and THB, indicating linear pharmacokinetics (except for THB at the lowest dose). THP and THB's large tissue-to-plasma concentration ratios indicated considerable tissue distribution. High concentrations of THP and THB in the stomach and small intestine suggest an explanation for DA-9701's potent gastroprokinetic activity. The maximum concentrations of THP and THB in brain following multiple oral DA-9701 for 7 d (150 mg/kg/d) was observed at 30 min after the last oral DA-9701 treatment: 131±67.7 ng/g for THP and 6.97±4.03 ng/g for THB. Although both THP and THB pass through the blood-brain barrier, as indicated by brain-to-plasma concentration ratios greater than unity (approximately 2-4), oral administration of DA-9701 at the effective dose in humans is not expected to lead to sufficient brain concentrations to exert central dopamine D2 receptor antagonism.

  3. Carprofen pharmacokinetics in plasma and in control and inflamed canine tissue fluid using in vivo ultrafiltration.

    PubMed

    Messenger, K M; Wofford, J A; Papich, M G

    2016-02-01

    Measurement of unbound drug concentrations at their sites of action is necessary for accurate PK/PD modeling. The objective of this study was to determine the unbound concentration of carprofen in canine interstitial fluid (ISF) using in vivo ultrafiltration and to compare pharmacokinetic parameters of free carprofen concentrations between inflamed and control tissue sites. We hypothesized that active concentrations of carprofen would exhibit different dispositions in ISF between inflamed vs. normal tissues. Bilateral ultrafiltration probes were placed subcutaneously in six healthy Beagle dogs 12 h prior to induction of inflammation. Two milliliters of either 2% carrageenan or saline control was injected subcutaneously at each probe site, 12 h prior to intravenous carprofen (4 mg/kg) administration. Plasma and ISF samples were collected at regular intervals for 72 h, and carprofen concentrations were determined using HPLC. Prostaglandin E2 (PGE2 ) concentrations were quantified in ISF using ELISA. Unbound carprofen concentrations were higher in ISF compared with predicted unbound plasma drug concentrations. Concentrations were not significantly higher in inflamed ISF compared with control ISF. Compartmental modeling was used to generate pharmacokinetic parameter estimates, which were not significantly different between sites. Terminal half-life (T½) was longer in the ISF compared with plasma. PGE2 in ISF decreased following administration of carprofen. In vivo ultrafiltration is a reliable method to determine unbound carprofen in ISF, and that disposition of unbound drug into tissue is much higher than predicted from unbound drug concentration in plasma. However, concentrations and pharmacokinetic parameter estimates are not significantly different in inflamed vs. un-inflamed tissues. © 2015 John Wiley & Sons Ltd.

  4. Pharmacokinetics, tissue distribution and metabolism of acriflavine and proflavine in the channel catfish (Ictalurus punctatus).

    PubMed

    Plakas, S M; el Said, K R; Bencsath, F A; Musser, S M; Hayton, W L

    1998-06-01

    1. The disposition of proflavine (PRO) and acriflavine (ACR) were examined in channel catfish after intravascular (i.v.) dosing (1 mg/kg) or waterborne exposure (10 mg/l for 4 h). 2. After i.v. dosing, plasma concentration-time profiles of parent PRO and ACR were best described by two- and three-compartment pharmacokinetic models respectively. Terminal elimination half-lives of PRO and ACR in plasma were 8.7 and 11.4 h respectively. 3. In animals dosed with 14C-PRO or 14C-ACR, total drug equivalent concentrations were highest in the excretory organs and lowest in muscle, fat and plasma. In PRO-dosed animals, residues in the liver and trunk kidney were composed primarily of glucuronosyl and acetyl conjugates of PRO; residues in muscle were composed mostly (> 95%) of the parent drug. In ACR-dosed animals, the parent compound comprised > 90% of the total residues in all tissues examined. 4. PRO and ACR were poorly absorbed in catfish during waterborne exposure. At the end of a 4-h exposure, parent PRO and ACR concentrations in muscle were 0.064 and 0.020 microgram/g respectively. Levels in muscle declined below the limit of determination (0.005 microgram/g) within 1-2 weeks.

  5. On the search for new anticancer drugs 14: the plasma pharmacokinetics and tissue distribution of spin-labeled thio-TEPA (SL-O-TT).

    PubMed

    Gutierrez, P L; Cohen, B E; Sosnovsky, G; Davis, T A; Egorin, M J

    1985-01-01

    We defined the plasma and tissue concentrations and pharmacokinetics of SL-O-TT, a spin-labeled analog of thio-TEPA, in 35-44-g male Swiss Webster mice that had received spin-labeled thio-TEPA at a dosage of 10 mg/kg. Concentrations of spin-labeled thio-TEPA in ethyl acetate extracts of tissue and plasma were determined by gas-liquid chromatography and electron spin resonance spectroscopy. Plasma concentrations of spin-labeled thio-TEPA declined in a biexponential fashion that was well described by the equation: Ct = 21.5e-0.276t + 2.30e-0.026t indicating a half-life alpha of 2.5 min and a half-life beta of 26.6 min. After 2 h there was still spin-labeled thio-TE-PA in plasma, but not in tissues. In tissues, no spin-labeled thio-TEPA was detected with gas-liquid chromatography 15 min after injection, but with electron-spin resonance label was found in lung and skeletal muscle. The main metabolite of spin-labeled thio-TEPA is spin-labeled TEPA, where oxidative desulfurization is invoked as the main metabolic mechanism. Reduction of the spin label to the hydroxylamine was also observed with time.

  6. Euthanasia method for mice in rapid time-course pulmonary pharmacokinetic studies.

    PubMed

    Schoell, Adam R; Heyde, Bruce R; Weir, Dana E; Chiang, Po-Chang; Hu, Yiding; Tung, David K

    2009-09-01

    To develop a means of euthanasia to support rapid time-course pharmacokinetic studies in mice, we compared retroorbital and intravenous lateral tail vein injection of ketamine-xylazine with regard to preparation time, utility, tissue distribution, and time to onset of euthanasia. Tissue distribution and time to onset of euthanasia did not differ between administration methods. However, retroorbital injection could be performed more rapidly than intravenous injection and was considered to be a technically simple and superior alternative for mouse euthanasia. Retroorbital ketamine-xylazine, CO(2) gas, and intraperitoneal pentobarbital then were compared as euthanasia agents in a rapid time-point pharmacokinetic study. Retroorbital ketamine-xylazine was the most efficient and consistent of the 3 methods, with an average time to death of approximately 5 s after injection. In addition, euthanasia by retroorbital ketamine-xylazine enabled accurate sample collection at closely spaced time points and satisfied established criteria for acceptable euthanasia technique.

  7. Pharmacokinetics and Pharmacodynamics in Space

    NASA Technical Reports Server (NTRS)

    Putcha, Lakshmi; Cintron, Nitza M.

    1990-01-01

    The Pharmacokinetics and Pharmacodynamics Panel met on 29-30 Aug. 1988 at the Lunar and Planetary Institute in Houston, Texas to discuss pharmacokinetic and pharmacodynamic implications of space flight and make recommendations for operational and research strategies. Based on the knowledge available on the physiological changes that occur during space flight, the dependence of pharmacokinetics on physiological factors, and the therapeutic requirements for future space missions, the panel made several recommendations for research. It was suggested that using medications available with a large (wide) therapeutic window will avoid unforeseen therapeutic consequences during flight. The sequence for conducting research was outlined as follows: (1) identify ground-based simulation models (e.g., antiorthostatic bed rest) for conducting pharmacokinetic and pharmacodynamic research; (2) estimate parametric changes in these models using pharmacologic agents that have different pharmacokinetic characteristics and a narrow therapeutic index; (3) verify these findings during flight; and (4) develop and identify appropriate and effective drug delivery systems, dosage forms, and regimens. The panel recommended gaining a thorough understanding of the pharmacokinetic deviations of medications that have a narrow therapeutic index (e.g. cardiovascular drugs and sedative hypnotics) in order to ensure safe and effective treatment during flight with these agents. It was also suggested that basic information on physiological factors such as organ blood flow, protein composition and binding, tissue distribution, and metabolism by hepatic enzymes must be accumulated by conducting ground-based animal and human studies using models of weightlessness. This information will be useful to construct and identify physiologically based pharmacokinetic models that can provide valuable information on the pharmacodynamic consequences of space flight and aid in identifying appropriate therapeutic

  8. Pharmacokinetics, brain distribution, release and blood-brain barrier transport of Shunaoxin pills.

    PubMed

    Wu, Kai; Wang, Zhan-Zhang; Liu, Dan; Qi, Xian-Rong

    2014-02-12

    Shunaoxin pills, a traditional Chinese medicine (TCM) product, have been used to treat cerebrovascular diseases in China since 2005. The main active components of Shunaoxin pills are ferulic acid and ligustilide from Chuanxiong (Ligusticum chuanxiong Hort, Umbelliferae) and Danggui (Angelica sinensis radix, Umbelliferae). As Shunaoxin shows excellent activity in the central nervous system (CNS), the extent to which the major constituents of Shunaoxin reach the CNS should be investigated. Moreover, the in vivo-in vitro correlations (IVIVC) of the formulation should be studied to elucidate the mechanisms of action of TCM in the CNS. However, these data have not previously been available. Thus we intended to investigate what the extent when these constituents of Shunaoxin pills reach the CNS, and evaluate the IVIVC of release and pharmacokinetics. In this study, we evaluated the release of ferulic acid and ligustilide from Shunaoxin pills, and their transport across an in vitro model of the BBB. We also evaluated their pharmacokinetics and brain distribution in vivo. High-performance liquid chromatography (HPLC) was used to quantify both compounds simultaneously. Based on the release in vitro and absorption of ferulic acid and ligustilide in vivo, IVIVC permitted prediction of the pharmacokinetics of these compounds. The release of ferulic acid and ligustilide reached a platform phase within 1h. Ferulic acid and ligustilide rapidly crossed the BBB in different patterns; the transport ratio increased over time. After intragastric (i.g.) administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed into brain, which may result in a rapid onset of action. Ferulic acid and ligustilide were transported across a model BBB. After i.g. administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed in brain; this may lead to rapid pharmacological onset. The IVIVC can be used to predict in vivo

  9. Euthanasia Method for Mice in Rapid Time-Course Pulmonary Pharmacokinetic Studies

    PubMed Central

    Schoell, Adam R; Heyde, Bruce R; Weir, Dana E; Chiang, Po-Chang; Hu, Yiding; Tung, David K

    2009-01-01

    To develop a means of euthanasia to support rapid time-course pharmacokinetic studies in mice, we compared retroorbital and intravenous lateral tail vein injection of ketamine–xylazine with regard to preparation time, utility, tissue distribution, and time to onset of euthanasia. Tissue distribution and time to onset of euthanasia did not differ between administration methods. However, retroorbital injection could be performed more rapidly than intravenous injection and was considered to be a technically simple and superior alternative for mouse euthanasia. Retroorbital ketamine–xylazine, CO2 gas, and intraperitoneal pentobarbital then were compared as euthanasia agents in a rapid time-point pharmacokinetic study. Retroorbital ketamine–xylazine was the most efficient and consistent of the 3 methods, with an average time to death of approximately 5 s after injection. In addition, euthanasia by retroorbital ketamine–xylazine enabled accurate sample collection at closely spaced time points and satisfied established criteria for acceptable euthanasia technique. PMID:19807971

  10. Integrating Dynamic Positron Emission Tomography and Conventional Pharmacokinetic Studies to Delineate Plasma and Tumor Pharmacokinetics of FAU, a Prodrug Bioactivated by Thymidylate Synthase.

    PubMed

    Li, Jing; Kim, Seongho; Shields, Anthony F; Douglas, Kirk A; McHugh, Christopher I; Lawhorn-Crews, Jawana M; Wu, Jianmei; Mangner, Thomas J; LoRusso, Patricia M

    2016-11-01

    FAU, a pyrimidine nucleotide analogue, is a prodrug bioactivated by intracellular thymidylate synthase to form FMAU, which is incorporated into DNA, causing cell death. This study presents a model-based approach to integrating dynamic positron emission tomography (PET) and conventional plasma pharmacokinetic studies to characterize the plasma and tissue pharmacokinetics of FAU and FMAU. Twelve cancer patients were enrolled into a phase 1 study, where conventional plasma pharmacokinetic evaluation of therapeutic FAU (50-1600 mg/m 2 ) and dynamic PET assessment of 18 F-FAU were performed. A parent-metabolite population pharmacokinetic model was developed to simultaneously fit PET-derived tissue data and conventional plasma pharmacokinetic data. The developed model enabled separation of PET-derived total tissue concentrations into the parent drug and metabolite components. The model provides quantitative, mechanistic insights into the bioactivation of FAU and retention of FMAU in normal and tumor tissues and has potential utility to predict tumor responsiveness to FAU treatment. © 2016, The American College of Clinical Pharmacology.

  11. Absorption, distribution and excretion of the anti-tuberculosis drug delamanid in rats: Extensive tissue distribution suggests potential therapeutic value for extrapulmonary tuberculosis.

    PubMed

    Shibata, Masakazu; Shimokawa, Yoshihiko; Sasahara, Katsunori; Yoda, Noriaki; Sasabe, Hiroyuki; Suzuki, Mitsunari; Umehara, Ken

    2017-05-01

    Delamanid (OPC-67683, Deltyba™, nitro-dihydro-imidazooxazoles derivative) is approved for the treatment of adult pulmonary multidrug-resistant tuberculosis. The absorption, distribution and excretion of delamanid-derived radioactivity were investigated after a single oral administration of 14 C-delamanid at 3 mg/kg to rats. In both male and female rats, radioactivity in blood and all tissues reached peak levels by 8 or 24 h post-dose, and thereafter decreased slowly. Radioactivity levels were 3- to 5-fold higher in lung tissue at time to maximum concentration compared with plasma. In addition, radioactivity was broadly distributed in various tissues, including the central nervous system, eyeball, placenta and fetus, indicating that 14 C-delamanid permeated the brain, retinal and placental blood barriers. By 168 h post-dose, radioactivity in almost all the tissues was higher than that in the plasma. Radioactivity was also transferred into the milk of lactating rats. Approximately 6% and 92% of radioactivity was excreted in the urine and feces, respectively, indicating that the absorbed radioactivity was primarily excreted via the biliary route. No significant differences in the absorption, distribution and excretion of 14 C-delamanid were observed between male and female rats. The pharmacokinetic results suggested that delamanid was broadly distributed to the lungs and various tissues for a prolonged duration of time at concentrations expected to effectively target tuberculosis bacteria. These data indicate that delamanid, in addition to its previously demonstrated efficacy in pulmonary tuberculosis, might be an effective therapeutic approach to treating extrapulmonary tuberculosis. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  12. Tissue Distribution of Enrofloxacin in African Clawed Frogs (Xenopus laevis) after Intramuscular and Subcutaneous Administration

    PubMed Central

    Felt, Stephen; Papich, Mark G; Howard, Antwain; Long, Tyler; McKeon, Gabriel; Torreilles, Stéphanie; Green, Sherril

    2013-01-01

    As part of an enrofloxacin pharmacokinetic study, concentrations of enrofloxacin and ciprofloxacin (metabolite) were measured in various tissues (brain, heart, kidney, liver, lung, and spleen) collected from treated (subcutaneous delivery, n = 3; intramuscular delivery, n = 3; untreated controls, n = 2) adult female Xenopus laevis by using HPLC. Enrofloxacin was rapidly absorbed after administration by either route and readily diffused into all sampled tissues. Enrofloxacin and ciprofloxacin were present in the tissue samples collected at 8 h. The highest average tissue concentrations for enrofloxacin were found in kidney, with the lowest concentrations in liver. Ciprofloxacin tissue concentrations paralleled but were always lower than those of enrofloxacin for all time points and tissues except brain and kidney. These results, together with previously published pharmacokinetic data and known minimal inhibitory concentrations of common pathogenic bacteria, provide a strong evidence-based rationale for choosing enrofloxacin to treat infectious diseases in X. laevis. PMID:23562103

  13. Tissue distribution of enrofloxacin in African clawed frogs (Xenopus laevis) after intramuscular and subcutaneous administration.

    PubMed

    Felt, Stephen; Papich, Mark G; Howard, Antwain; Long, Tyler; McKeon, Gabriel; Torreilles, Stéphanie; Green, Sherril

    2013-03-01

    As part of an enrofloxacin pharmacokinetic study, concentrations of enrofloxacin and ciprofloxacin (metabolite) were measured in various tissues (brain, heart, kidney, liver, lung, and spleen) collected from treated (subcutaneous delivery, n = 3; intramuscular delivery, n = 3; untreated controls, n = 2) adult female Xenopus laevis by using HPLC. Enrofloxacin was rapidly absorbed after administration by either route and readily diffused into all sampled tissues. Enrofloxacin and ciprofloxacin were present in the tissue samples collected at 8 h. The highest average tissue concentrations for enrofloxacin were found in kidney, with the lowest concentrations in liver. Ciprofloxacin tissue concentrations paralleled but were always lower than those of enrofloxacin for all time points and tissues except brain and kidney. These results, together with previously published pharmacokinetic data and known minimal inhibitory concentrations of common pathogenic bacteria, provide a strong evidence-based rationale for choosing enrofloxacin to treat infectious diseases in X. laevis.

  14. Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

    PubMed Central

    Hosseini-Yeganeh, Mahboubeh; McLachlan, Andrew J.

    2002-01-01

    The aim of this study was to develop a physiologically based pharmacokinetic (PB-PK) model capable of describing and predicting terbinafine concentrations in plasma and tissues in rats and humans. A PB-PK model consisting of 12 tissue and 2 blood compartments was developed using concentration-time data for tissues from rats (n = 33) after intravenous bolus administration of terbinafine (6 mg/kg of body weight). It was assumed that all tissues except skin and testis tissues were well-stirred compartments with perfusion rate limitations. The uptake of terbinafine into skin and testis tissues was described by a PB-PK model which incorporates a membrane permeability rate limitation. The concentration-time data for terbinafine in human plasma and tissues were predicted by use of a scaled-up PB-PK model, which took oral absorption into consideration. The predictions obtained from the global PB-PK model for the concentration-time profile of terbinafine in human plasma and tissues were in close agreement with the observed concentration data for rats. The scaled-up PB-PK model provided an excellent prediction of published terbinafine concentration-time data obtained after the administration of single and multiple oral doses in humans. The estimated volume of distribution at steady state (Vss) obtained from the PB-PK model agreed with the reported value of 11 liters/kg. The apparent volume of distribution of terbinafine in skin and adipose tissues accounted for 41 and 52%, respectively, of the Vss for humans, indicating that uptake into and redistribution from these tissues dominate the pharmacokinetic profile of terbinafine. The PB-PK model developed in this study was capable of accurately predicting the plasma and tissue terbinafine concentrations in both rats and humans and provides insight into the physiological factors that determine terbinafine disposition. PMID:12069977

  15. USE OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL (PBPK) FOR RATS TO STUDY THE INFLUENCE OF BODY FAT MASS AND INDUCTION OF CYP1A2 ON THE PHARMACOKINETICS OF TCDD

    EPA Science Inventory

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly lipophilic chemical which distributes into adipose tissue, especially at low doses. However, at high doses TCDD sequesters in liver because it induces CYP1A2 that binds TCDD. A physiologically based pharmacokinetic (PBPK) mod...

  16. Interrogating the relationship between rat in vivo tissue distribution and drug property data for >200 structurally unrelated molecules

    PubMed Central

    Harrell, Andrew W; Sychterz, Caroline; Ho, May Y; Weber, Andrew; Valko, Klara; Negash, Kitaw

    2015-01-01

    The ability to explain distribution patterns from drug physicochemical properties and binding characteristics has been explored for more than 200 compounds by interrogating data from quantitative whole body autoradiography studies (QWBA). These in vivo outcomes have been compared to in silico and in vitro drug property data to determine the most influential properties governing drug distribution. Consistent with current knowledge, in vivo distribution was most influenced by ionization state and lipophilicity which in turn affected phospholipid and plasma protein binding. Basic and neutral molecules were generally better distributed than acidic counterparts demonstrating weaker plasma protein and stronger phospholipid binding. The influence of phospholipid binding was particularly evident in tissues with high phospholipid content like spleen and lung. Conversely, poorer distribution of acidic drugs was associated with stronger plasma protein and weaker phospholipid binding. The distribution of a proportion of acidic drugs was enhanced, however, in tissues known to express anionic uptake transporters such as the liver and kidney. Greatest distribution was observed into melanin containing tissues of the eye, most likely due to melanin binding. Basic molecules were consistently better distributed into parts of the eye and skin containing melanin than those without. The data, therefore, suggest that drug binding to macromolecules strongly influences the distribution of total drug for a large proportion of molecules in most tissues. Reducing lipophilicity, a strategy often used in discovery to optimize pharmacokinetic properties such as absorption and clearance, also decreased the influence of nonspecific binding on drug distribution. PMID:26516585

  17. Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats.

    PubMed

    Lu, Ying-Yuan; Wang, Xiao-Wei; Wang, Xin; Dai, Wen-Bing; Zhang, Qiang; Li, Pu; Lou, Ya-Qing; Lu, Chuang; Liu, Jun-Yi; Zhang, Guo-Liang

    2016-07-01

    The purpose of this study was to characterize the disposition, distribution, excretion and plasma protein binding of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) in rats. Concentrations of W-1 within biological samples were determined using a validated high performance liquid chromatography method. The plasma protein binding of W-1 was examined by equilibrium dialysis method. After oral administration of W-1 (50, 100 and 200 mg/kg, respectively) in self-microemulsifying drug delivery system formulation, the pharmacokinetic parameters of W-1 were as follows: the peak plasma concentrations (C max) were 0.42, 1.50 and 2.55 μg/mL, the area under the curve (AUC0-t) were 0.89, 2.27 and 3.96 µg/h mL and the plasma half-life (t 1/2) were 5.15, 3.77 and 3.77 h, respectively. Moreover, the prototype of W-1 was rapidly and extensively distributed into fifteen tissues, especially higher concentrations were detected in intestine, stomach and liver, respectively. The plasma protein binding of W-1 in rat, beagle dog and human were in the range of 97.96-99.13 %. This study suggested that W-1 has an appropriate pharmacokinetics in rats, such as rapid absorption, moderate clearance, and rapid distribution to multiple tissues. Those properties provide important information for further development W-1 as an anti-HIV-1 drug candidate.

  18. Interspecies Mixed-Effect Pharmacokinetic Modeling of Penicillin G in Cattle and Swine

    PubMed Central

    Li, Mengjie; Gehring, Ronette; Tell, Lisa; Baynes, Ronald; Huang, Qingbiao

    2014-01-01

    Extralabel drug use of penicillin G in food-producing animals may cause an excess of residues in tissue which will have the potential to damage human health. Of all the antibiotics, penicillin G may have the greatest potential for producing allergic responses to the consumer of food animal products. There are, however, no population pharmacokinetic studies of penicillin G for food animals. The objective of this study was to develop a population pharmacokinetic model to describe the time-concentration data profile of penicillin G across two species. Data were collected from previously published pharmacokinetic studies in which several formulations of penicillin G were administered to diverse populations of cattle and swine. Liver, kidney, and muscle residue data were also used in this study. Compartmental models with first-order absorption and elimination were fit to plasma and tissue concentrations using a nonlinear mixed-effect modeling approach. A 3-compartment model with extra tissue compartments was selected to describe the pharmacokinetics of penicillin G. Typical population parameter estimates (interindividual variability) were central volumes of distribution of 3.45 liters (12%) and 3.05 liters (8.8%) and central clearance of 105 liters/h (32%) and 16.9 liters/h (14%) for cattle and swine, respectively, with peripheral clearance of 24.8 liters/h (13%) and 9.65 liters/h (23%) for cattle and 13.7 liters/h (85%) and 0.52 liters/h (40%) for swine. Body weight and age were the covariates in the final pharmacokinetic models. This study established a robust model of penicillin for a large and diverse population of food-producing animals which could be applied to other antibiotics and species in future analyses. PMID:24867969

  19. Pharmacokinetics of Exosomes-An Important Factor for Elucidating the Biological Roles of Exosomes and for the Development of Exosome-Based Therapeutics.

    PubMed

    Morishita, Masaki; Takahashi, Yuki; Nishikawa, Makiya; Takakura, Yoshinobu

    2017-09-01

    Exosomes are small membrane vesicles containing lipids, proteins, and nucleic acids. Recently, researchers have uncovered that exosomes are involved in various biological events, such as tumor growth, metastasis, and the immune response, by delivering their cargos to exosome-receiving cells. Moreover, exosomes are expected to be used in therapeutic treatments, such as tissue regeneration therapy and antitumor immunotherapy, because exosomes are effective delivery vehicles for proteins, nucleic acids, and other bioactive compounds. To elucidate the biological functions of exosomes, and for the development of exosome-based therapeutics, the pharmacokinetics of exosomes is important. In this review, we aim to summarize current knowledge about the pharmacokinetics and biodistribution of exosomes. The pharmacokinetics of exogenously administered exosomes is discussed based on the tissue distribution, types of cells taking up exosomes, and key molecules in the pharmacokinetics of exosomes. In addition, recent progress in the methods to control the pharmacokinetics of exosomes is reviewed. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  20. A paradigm shift in pharmacokinetic-pharmacodynamic (PKPD) modeling: rule of thumb for estimating free drug level in tissue compared with plasma to guide drug design.

    PubMed

    Poulin, Patrick

    2015-07-01

    fraction in plasma derived from a static in vitro environment might be biased to guide drug design (the old paradigm), and, hence, it is recommended to use a PBPK model to reproduce more accurately the in vivo condition in tissue (the new paradigm). This newly developed approach can be used to predict free drug concentration in diverse tissue compartments for small molecules in toxicology and pharmacology studies, which can be leveraged to optimize the pharmacokinetics drivers of tissue distribution based upon physicochemical and physiological input parameters in an attempt to optimize free drug level in tissue. Overall, this present study provides guidance on the application of plasma and tissue concentration information in PBPK/PD research in preclinical and clinical studies, which is in accordance with the recent literature. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  1. PRECLINICAL PHARMACOKINETIC ANALYSIS OF (E)-METHYL-4-ARYL-4-OXABUT-2-ENOATE, A NOVEL SER/THR PROTEIN KINASE B INIBITOR, IN RATS.

    PubMed

    Zhai, Qian-Qian; Pang, Jing; Li, Guo-Qing; Li, Cong-Ran; Wang, Yu-Cheng; Yu, Li-Yan; Li, Jian; YOUm, Xue-Fu

    2017-01-01

    (E)-Methyl-4-aryl-4-oxabut-2-enoate, designated YH-8, is a novel Serflhr protein kinase B (PknB) inhibitor, which is designed for the treatment of tuberculosis. The aim of this study was to investigate the pharmacokinetics, bioavailability, tissue distribution and excretion characteristics of YH-8 in rats and study its plasma protein binding in vitro. The pharmacokinetic properties were examined after intravenously injected YH-8 at 10 and 20 mg/kg and oral administrated YH-8 at 50, 100 and 200 mg/kg to rats. The concentrations of YH-8 in plasma were determined with LC-MS/MS, with a liquid-liquid extraction. The tissue distribution and urinary, fecal and -biliary excretion patterns of YH-8 were investigated following a single oral dosing of 100 mg/kg. The plasma protein binding rates of YH-8 were determined using ultra-filtration method. After intra- venous and oral administration, YH-8 showed dose-independent pharmacokinetic characteristics, with T(1/2) of approximately 5.5 h and 7.1 h, respectively. The oral absolute bioavailability of YH-8 was relatively low (about 12%). YH-8 was widely distributed in various tissues and showed substantial deposition in intestine, stomach, liver, lung and kidney. The drug was mainly eliminated via fecal excretion and its binding rate with plasma protein was concentration-dependent. In conclusion, this study as first provided the full pharmacokinetic characteristics of YH-8, which would be helpful for its further development and clinical application.

  2. Simultaneous confocal fluorescence microscopy and optical coherence tomography for drug distribution and tissue integrity assessment

    NASA Astrophysics Data System (ADS)

    Rinehart, Matthew T.; LaCroix, Jeffrey; Henderson, Marcus; Katz, David; Wax, Adam

    2011-03-01

    The effectiveness of microbicidal gels, topical products developed to prevent infection by sexually transmitted diseases including HIV/AIDS, is governed by extent of gel coverage, pharmacokinetics of active pharmaceutical ingredients (APIs), and integrity of vaginal epithelium. While biopsies provide localized information about drug delivery and tissue structure, in vivo measurements are preferable in providing objective data on API and gel coating distribution as well as tissue integrity. We are developing a system combining confocal fluorescence microscopy with optical coherence tomography (OCT) to simultaneously measure local concentrations and diffusion coefficients of APIs during transport from microbicidal gels into tissue, while assessing tissue integrity. The confocal module acquires 2-D images of fluorescent APIs multiple times per second allowing analysis of lateral diffusion kinetics. The custom Fourier domain OCT module has a maximum a-scan rate of 54 kHz and provides depth-resolved tissue integrity information coregistered with the confocal fluorescence measurements. The combined system is validated by imaging phantoms with a surrogate fluorophore. Time-resolved API concentration measured at fixed depths is analyzed for diffusion kinetics. This multimodal system will eventually be implemented in vivo for objective evaluation of microbicide product performance.

  3. Pharmacokinetics in pregnancy; clinical significance.

    PubMed

    Koren, Gideon

    2011-01-01

    In pharmacokinetics drug absorption, distribution, clearance, and bioequivalence are usually considered, but during pregnancy the most important variable is adherence or compliance. Pharmacokinetic changes during pregnancy that may lead to changes in maternal drug use are described through presentation of cases highlighting the relevance of these changes. Non-invasive methods of pharmacokinetic analysis, such as determining concentrations of drug in hair, are now being tested and used.Pharmacokinetics are important, but one needs to consider the entire pregnant state and its circumstances when treating women. One treats people, not a "volume of distribution" or a drug level. Therapy should be individualized as much as possible, addressing kinetic changes in the context of dynamic alterations and the effects of underlying medical conditions. To ensure that women are not orphaned from advances in drug therapy, much more research is needed into the determinants of pharmacokinetic and pharmacodynamic changes in pregnancy.

  4. Pharmacokinetics and distribution of SN 28049, a novel DNA binding anticancer agent, in mice.

    PubMed

    Lukka, Pradeep B; Paxton, James W; Kestell, Philip; Baguley, Bruce C

    2010-05-01

    N-[2-(Dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide (SN 28049) is a potent DNA binding topoisomerase II poison that shows excellent antitumour activity in a colon-38 murine tumour model in comparison to standard topoisomerase II poisons. We report here the preclinical pharmacokinetics of SN 28049. C57 Bl/6 mice (n = 3 per time point) were treated with a single i.v., i.p. or p.o. administration (8.9 mg/kg). Plasma and tissue samples were analysed using a validated LC/MS method utilizing a homologue as an internal standard. The assay range was 0.062-2.5 microM with a quantitation limit of 0.062 microM and a detection limit of 0.025 microM. Acceptable intra- and inter-assay accuracy (95-105%) and precision (<6.5% RSD) were achieved. Following i.v. administration, SN 28049 demonstrated 2-compartment model kinetics with a volume of distribution of 42.3 +/- 4.1 l/kg, a plasma clearance of 12.1 +/- 0.5 l/h per kg and distribution and elimination half-lives of 0.15 +/- 0.02 and 2.8 +/- 0.2 h (mean +/- SE), respectively. For all administration routes, SN 28049 concentrations in normal tissues (brain, heart, liver, lung, and kidney) were 12- to 120-fold higher than those in plasma, but half-lives and mean residence times were similar. The i.p. and p.o. bioavailabilities were 83.1 +/- 1.5 and 54.5 +/- 1.1%, respectively. In the tumour tissue, elimination half-life (9.1 +/- 0.7 h) and the mean residence time (18.2 +/- 0.7 h) were significantly (P < 0.001) longer than those of plasma and normal tissues. The tumour area under the concentration-time curve (AUC) (1,316 +/- 66 microM h) was also 693-fold greater than the plasma AUC, and considerably higher (approximately 5-fold) than any other tissue examined, indicating selective uptake and retention of SN 28049 in the tumour. We conclude that SN 28049's high tumour exposure and long tumour retention time is likely to contribute to its high antitumour activity in vivo.

  5. A stochastic whole-body physiologically based pharmacokinetic model to assess the impact of inter-individual variability on tissue dosimetry over the human lifespan.

    PubMed

    Beaudouin, Rémy; Micallef, Sandrine; Brochot, Céline

    2010-06-01

    Physiologically based pharmacokinetic (PBPK) models have proven to be successful in integrating and evaluating the influence of age- or gender-dependent changes with respect to the pharmacokinetics of xenobiotics throughout entire lifetimes. Nevertheless, for an effective application of toxicokinetic modelling to chemical risk assessment, a PBPK model has to be detailed enough to include all the multiple tissues that could be targeted by the various xenobiotics present in the environment. For this reason, we developed a PBPK model based on a detailed compartmentalization of the human body and parameterized with new relationships describing the time evolution of physiological and anatomical parameters. To take into account the impact of human variability on the predicted toxicokinetics, we defined probability distributions for key parameters related to the xenobiotics absorption, distribution, metabolism and excretion. The model predictability was evaluated by a direct comparison between computational predictions and experimental data for the internal concentrations of two chemicals (1,3-butadiene and 2,3,7,8-tetrachlorodibenzo-p-dioxin). A good agreement between predictions and observed data was achieved for different scenarios of exposure (e.g., acute or chronic exposure and different populations). Our results support that the general stochastic PBPK model can be a valuable computational support in the area of chemical risk analysis. (c)2010 Elsevier Inc. All rights reserved.

  6. Pharmacokinetic studies of a novel trioxane antimalarial (99/411) in rats and monkeys using LC-MS/MS.

    PubMed

    Pandey, Saurabh; Gautam, Nagsen; Kushwaha, Hari Narayan; Singh, Shio Kumar

    2016-12-01

    The pharmacokinetic profile of 99/411, a novel anti-malarial drug, was established in rats (12 mg/kg of body weight) and monkeys (20 mg/kg of body weight). Following oral administration, the presence of 99/411 was rapidly determined in rat plasma, tissues, urine, feces and monkey plasma using a validated LC-MS/MS method. The tissue distribution studies in rats indicated that the drug was partially distributed in all major tissues and plasma, and peak concentration levels were achieved within 0.5-4 h. Area under the curve in different rat tissues and plasma was found in order of blood > lung > intestine > heart > muscle > brain > kidney > spleen > liver. The total recoveries (within 86 h) of 99/411 were <0.0017% and <0.08% in urine and feces, respectively. The peak plasma concentration was 3499 ng/mL in rats after ~2 h of oral administration and 697-767 ng/mL in monkeys after ~6 h of oral administration. No plasma accumulation was observed in both male and female monkeys, even after multiple dosing. The preclinical pharmacokinetic profile and tissue distribution data are expected to assist in future clinical explorations of 99/411 as a promising anti-malarial agent. Copyright © 2016 John Wiley & Sons, Ltd.

  7. [Experimental study of the basic pharmacokinetic characteristics of dipeptide carnosine and its efficiency of penetration into brain tissues].

    PubMed

    Sariev, A K; Abaimov, D A; Tankevich, M V; Pantyukhova, E Yu; Prokhorov, D I; Fedorova, T N; Lopachev, A V; Stvolinskii, S L; Konovalova, E V; Seifulla, R D

    2015-01-01

    We have used an original chromatography/mass spectrometry technique to study the pharmacokinetics of dipeptide carnosine in C57 Black/6 mice after intra-peritoneal administration of the drug at a dose of 1 g/kg. The basic pharmacokinetic characteristics of carnosine were measured the in the blood and brain. The obtained concentration-time curve has a biexponential character. It is shown that the maximum concentration of carnosine in the blood plasma is Cmax = 1081.75 ± 124.24 μg/mL and it is achieved in a time interval of Tmax = 0.25 h. We showed that i.p. administration of exogenous carnosine could significantly increase the concentration of that substance in the brain. Tissue availability of dipeptide carnosine for brain tissue is relatively good and constitutes 59% from the total amount of blood carnosine. It was found that the maximum concentration of carnosine in the brain occurs at the sixth hour after i.p. administration when the concentration of drug in the blood is minimal.

  8. UNCERTAINTIES IN TRICHLOROETHYLENE PHARMACOKINETIC MODELS

    EPA Science Inventory

    Understanding the pharmacokinetics of a chemical¯its absorption, distribution, metabolism, and excretion in humans and laboratory animals ¯ is critical to the assessment of its human health risks. For trichloroethylene (TCE), numerous physiologically-based pharmacokinetic (PBPK)...

  9. GSK1265744 pharmacokinetics in plasma and tissue after single-dose long-acting injectable administration in healthy subjects.

    PubMed

    Spreen, William; Ford, Susan L; Chen, Shuguang; Wilfret, David; Margolis, David; Gould, Elizabeth; Piscitelli, Stephen

    2014-12-15

    GSK1265744 (744) is an HIV-1 integrase inhibitor in clinical development as a long-acting (LA) injectable formulation. This study evaluated plasma and tissue pharmacokinetics after single-dose administration of 744 LA administered by intramuscular (IM) or subcutaneous injections. This was a phase I, open-label, 9-cohort, parallel study of 744 in healthy subjects. 744 was administered as a 200 mg/mL nanosuspension at doses of 100-800 mg IM and 100-400 mg subcutaneous. Eight (6 active and 2 placebo) male and female subjects participated in each of the first 7 cohorts. All 8 subjects, 4 males and 4 females, received active 744 LA in cohorts 8 and 9 and underwent rectal and cervicovaginal tissue sampling, respectively. Plasma pharmacokinetic sampling was performed for a minimum of 12 weeks or until 744 concentrations were ≤0.1 μg/mL. Rectal and cervicovaginal tissue biopsies were performed at weeks 2 and 8 (cohort 8) and weeks 4 and 12 (cohort 9). 744 LA was generally safe and well tolerated after single injections. A majority of subjects reported injection site reactions, all graded as mild in intensity. Plasma concentration-time profiles were prolonged with measureable concentrations up to 52 weeks after dosing. 744 LA 800 mg IM achieved mean concentrations above protein adjusted-IC90 for approximately 16 weeks. Rectal and cervicovaginal tissue concentrations ranged from <8% to 28% of corresponding plasma concentrations. These data suggest 744 LA injection has potential application as a monthly or less frequent HIV treatment or prevention agent.

  10. Pharmacokinetics of Drugs in Cachectic Patients: A Systematic Review

    PubMed Central

    Trobec, Katja; Kerec Kos, Mojca; von Haehling, Stephan; Springer, Jochen; Anker, Stefan D.; Lainscak, Mitja

    2013-01-01

    Cachexia is a weight-loss process caused by an underlying chronic disease such as cancer, chronic heart failure, chronic obstructive pulmonary disease, or rheumatoid arthritis. It leads to changes in body structure and function that may influence the pharmacokinetics of drugs. Changes in gut function and decreased subcutaneous tissue may influence the absorption of orally and transdermally applied drugs. Altered body composition and plasma protein concentration may affect drug distribution. Changes in the expression and function of metabolic enzymes could influence the metabolism of drugs, and their renal excretion could be affected by possible reduction in kidney function. Because no general guidelines exist for drug dose adjustments in cachectic patients, we conducted a systematic search to identify articles that investigated the pharmacokinetics of drugs in cachectic patients. PMID:24282510

  11. Simultaneous determination of aditoprim and its three major metabolites in pigs, broilers and carp tissues, and its application in tissue distribution and depletion studies.

    PubMed

    Wang, Liye; Huang, Lingli; Pan, Yuanhu; Wu, Qinghua; Xie, Shuyu; Yuan, Zonghui

    2016-08-01

    Aditoprim (ADP) is a recently developed dihydrofolate reductase inhibitor that has shown promise for therapeutic use in veterinary medicine because of its excellent pharmacokinetic properties. In this study, a sensitive and reliable multi-residue chromatography-ultraviolet (HPLC-UV) method for the quantitative analysis of ADP and its three major metabolites was developed, and the tissue distribution and depletion profiles of ADP and its major metabolites in pigs, broilers and carp were investigated. Edible and additional tissues (heart, lung, stomach, intestine and swim bladder) were collected for analysis at six different withdrawal periods after ADP administration for 7 days. ADP, N-monomethyl-ADP and N-didesmethyl-ADP were detected in almost all tissues in the three species. The liver, kidney and lung showed higher residue concentrations, and the liver showed a longer residue half-life (t1/2) than other tissues. In the liver, ADP was the most abundant component with the longest persistence. The results suggest that the liver was the residual target tissue and ADP was the marker residue, and the conclusive withdrawal time (WDT) of 20 days in pigs, 16 days in broilers and 25 days in carp was estimated using the assessment methodologies approved by the Joint FAO/WHO Expert Committee on Food Additives (JECFA).

  12. Marqibo® (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine.

    PubMed

    Silverman, Jeffrey A; Deitcher, Steven R

    2013-03-01

    Vincristine (VCR) is a mainstay of treatment of hematologic malignancies and solid tumors due to its well-defined mechanism of action, demonstrated anticancer activity and its ability to be combined with other agents. VCR is an M-phase cell cycle-specific anticancer drug with activity that is concentration and exposure duration dependent. The pharmacokinetic profile of standard VCR is described by a bi-exponential elimination pattern with a very fast initial distribution half-life followed by a longer elimination half-life. VCR also has a large volume of distribution, suggesting diffuse distribution and tissue binding. These properties may limit optimal drug exposure and delivery to target tissues as well as clinical utility as a single agent or as an effective component of multi-agent regimens. Vincristine sulfate liposome injection (VSLI), Marqibo(®), is a sphingomyelin and cholesterol-based nanoparticle formulation of VCR that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR. VSLI was developed to increase the circulation time, optimize delivery to target tissues and facilitate dose intensification without increasing toxicity. In xenograft studies in mice, VSLI had a higher maximum tolerated dose, superior antitumor activity and delivered higher amounts of active drug to target tissues compared to standard VCR. VSLI recently received accelerated FDA approval for use in adults with advanced, relapsed and refractory Philadelphia chromosome-negative ALL and is in development for untreated adult ALL, pediatric ALL and untreated aggressive NHL. Here, we summarize the nonclinical data for VSLI that support its continued clinical development and recent approval for use in adult ALL.

  13. Assessment of veterinary drugs in plants using pharmacokinetic approaches: The absorption, distribution and elimination of tetracycline and sulfamethoxazole in ephemeral vegetables

    PubMed Central

    Chen, Hui-Ru; Rairat, Tirawat; Loh, Shih-Hurng; Wu, Yu-Chieh; Vickroy, Thomas W.

    2017-01-01

    The present study was carried out to demonstrate novel use of pharmacokinetic approaches to characterize drug behaviors/movements in the vegetables with implications to food safety. The absorption, distribution, metabolism and most importantly, the elimination of tetracycline (TC) and sulfamethoxazole (SMX) in edible plants Brassica rapa chinensis and Ipomoea aquatica grown hydroponically were demonstrated and studied using non-compartmental pharmacokinetic analysis. The results revealed drug-dependent and vegetable-dependent pharmacokinetic differences and indicated that ephemeral vegetables could have high capacity accumulating antibiotics (up to 160 μg g-1 for TC and 38 μg g-1 for SMX) within hours. TC concentration in the root (Cmax) could reach 11 times higher than that in the cultivation fluid and 3–28 times higher than the petioles/stems. Based on the volume of distribution (Vss), SMX was 3–6 times more extensively distributed than TC. Both antibiotics showed evident, albeit slow elimination phase with elimination half-lives ranging from 22 to 88 hours. For the first time drug elimination through the roots of a plant was demonstrated, and by viewing the root as a central compartment and continuous infusion without a loading dose as drug administration mode, it is possible to pharmacokinetically monitor the movement of antibiotics and their fate in the vegetables with more detailed information not previously available. Phyto-pharmacokinetic could be a new area worth developing new models for the assessment of veterinary drugs in edible plants. PMID:28797073

  14. PHARMACOKINETIC/PHARMACODYNAMIC MODELING OF PERMETHRIN IN THE RAT

    EPA Science Inventory

    A physiologically-based pharmacokinetic (PBPK) model was used to describe pharmacokinetics of permethrin and calibrated using experimental data on the concentration time-course of cis- and trans-permethrin in rat blood and brain tissues following oral administration...

  15. PET Pharmacokinetic Modelling

    NASA Astrophysics Data System (ADS)

    Müller-Schauenburg, Wolfgang; Reimold, Matthias

    Positron Emission Tomography is a well-established technique that allows imaging and quantification of tissue properties in-vivo. The goal of pharmacokinetic modelling is to estimate physiological parameters, e.g. perfusion or receptor density from the measured time course of a radiotracer. After a brief overview of clinical application of PET, we summarize the fundamentals of modelling: distribution volume, Fick's principle of local balancing, extraction and perfusion, and how to calculate equilibrium data from measurements after bolus injection. Three fundamental models are considered: (i) the 1-tissue compartment model, e.g. for regional cerebral blood flow (rCBF) with the short-lived tracer [15O]water, (ii) the 2-tissue compartment model accounting for trapping (one exponential + constant), e.g. for glucose metabolism with [18F]FDG, (iii) the reversible 2-tissue compartment model (two exponentials), e.g. for receptor binding. Arterial blood sampling is required for classical PET modelling, but can often be avoided by comparing regions with specific binding with so called reference regions with negligible specific uptake, e.g. in receptor imaging. To estimate the model parameters, non-linear least square fits are the standard. Various linearizations have been proposed for rapid parameter estimation, e.g. on a pixel-by-pixel basis, for the prize of a bias. Such linear approaches exist for all three models; e.g. the PATLAK-plot for trapping substances like FDG, and the LOGAN-plot to obtain distribution volumes for reversibly binding tracers. The description of receptor modelling is dedicated to the approaches of the subsequent lecture (chapter) of Millet, who works in the tradition of Delforge with multiple-injection investigations.

  16. Distribution and chloramphenicol in the bovine genital tract and pharmacokinetic studies of florfenicol in cattle

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bretzlaff, K.N.

    1986-01-01

    The objectives were to investigate selected aspects of the distribution of chloramphenicol (CAP) in the bovine genital tract and to conduct preliminary pharmacologic studies with florfenicol (FLO), a fluorinated analogue of thiamphenicol, in cattle. After 8 hours' continuous intravenous (IV) infusion of CAP to 7 postpartum cows, steady state plasma-to-genital tissue ratios of CAP were approximately 3. After intrauterine infusion of 20 mg CAP/kg to 3 postpartum cows, approximately 40% of the dose was absorbed into the bloodstream. Tissue concentrations were high at 8 hour postdosing in tissues lining the uterine lumen but were below desired therapeutic concentrations in themore » myometrium of 2 of the cows. Eighty cows with retained fetal membranes (RFM) were assigned to receive on the following treatments: (1) removal of membranes only; (2) removal plus CAP; (3) nonremoval; (4) nonremoval plus CAP. CAP treatment consisted of 5 g administered IU twice daily for 3 days. The majority of cows in all groups acquired endometritis, although CAP reduced the prevalence and severity of the disease. A quantitative assay for FLO in plasma was developed and validated on a high performance liquid chromatographic (HPLC) system. The pharmacokinetics of FLO determined after IV administration of 50 mg FLO/kg to 5 cows were best described by a three-compartment model. FLO was approximately 18% bound to plasma proteins as determined by equilibrium dialysis and ultrafiltration. In an in vitro system, 5, 125, or 1000 ug/ml of CAP had no effect on neutrophils from 6 cows.« less

  17. Physiologically based pharmacokinetic modeling of polyethylene glycol-coated polyacrylamide nanoparticles in rats.

    PubMed

    Li, Dingsheng; Johanson, Gunnar; Emond, Claude; Carlander, Ulrika; Philbert, Martin; Jolliet, Olivier

    2014-08-01

    Nanoparticles' health risks depend on their biodistribution in the body. Phagocytosis may greatly affect this distribution but has not yet explicitly accounted for in whole body pharmacokinetic models. Here, we present a physiologically based pharmacokinetic model that includes phagocytosis of nanoparticles to explore the biodistribution of intravenously injected polyethylene glycol-coated polyacrylamide nanoparticles in rats. The model explains 97% of the observed variation in nanoparticles amounts across organs. According to the model, phagocytizing cells quickly capture nanoparticles until their saturation and thereby constitute a major reservoir in richly perfused organs (spleen, liver, bone marrow, lungs, heart and kidneys), storing 83% of the nanoparticles found in these organs 120 h after injection. Key determinants of the nanoparticles biodistribution are the uptake capacities of phagocytizing cells in organs, the partitioning between tissue and blood, and the permeability between capillary blood and tissues. This framework can be extended to other types of nanoparticles by adapting these determinants.

  18. Pharmacokinetics and tissue behavior of enrofloxacin and its metabolite ciprofloxacin in turbot Scophthalmus maximus at two water temperatures

    NASA Astrophysics Data System (ADS)

    Liang, Junping; Li, Jian; Zhao, Fazhen; Liu, Ping; Chang, Zhiqiang

    2012-07-01

    Turbot Scophthalmus maximus, an important aquaculture species in China, currently suffers from epizootic diseases because of high density aquaculture. Enrofloxacin has been used to treat various systemic bacterial fish infections. However, studies concerning the pharmacokinetics of enrofloxacin in turbot are limited. In this study, the pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin, were investigated in the turbot following intravenous and oral administration at 10 mg enrofloxacin/kg body weight, at 16°C and 10°C water temperatures. The concentrations of enrofloxacin and ciprofloxacin in the main tissues (plasma, muscle, liver and kidney) were detected by HPLC. The results show that the plasma concentration-time data for enrofloxacin were best described as a two-compartment open model after intravenous and oral administration. Three pharmacokinetic equations were established between the concentrations and temperatures. The kinetic profile of enrofloxacin was temperature dependent. The absorption half-life of enrofloxacin was 1.99 h and 2.17 h after oral administration, whereas the elimination half-life of the drug was 98.63 h and 136.59 h at 16°C and 10°C, respectively. The peak concentration of enrofloxacin in plasma and tissues was higher at 16°C than that at 10°C, and the peak plasma concentration time in the liver was the shortest at both temperatures among those of other tissues. The plasma C max /MIC ratio varied between 11.08 and 5 540.00 at 16°C; and between 7.92 and 3 960.00 at 10°C. The AUC/MIC ratio was 467.82-280 690.00 at 16°C, and 359.48-215 690.00 at 10°C. These ratios indicate that it is possible to obtain therapeutic efficacy. Very low levels of ciprofloxacin were detected. The AUC ratios of ciprofloxacin and enrofloxacin in plasma suggest that plasma ciprofloxacin might play a minor role in enrofloxacin treatment for turbot.

  19. Population modelling to describe pharmacokinetics of amiodarone in rats: relevance of plasma protein and tissue depot binding.

    PubMed

    Campos Moreno, Eduardo; Merino Sanjuán, Matilde; Merino, Virginia; Nácher, Amparo; Martín Algarra, Rafael V; Casabó, Vicente G

    2007-02-01

    The objective of this paper was to characterize the disposition phase of AM in rats, after different high doses and modalities of i.v. administration. Three fitting programs, WINNONLIN, ADAPT II and NONMEM were employed. The two-stage fitting methods led to different results, none of which can adequately explain amiodarone's behaviour, although a great amount of data per subject is available. The non-linear mixed effect modelling approach allows satisfactory estimation of population pharmacokinetic parameters, and their respective variability. The best model to define the AM pharmacokinetic profile is a two-compartment model, with saturable and dynamic plasma protein binding and linear tissular depot dynamic binding. These results indicate that peripheral tissues act as depots, causing an important fall in AM plasma levels in the first moment after dosing. Later, the return of the drug from these depots causes a slow increase in serum concentration whenever the dose is reduced.

  20. The Local Pharmacokinetics of 3H-Ropivacaine and 14C-Lidocaine After Maxillary Infiltration Anesthesia in Rats

    PubMed Central

    Kimi, Hiromi; Yamashiro, Mikiko; Hashimoto, Shuichi

    2012-01-01

    The effects of infiltration anesthesia with ropivacaine on the dental pulp are considered to be weak. This may be partly associated with its permeation into the oral tissue. With the objective of investigating the local pharmacokinetics of ropivacaine and lidocaine following infiltration anesthesia, we injected 3H-ropivacaine or 14C-lidocaine to the palatal mucosa in rats, measured distributions of radioactivity in the maxilla, and compared the local pharmacokinetics of these agents. The animals were sacrificed at various times and the maxillas were removed. The palatal mucosa and maxillary nerve were resected, and the bone was divided into 6 portions. We measured radioactivity in each tissue and calculated the level of each local anesthetic (n  =  8). Lidocaine diffused to the surrounding tissue immediately after the injection, whereas ropivacaine tended to remain in the palatal mucosa for a longer period. Lidocaine showed a higher affinity for the maxillary bone than ropivacaine. There was a correlation between the distribution level of local anesthetics in the maxillary bone and that in the maxillary nerve. The lower-level effects of infiltration anesthesia with ropivacaine on the dental pulp may be because ropivacaine has a high affinity for soft tissue, and its transfer to bone is slight. PMID:22822994

  1. Evaluation of the pre-posterior distribution of optimized sampling times for the design of pharmacokinetic studies.

    PubMed

    Duffull, Stephen B; Graham, Gordon; Mengersen, Kerrie; Eccleston, John

    2012-01-01

    Information theoretic methods are often used to design studies that aim to learn about pharmacokinetic and linked pharmacokinetic-pharmacodynamic systems. These design techniques, such as D-optimality, provide the optimum experimental conditions. The performance of the optimum design will depend on the ability of the investigator to comply with the proposed study conditions. However, in clinical settings it is not possible to comply exactly with the optimum design and hence some degree of unplanned suboptimality occurs due to error in the execution of the study. In addition, due to the nonlinear relationship of the parameters of these models to the data, the designs are also locally dependent on an arbitrary choice of a nominal set of parameter values. A design that is robust to both study conditions and uncertainty in the nominal set of parameter values is likely to be of use clinically. We propose an adaptive design strategy to account for both execution error and uncertainty in the parameter values. In this study we investigate designs for a one-compartment first-order pharmacokinetic model. We do this in a Bayesian framework using Markov-chain Monte Carlo (MCMC) methods. We consider log-normal prior distributions on the parameters and investigate several prior distributions on the sampling times. An adaptive design was used to find the sampling window for the current sampling time conditional on the actual times of all previous samples.

  2. Enrofloxacin: pharmacokinetics and metabolism in domestic animal species.

    PubMed

    López-Cadenas, Cristina; Sierra-Vega, Matilde; García-Vieitez, Juan J; Diez-Liébana, M José; Sahagún-Prieto, Ana; Fernández-Martínez, Nélida

    2013-12-01

    Enrofloxacin is a fluorquinolone exclusively developed for use in veterinary medicine (1980). The kinetics of enrofloxacin are characterized, in general terms, by high bioavailability in most species and rapid absorption after IM, SC or oral administration. However, several studies reported that enrofloxacin showed low bioavailability after oral administration in ruminants. This drug has a broad distribution in the organism, excellent tissue penetration and long serum half-life. Also, enrofloxacin is characterized by a low host toxicity, a broad antibacterial spectrum and high bactericidal activity against major pathogenic bacteria (both Gram-positive and Gram-negative), and intracellular organisms found in diseased animals. The kinetics vary according to the route of administration, formulation, animal species, age, body condition, and physiological status, all of which contribute to differences in drug efficacy. The pharmacokinetic properties of drugs are closely related to their pharmacological efficiency, so it is important to know their behavior in each species that is used. This article reviews the pharmacokinetics of enrofloxacin in several domestic animal species.

  3. The Holy Grail of Polymer Therapeutics for Cancer Therapy: An Overview on the Pharmacokinetics and Bio Distribution.

    PubMed

    Dyawanapelly, Sathish; Junnuthula, Vijayabhaskar Reddy; Singh, AkhileshVikram

    2015-01-01

    In recent years, multifaceted clinical benefits of polymeric therapeutics have been reported. Over the past decades, cancer has been one of the leading causes of mortality in the world. Many clinically approved chemotherapeutics encounter potential challenges against deadly cancer. Moreover, safety and efficacy of anticancer agents have been limited by undesirable pharmacokinetics and biodistribution. To address these limitations, various polymer drug conjugates are being studied and developed to improve the antitumor efficacy. Among other therapeutics, polymer therapeutics are well established platforms that circumvent anticancer therapeutics from enzymatic metabolism via direct conjugation to therapeutic molecules. Interestingly, polymer therapeutics meets an unmet need of small molecules. Further clinical study showed that polymer-drug conjugation can achieve desired pharmacokinetics and biodistribution properties of several anticancer drugs. The present retrospective review mainly enlightens the most recent preclinical and clinical studies include safety, stability, pharmacokinetic behavior and distribution of polymer therapeutics.

  4. Biotransformation and tissue distribution of protopine and allocryptopine and effects of Plume Poppy Total Alkaloid on liver drug-metabolizing enzymes.

    PubMed

    Huang, Ya-Jun; Cheng, Pi; Zhang, Zhuo-Yi; Tian, Shi-Jie; Sun, Zhi-Liang; Zeng, Jian-Guo; Liu, Zhao-Ying

    2018-01-11

    In this study, the biotransformation in the plasma, urine and feces of rats following oral administration of protopine (PRO) and allocryptopine (ALL)were explored using HPLC-QqTOF MS. An HPLC-MS/MS method for the determination of tissues was developed and applied to the tissue distribution study in rats following intragastric administration of Plume Poppy Total Alkaloid for 3 weeks. A total of ten PRO metabolites and ten ALL metabolites were characterized in rats in vivo. Among these metabolites, six PRO metabolites and five ALL metabolites were reported for the first time. The predicated metabolic pathways including ring cleavage, demethylation following ring cleavage, and glucuronidation were proposed. The low-concentration residue of PRO and ALL in various tissues was detected at 24 h and 48 h after dosing, which indicated that both compounds could be widely distributed in tissues and exist as low levels of residue. The activities of erythromycin N-demethylase, aminopyrine N-demethylase and NAD (P)H quinone oxidoreductase in female rats can be induced post-dose, but these activities were inhibited in male rats. The proposed biotransformation and residues of PRO and ALL and their effects on enzymes may provide a basis for clarifying the metabolism and interpreting pharmacokinetics.

  5. A Physiologically Based Pharmacokinetic Model to Predict the Pharmacokinetics of Highly Protein-Bound Drugs and Impact of Errors in Plasma Protein Binding

    PubMed Central

    Ye, Min; Nagar, Swati; Korzekwa, Ken

    2015-01-01

    Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data was often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding, and blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for terminal elimination half-life (t1/2, 100% of drugs), peak plasma concentration (Cmax, 100%), area under the plasma concentration-time curve (AUC0–t, 95.4%), clearance (CLh, 95.4%), mean retention time (MRT, 95.4%), and steady state volume (Vss, 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. PMID:26531057

  6. Organophosphorus Insecticide Pharmacokinetics

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Timchalk, Charles

    2010-01-01

    This chapter highlights a number of current and future applications of pharmacokinetics to assess organophosphate (OP) insecticide dosimetry, biological response and risk in humans exposed to these agents. Organophosphates represent a large family of pesticides where insecticidal as well as toxicological mode of action is associated with their ability to target and inhibit acetylcholinesterase (AChE). Pharmacokinetics entails the quantitative integration of physiological and metabolic processes associated with the absorption, distribution, metabolism and excretion (ADME) of drugs and xenobiotics. Pharmacokinetic studies provide important data on the amount of toxicant delivered to a target site as well as species-, age-, gender-specific andmore » dose-dependent differences in biological response. These studies have been conducted with organophosphorus insecticides in multiple species, at various dose levels, and across different routes of exposure to understand their in vivo pharmacokinetics and how they contribute to the observed toxicological response. To access human exposure to organophosphorus insecticides, human pharmacokinetic studies have been conducted and used to develop biological monitoring strategies based on the quantitation of key metabolites in biological fluids. Pharmacokinetic studies with these insecticides are also useful to facilitate extrapolation of dosimetry and biological response from animals to humans and for the assessment of human health risk. In this regard, physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models are being utilized to assess risk and understand the toxicological implications of known or suspected exposures to various insecticides. In this chapter a number of examples are presented that illustrate the utility and limitation of pharmacokinetic studies to address human health concerns associated with organophosphorus insecticides.« less

  7. In vitro pharmacokinetics of phosphorothioate antisense oligonucleotides.

    PubMed

    Crooke, R M; Graham, M J; Cooke, M E; Crooke, S T

    1995-10-01

    ISIS 2105 (Afovirsen), a 20-mer phosphorothioate oligonucleotide that inhibits the production of a gene product essential to the growth of human papillomavirus, is in phase II clinical trials for the treatment of genital warts induced by human papillomavirus-6 and human papillomavirus-11. The uptake, subcellular distribution and metabolism of ISIS 2105 and three other similar length phosphorothioates have been studied in a variety of cell lines. Our experiments indicated that ISIS 2105 and other phosphorothioates are internalized and distributed in a time-, temperature-, concentration-, sequence- and cell line-dependent manner. Cell association was also influenced by the tissue culture medium. Several different analytical techniques revealed that phosphorothioates were more rapidly degraded in vitro than previously reported. These data suggest that phosphorothioate oligonucleotide uptake and stability observed in tissue culture can vary as a function of cellular assay conditions and analytical methods used. Comparison of these results with those obtained in vivo suggests that the pharmacokinetic behavior of this class of compounds cannot necessarily be predicted from in vitro studies.

  8. Preliminary experiments on pharmacokinetic diffuse fluorescence tomography of CT-scanning mode

    NASA Astrophysics Data System (ADS)

    Zhang, Yanqi; Wang, Xin; Yin, Guoyan; Li, Jiao; Zhou, Zhongxing; Zhao, Huijuan; Gao, Feng; Zhang, Limin

    2016-10-01

    In vivo tomographic imaging of the fluorescence pharmacokinetic parameters in tissues can provide additional specific and quantitative physiological and pathological information to that of fluorescence concentration. This modality normally requires a highly-sensitive diffuse fluorescence tomography (DFT) working in dynamic way to finally extract the pharmacokinetic parameters from the measured pharmacokinetics-associated temporally-varying boundary intensity. This paper is devoted to preliminary experimental validation of our proposed direct reconstruction scheme of instantaneous sampling based pharmacokinetic-DFT: A highly-sensitive DFT system of CT-scanning mode working with parallel four photomultiplier-tube photon-counting channels is developed to generate an instantaneous sampling dataset; A direct reconstruction scheme then extracts images of the pharmacokinetic parameters using the adaptive-EKF strategy. We design a dynamic phantom that can simulate the agent metabolism in living tissue. The results of the dynamic phantom experiments verify the validity of the experiment system and reconstruction algorithms, and demonstrate that system provides good resolution, high sensitivity and quantitativeness at different pump speed.

  9. Combined Recirculatory-compartmental Population Pharmacokinetic Modeling of Arterial and Venous Plasma S(+) and R(-) Ketamine Concentrations.

    PubMed

    Henthorn, Thomas K; Avram, Michael J; Dahan, Albert; Gustafsson, Lars L; Persson, Jan; Krejcie, Tom C; Olofsen, Erik

    2018-05-16

    The pharmacokinetics of infused drugs have been modeled without regard for recirculatory or mixing kinetics. We used a unique ketamine dataset with simultaneous arterial and venous blood sampling, during and after separate S(+) and R(-) ketamine infusions, to develop a simplified recirculatory model of arterial and venous plasma drug concentrations. S(+) or R(-) ketamine was infused over 30 min on two occasions to 10 healthy male volunteers. Frequent, simultaneous arterial and forearm venous blood samples were obtained for up to 11 h. A multicompartmental pharmacokinetic model with front-end arterial mixing and venous blood components was developed using nonlinear mixed effects analyses. A three-compartment base pharmacokinetic model with additional arterial mixing and arm venous compartments and with shared S(+)/R(-) distribution kinetics proved superior to standard compartmental modeling approaches. Total pharmacokinetic flow was estimated to be 7.59 ± 0.36 l/min (mean ± standard error of the estimate), and S(+) and R(-) elimination clearances were 1.23 ± 0.04 and 1.06 ± 0.03 l/min, respectively. The arm-tissue link rate constant was 0.18 ± 0.01 min and the fraction of arm blood flow estimated to exchange with arm tissue was 0.04 ± 0.01. Arterial drug concentrations measured during drug infusion have two kinetically distinct components: partially or lung-mixed drug and fully mixed-recirculated drug. Front-end kinetics suggest the partially mixed concentration is proportional to the ratio of infusion rate and total pharmacokinetic flow. This simplified modeling approach could lead to more generalizable models for target-controlled infusions and improved methods for analyzing pharmacokinetic-pharmacodynamic data.

  10. Randomized pharmacokinetic cross-over study comparing two curcumin preparations in plasma and rectal tissue of healthy human volunteers

    PubMed Central

    Asher, Gary N.; Xie, Ying; Moaddel, Ruin; Sanghvi, Mitesh; Dossou, Katina S.S.; Kashuba, Angela D. M.; Sandler, Robert S.; Hawke, Roy L.

    2016-01-01

    Curcumin is poorly absorbed driving interest in new preparations. However, little is known about pharmacokinetics and tissue bioavailability between formulations. In this randomized, crossover study we evaluated the relationship between steady-state plasma and rectal tissue curcuminoid concentrations using standard and phosphatidylcholine curcumin extracts. There was no difference in the geometric mean plasma AUCs when adjusted for the 10-fold difference in curcumin dose between the two formulations. Phosphatidylcholine curcumin extract yielded only 20–30% plasma demethoxycurcumin and bisdemethoxycurcumin conjugates compared to standard extract, yet yielded 20-fold greater hexahydrocurcumin. When adjusting for curcumin dose, tissue curcumin concentrations were 5-fold greater for the phosphatidylcholine extract. Improvements in curcuminoid absorption due to phosphatidylcholine are not uniform across the curcuminoids. Furthermore, curcuminoid exposures in the intestinal mucosa are most likely due to luminal exposure rather than plasma disposition. Finally, once-daily dosing is sufficient to maintain detectable curcuminoids at steady-state in both plasma and rectal tissues. PMID:27503249

  11. Issues in the Pharmacokinetics of Trichloroethylene and Its Metabolites

    PubMed Central

    Chiu, Weihsueh A.; Okino, Miles S.; Lipscomb, John C.; Evans, Marina V.

    2006-01-01

    Much progress has been made in understanding the complex pharmacokinetics of trichloroethylene (TCE). Qualitatively, it is clear that TCE is metabolized to multiple metabolites either locally or into systemic circulation. Many of these metabolites are thought to have toxicologic importance. In addition, efforts to develop physiologically based pharmacokinetic (PBPK) models have led to a better quantitative assessment of the dosimetry of TCE and several of its metabolites. As part of a mini-monograph on key issues in the health risk assessment of TCE, this article is a review of a number of the current scientific issues in TCE pharmacokinetics and recent PBPK modeling efforts with a focus on literature published since 2000. Particular attention is paid to factors affecting PBPK modeling for application to risk assessment. Recent TCE PBPK modeling efforts, coupled with methodologic advances in characterizing uncertainty and variability, suggest that rigorous application of PBPK modeling to TCE risk assessment appears feasible at least for TCE and its major oxidative metabolites trichloroacetic acid and trichloroethanol. However, a number of basic structural hypotheses such as enterohepatic recirculation, plasma binding, and flow- or diffusion-limited treatment of tissue distribution require additional evaluation and analysis. Moreover, there are a number of metabolites of potential toxicologic interest, such as chloral, dichloroacetic acid, and those derived from glutathione conjugation, for which reliable pharmacokinetic data is sparse because of analytical difficulties or low concentrations in systemic circulation. It will be a challenge to develop reliable dosimetry for such cases. PMID:16966104

  12. Randomized Pharmacokinetic Crossover Study Comparing 2 Curcumin Preparations in Plasma and Rectal Tissue of Healthy Human Volunteers.

    PubMed

    Asher, Gary N; Xie, Ying; Moaddel, Ruin; Sanghvi, Mitesh; Dossou, Katina S S; Kashuba, Angela D M; Sandler, Robert S; Hawke, Roy L

    2017-02-01

    Curcumin is poorly absorbed, which is interest in new preparations. However, little is known about variations in its pharmacokinetics and tissue bioavailability between formulations. In this randomized, crossover study we evaluated the relationship between steady-state plasma and rectal tissue curcuminoid concentrations using standard and phosphatidylcholine curcumin extracts. There was no difference in the geometric mean plasma AUCs when adjusted for the 10-fold difference in curcumin dose between the 2 formulations. Phosphatidylcholine curcumin extract yielded only 20% to 30% plasma demethoxycurcumin and bisdemethoxycurcumin conjugates compared to standard extract, yet yielded 20-fold greater hexahydrocurcumin. When adjusting for curcumin dose, tissue curcumin concentrations were 5-fold greater for the phosphatidylcholine extract. Improvements in curcuminoid absorption due to phosphatidylcholine are not uniform across the curcuminoids. Furthermore, curcuminoid exposures in the intestinal mucosa are most likely due to luminal exposure rather than to plasma disposition. Finally, once-daily dosing is sufficient to maintain detectable curcuminoids at steady state in both plasma and rectal tissues. © 2016, The American College of Clinical Pharmacology.

  13. Continuous versus short-term infusion of cefuroxime: assessment of concept based on plasma, subcutaneous tissue, and bone pharmacokinetics in an animal model.

    PubMed

    Tøttrup, Mikkel; Bibby, Bo M; Hardlei, Tore F; Bue, Mats; Kerrn-Jespersen, Sigrid; Fuursted, Kurt; Søballe, Kjeld; Birke-Sørensen, Hanne

    2015-01-01

    The relatively short half-lives of most β-lactams suggest that continuous infusion of these time-dependent antimicrobials may be favorable compared to short-term infusion. Nevertheless, only limited solid-tissue pharmacokinetic data are available to support this theory. In this study, we randomly assigned 12 pigs to receive cefuroxime as either a short-term or continuous infusion. Measurements of cefuroxime were obtained every 30 min in plasma, subcutaneous tissue, and bone. For the measurements in solid tissues, microdialysis was applied. A two-compartment population model was fitted separately to the drug concentration data for the different tissues using a nonlinear mixed-effects regression model. Estimates of the pharmacokinetic parameters and time with concentrations above the MIC were derived using Monte Carlo simulations. Except for subcutaneous tissue in the short-term infusion group, the tissue penetration was incomplete for all tissues. For short-term infusion, the tissue penetration ratios were 0.97 (95% confidence interval [CI], 0.67 to 1.39), 0.61 (95% CI, 0.51 to 0.73), and 0.45 (95% CI, 0.36 to 0.56) for subcutaneous tissue, cancellous bone, and cortical bone, respectively. For continuous infusion, they were 0.53 (95% CI, 0.33 to 0.84), 0.38 (95% CI, 0.23 to 0.57), and 0.27 (95% CI, 0.13 to 0.48) for the same tissues, respectively. The absolute areas under the concentration-time curve were also lower in the continuous infusion group. Nevertheless, a significantly longer time with concentrations above the MIC was found for continuous infusion up until MICs of 4, 2, 2, and 0.5 μg/ml for plasma and the same three tissues mentioned above, respectively. For drugs with a short half-life, like cefuroxime, continuous infusion seems to be favorable compared to short-term infusion; however, incomplete tissue penetration and high MIC strains may jeopardize the continuous infusion approach. Copyright © 2015, American Society for Microbiology. All Rights

  14. Nanodrugs: pharmacokinetics and safety

    PubMed Central

    Onoue, Satomi; Yamada, Shizuo; Chan, Hak-Kim

    2014-01-01

    To date, various nanodrug systems have been developed for different routes of administration, which include dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Nanodrug systems have been employed to improve the efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profile of pharmaceutical substances. In particular, functionalized nanodrug systems can offer enhanced bioavailability of orally taken drugs, prolonged half-life of injected drugs (by reducing immunogenicity), and targeted delivery to specific tissues. Thus, nanodrug systems might lower the frequency of administration while providing maximized pharmacological effects and minimized systemic side effects, possibly leading to better therapeutic compliance and clinical outcomes. In spite of these attractive pharmacokinetic advantages, recent attention has been drawn to the toxic potential of nanodrugs since they often exhibit in vitro and in vivo cytotoxicity, oxidative stress, inflammation, and genotoxicity. A better understanding of the pharmacokinetic and safety characteristics of nanodrugs and the limitations of each delivery option is necessary for the further development of efficacious nanodrugs with high therapeutic potential and a wide safety margin. This review highlights the recent progress in nanodrug system development, with a focus on the pharmacokinetic advantages and safety challenges. PMID:24591825

  15. Methodological issues in microdialysis sampling for pharmacokinetic studies.

    PubMed

    de Lange, E C; de Boer, A G; Breimer, D D

    2000-12-15

    Microdialysis is an in vivo technique that permits monitoring of local concentrations of drugs and metabolites at specific sites in the body. Microdialysis has several characteristics, which makes it an attractive tool for pharmacokinetic research. About a decade ago the microdialysis technique entered the field of pharmacokinetic research, in the brain, and later also in peripheral tissues and blood. Within this period much has been learned on the proper use of this technique. Today, it has outgrown its child diseases and its potentials and limitations have become more or less well defined. As microdialysis is a delicate technique for which experimental factors appear to be critical with respect to the validity of the experimental outcomes, several factors should be considered. These include the probe; the perfusion solution; post-surgery interval in relation to surgical trauma, tissue integrity and repeated experiments; the analysis of microdialysate samples; and the quantification of microdialysate data. Provided that experimental conditions are optimized to give valid and quantitative results, microdialysis can provide numerous data points from a relatively small number of individual animals to determine detailed pharmacokinetic information. An example of one of the added values of this technique compared with other in vivo pharmacokinetic techniques, is that microdialysis reflects free concentrations in tissues and plasma. This gives the opportunity to assess information on drug transport equilibration across membranes such as the blood-brain barrier, which already has provided new insights. With the progress of analytical methodology, especially with respect to low volume/low concentration measurements and simultaneous measurement of multiple compounds, the applications and importance of the microdialysis technique in pharmacokinetic research will continue to increase.

  16. Lisdexamfetamine: A pharmacokinetic review.

    PubMed

    Comiran, Eloisa; Kessler, Félix Henrique; Fröehlich, Pedro Eduardo; Limberger, Renata Pereira

    2016-06-30

    Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Intranasal melatonin nanoniosomes: pharmacokinetic, pharmacodynamics and toxicity studies.

    PubMed

    Priprem, Aroonsri; Johns, Jeffrey R; Limsitthichaikoon, Sucharat; Limphirat, Wanwisa; Mahakunakorn, Pramote; Johns, Nutjaree Prateepawanit

    2017-06-01

    Intranasal melatonin encapsulated in nanosized niosomes was preclinically evaluated. A formula of melatonin niosomes (MN) was selected through physicochemical and cytotoxic data for pharmacokinetic, pharmacodynamics and toxicity studies in male Wistar rats. Intranasal MN was bioequivalent to intravenous injection of melatonin, providing therapeutic level doses. Acute and subchronic toxicity screening showed no abnormal signs, symptoms or hematological effects in any animals. Transient nasal irritations with no inflammation were observed with intranasal MN, leading it to be categorized as relatively harmless. The intranasal MN could deliver melatonin to the brain to induce sleep and provide delayed systemic circulation, relative to intravenous injection and also distribute to peripheral tissue.

  18. EVALUATION OF ORAL AND INTRAVENOUS ROUTE PHARMACOKINETICS, PLASMA PROTEIN BINDING AND UTERINE TISSUE DOSE METRICS OF BPA: A PHYSIOLOGICALLY BASED PHARMACOKINETIC APPROACH

    EPA Science Inventory

    Bisphenol A (BPA) is a weakly estrogenic monomer used in the production of polycarbonate plastics and epoxy resins, both of which are used in food contact applications. A physiologically based pharmacokinetic (PBPK) model of BPA pharmacokinetics in rats and humans was developed t...

  19. EVALUATION OF ORAL AND INTRAVENOUS ROUTE PHARMACOKINETICS, PLASMA PROTEIN BINDING AND UTERINE TISSUE DOSE METRICS OF BPA: A PHYSIOLOGICALLY BASED PHARMACOKINETIC APPROACH

    EPA Science Inventory

    Bisphenol A (BPA) is a weakly estrogenic monomer used in the production of polycarbonate plastics and epoxy resins, both of which are used in food contact applications. A physiologically based pharmacokinetic (PBPK) model of BPA pharmacokinetics in rats and humans was developed ...

  20. A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein-bound drugs and the impact of errors in plasma protein binding.

    PubMed

    Ye, Min; Nagar, Swati; Korzekwa, Ken

    2016-04-01

    Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  1. Physiologically based pharmacokinetic model of amphotericin B disposition in rats following administration of deoxycholate formulation (Fungizone®): pooled analysis of published data.

    PubMed

    Kagan, Leonid; Gershkovich, Pavel; Wasan, Kishor M; Mager, Donald E

    2011-06-01

    The time course of tissue distribution of amphotericin B (AmB) has not been sufficiently characterized despite its therapeutic importance and an apparent disconnect between plasma pharmacokinetics and clinical outcomes. The goals of this work were to develop and evaluate a physiologically based pharmacokinetic (PBPK) model to characterize the disposition properties of AmB administered as deoxycholate formulation in healthy rats and to examine the utility of the PBPK model for interspecies scaling of AmB pharmacokinetics. AmB plasma and tissue concentration-time data, following single and multiple intravenous administration of Fungizone® to rats, from several publications were combined for construction of the model. Physiological parameters were fixed to literature values. Various structural models for single organs were evaluated, and the whole-body PBPK model included liver, spleen, kidney, lung, heart, gastrointestinal tract, plasma, and remainder compartments. The final model resulted in a good simultaneous description of both single and multiple dose data sets. Incorporation of three subcompartments for spleen and kidney tissues was required for capturing a prolonged half-life in these organs. The predictive performance of the final PBPK model was assessed by evaluating its utility in predicting pharmacokinetics of AmB in mice and humans. Clearance and permeability-surface area terms were scaled with body weight. The model demonstrated good predictions of plasma AmB concentration-time profiles for both species. This modeling framework represents an important basis that may be further utilized for characterization of formulation- and disease-related factors in AmB pharmacokinetics and pharmacodynamics.

  2. Fast and sensitive HPLC/UV method for cefazolin quantification in plasma and subcutaneous tissue microdialysate of humans and rodents applied to pharmacokinetic studies in obese individuals.

    PubMed

    Palma, Eduardo Celia; Laureano, João Victor; de Araújo, Bibiana Verlindo; Meinhardt, Nelson Guardiola; Stein, Airton Tetelbom; Dalla Costa, Teresa

    2018-04-14

    Antimicrobial prophylactic dosing of morbidly obese patients may differ from normal weighted individuals owing to alterations in drug tissue distribution. Drug subcutaneous tissue distribution can be investigated by microdialysis patients and animals. The need for cefazolin prophylactic dose adjustment in obese patients remains under discussion. The paper describes the validation of an HPLC-UV method for cefazolin quantification in plasma and microdialysate samples from clinical and pre-clinical studies. A C 18 column with an isocratic mobile phase was used for drug separation, with detection at 272 nm. Total and unbound cefazolin lower limit of quantitation was 5 μg/mL in human plasma, 2 μg/mL in rat plasma, and 0.5 and 0.025 μg/mL in human and rat microdialysate samples, respectively. The maximum intra- and inter-day imprecisions were 10.7 and 8.1%, respectively. The inaccuracy was <9.7%. The limit of quantitation imprecision and inaccuracy were < 15%. Cefazolin stability in the experimental conditions was confirmed. Cefazolin plasma concentrations and subcutaneous tissue penetration were determined by microdialysis in morbidly obese patients (2 g i.v. bolus) and diet-induced obese rats (30 mg/kg i.v. bolus) using the method. This method has the main advantages of easy plasma clean-up and practicability and has proven to be useful in cefazolin clinical and pre-clinical pharmacokinetic investigations. Copyright © 2018 John Wiley & Sons, Ltd.

  3. The potential influence of CO2, as an agent for euthanasia, on the pharmacokinetics of basic compounds in rodents.

    PubMed

    Angus, Derek W; Baker, James A; Mason, Rona; Martin, Iain J

    2008-02-01

    Rodent tissue distribution and pharmacokinetic studies were performed on basic compounds Org A and Org B in support of central nervous system drug discovery programs. A consistent observation from these studies was that drug concentrations in plasma obtained by cardiac puncture after CO(2) euthanasia were markedly higher compared with those from other sampling methods (serial sampling, isoflurane anesthesia, or cervical dislocation). Further investigations demonstrated that CO(2) euthanasia led to a reduction in blood pH in both rats and mice, which was not observed with the other sampling methods. The use of CO(2) euthanasia resulted in a decrease in the brain/plasma ratio of Org B, largely as a result of increased plasma concentrations. The pharmacokinetics of a basic drug, raloxifene, in rat were also influenced by sampling technique. CO(2) euthanasia before sampling, resulted in a 2- to 3-fold increase in the area under the drug concentration-time curve, a decrease in plasma clearance, and a decrease in the steady-state volume of distribution compared with isoflurane anesthesia. It is proposed that a decrease in the pH of blood relative to that of other tissues, as a consequence of CO(2) exposure, results in a redistribution of basic compounds out of the tissues, leading to higher concentrations in plasma.

  4. Physiologically based pharmacokinetic modeling of tea catechin mixture in rats and humans.

    PubMed

    Law, Francis C P; Yao, Meicun; Bi, Hui-Chang; Lam, Stephen

    2017-06-01

    Although green tea ( Camellia sinensis) (GT) contains a large number of polyphenolic compounds with anti-oxidative and anti-proliferative activities, little is known of the pharmacokinetics and tissue dose of tea catechins (TCs) as a chemical mixture in humans. The objectives of this study were to develop and validate a physiologically based pharmacokinetic (PBPK) model of tea catechin mixture (TCM) in rats and humans, and to predict an integrated or total concentration of TCM in the plasma of humans after consuming GT or Polyphenon E (PE). To this end, a PBPK model of epigallocatechin gallate (EGCg) consisting of 13 first-order, blood flow-limited tissue compartments was first developed in rats. The rat model was scaled up to humans by replacing its physiological parameters, pharmacokinetic parameters and tissue/blood partition coefficients (PCs) with human-specific values. Both rat and human EGCg models were then extrapolated to other TCs by substituting its physicochemical parameters, pharmacokinetic parameters, and PCs with catechin-specific values. Finally, a PBPK model of TCM was constructed by linking three rat (or human) tea catechin models together without including a description for pharmacokinetic interaction between the TCs. The mixture PBPK model accurately predicted the pharmacokinetic behaviors of three individual TCs in the plasma of rats and humans after GT or PE consumption. Model-predicted total TCM concentration in the plasma was linearly related to the dose consumed by humans. The mixture PBPK model is able to translate an external dose of TCM into internal target tissue doses for future safety assessment and dose-response analysis studies in humans. The modeling framework as described in this paper is also applicable to the bioactive chemical in other plant-based health products.

  5. A systems approach for tumor pharmacokinetics.

    PubMed

    Thurber, Greg Michael; Weissleder, Ralph

    2011-01-01

    Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design.

  6. Preparation, characterization, pharmacokinetics and tissue distribution of solid lipid nanoparticles loaded with tetrandrine.

    PubMed

    Li, Su; Ji, Zhaoshuai; Zou, Meijuan; Nie, Xin; Shi, Yijie; Cheng, Gang

    2011-09-01

    Tetrandrine (TET) is a poorly water-soluble bisbenzylisoquinoline alkaloid. In this study, TET solid lipid nanoparticles (SLNs) were prepared by a melt-emulsification and ultrasonication technique. Precirol(®) ATO 5, glyceryl monostearate, and stearic acid were used as the lipid matrix for the SLNs, while Lipoid E80, Pluronic F68, and sodium deoxycholate were used as emulsifying and stabilizing agents. The physicochemical characteristics of the TET-SLNs were investigated when it was found that the mean particle size and zeta potential of the TET-SLNs were 134 ± 1.3 nm and -53.8 ± 1.7 mV, respectively, and the entrapment efficiency (EE) was 89.57% ± 0.39%. Differential scanning calorimetry indicated that TET was in an amorphous state in SLNs. TET-SLNs exhibited a higher release rate at a lower pH and a lower release rate at a higher pH. The release pattern of the TET-SLNs followed the Weibull model. The pharmacokinetics of TET-SLNs after intravenous administration to male rats was studied. TET-SLN resulted in a higher plasma concentration and lower clearance. The biodistribution study indicated that TET-SLN showed a high uptake in reticuloendothelial system organs. In conclusion, TET-SLNs with a small particle size, and high EE, can be produced by the method described in this study. The SLN system is a promising approach for the intravenous delivery of tetrandrine.

  7. The prediction of drug metabolism, tissue distribution, and bioavailability of 50 structurally diverse compounds in rat using mechanism-based absorption, distribution, and metabolism prediction tools.

    PubMed

    De Buck, Stefan S; Sinha, Vikash K; Fenu, Luca A; Gilissen, Ron A; Mackie, Claire E; Nijsen, Marjoleen J

    2007-04-01

    The aim of this study was to assess a physiologically based modeling approach for predicting drug metabolism, tissue distribution, and bioavailability in rat for a structurally diverse set of neutral and moderate-to-strong basic compounds (n = 50). Hepatic blood clearance (CL(h)) was projected using microsomal data and shown to be well predicted, irrespective of the type of hepatic extraction model (80% within 2-fold). Best predictions of CL(h) were obtained disregarding both plasma and microsomal protein binding, whereas strong bias was seen using either blood binding only or both plasma and microsomal protein binding. Two mechanistic tissue composition-based equations were evaluated for predicting volume of distribution (V(dss)) and tissue-to-plasma partitioning (P(tp)). A first approach, which accounted for ionic interactions with acidic phospholipids, resulted in accurate predictions of V(dss) (80% within 2-fold). In contrast, a second approach, which disregarded ionic interactions, was a poor predictor of V(dss) (60% within 2-fold). The first approach also yielded accurate predictions of P(tp) in muscle, heart, and kidney (80% within 3-fold), whereas in lung, liver, and brain, predictions ranged from 47% to 62% within 3-fold. Using the second approach, P(tp) prediction accuracy in muscle, heart, and kidney was on average 70% within 3-fold, and ranged from 24% to 54% in all other tissues. Combining all methods for predicting V(dss) and CL(h) resulted in accurate predictions of the in vivo half-life (70% within 2-fold). Oral bioavailability was well predicted using CL(h) data and Gastroplus Software (80% within 2-fold). These results illustrate that physiologically based prediction tools can provide accurate predictions of rat pharmacokinetics.

  8. Effect of body temperature on the pharmacokinetics of a triarylmethyl-type paramagnetic contrast agent used in EPR oximetry.

    PubMed

    Matsumoto, Ken-Ichiro; Hyodo, Fuminori; Mitchell, James B; Krishna, Murali C

    2018-02-01

    Pharmacokinetics of the tri[8-carboxy-2,2,6,6-tetrakis(2-hydroxymethyl)benzo[1,2-d:4,5-d']bis(1,3)dithio-4-yl]methyl radical (Oxo63) after a single bolus and/or continuous intravenous infusion was investigated in tumor-bearing C3H mice with or without body temperature control while under anesthesia. The in vivo time course of Oxo63 in blood was measured using X-band electron paramagnetic resonance spectroscopy. Distribution of Oxo63 in normal muscle and tumor tissues was obtained using a surface coil resonator and a 700-MHz electron paramagnetic resonance spectrometer. The whole-body distribution of Oxo63 was obtained by 300-MHz continuous-wave electron paramagnetic resonance imaging. The high-resolution 300-MHz time-domain electron paramagnetic resonance imaging was also carried out to probe the distribution of Oxo63. Urination of mice was retarded at low body temperature, causing the concentration of Oxo63 in blood to attain high levels. However, the concentration of Oxo63 in tumor tissue was lower with no control of body temperature than active body temperature control. The nonsystemized blood flow in the tumor tissues may pool Oxo63 at lower body temperature. Pharmacokinetics of the contrast agent were found to be significantly affected by body temperature of the experimental animal, and can influence the probe distribution and the image patterns. Magn Reson Med 79:1212-1218, 2018. © Published 2017. This article is a U.S. Government work and is in the public domain in the USA. © Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

  9. Influence of enrofloxacin traces in drinking water to doxycycline tissue pharmacokinetics in healthy and infected by Mycoplasma gallisepticum broiler chickens.

    PubMed

    Gbylik-Sikorska, Malgorzata; Posyniak, Andrzej; Sniegocki, Tomasz; Sell, Bartosz; Gajda, Anna; Sawicka, Anna; Olszewska-Tomczyk, Monika; Bladek, Tomasz; Tomczyk, Grzegorz; Zmudzki, Jan

    2016-04-01

    Most of antibiotics, administrated in the treatment of poultry diseases are dissolved in drinking water, and it can lead to water supply systems contamination, especially when the regular cleaning is not using. This situation can lead to unconscious administration of low doses of antibiotics to untreated animals. The aim of this study was to clarify the impact of the exposure of enrofloxacin traces (500 μg l(-1)) to doxycycline pharmacokinetics in healthy and experimentally Mycoplasma gallisepticum infected broiler chickens., Two experimental groups, received of enrofloxacin in water and all groups, received 20 mg kg(-1) bw of doxycycline. The compounds concentrations in muscles and livers were determined by LC-MS/MS. The maximum drug tissue concentration (Cmax) of doxycycline was highest in liver obtained from infected chickens which, received enrofloxacin traces (ENR + DC/MG). It was about 40% higher than in healthy chickens from group I which received only doxycycline. It was found that the concentration-time curve AUC(0-t) values in group ENR + DC/MG were almost 75% higher than in the group (DC) and 35% higher than in group (ENR + DC) which also received enrofloxacin traces. The constant exposure of broiler chickens on enrofloxacin traces as well as infection, may significantly influenced on doxycycline tissue pharmacokinetic profile. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Overall Adiposity, Adipose Tissue Distribution, and Endometriosis: A Systematic Review.

    PubMed

    Backonja, Uba; Buck Louis, Germaine M; Lauver, Diane R

    2016-01-01

    Endometriosis has been associated with a lean body habitus. However, we do not understand whether endometriosis is also associated with other characteristics of adiposity, including adipose tissue distribution and amount of visceral adipose tissue (VAT; adipose tissue lining inner organs). Having these understandings may provide insights on how endometriosis develops-some of the physiological actions of adipose tissue differ depending on tissue amount and location and are related to proposed mechanisms of endometriosis development. The aim of this study was to review the literature regarding overall adiposity, adipose tissue distribution and/or VAT, and endometriosis. We reviewed and synthesized studies indexed in PubMed and/or Web of Science. We included studies that had one or more measures of overall adiposity, adipose tissue distribution, and/or VAT and women with and without endometriosis for comparison. We summarized the findings and commented on the methods used and potential sources of bias. Of 366 identified publications, 19 (5.2%) were eligible. Two additional publications were identified from reference lists. Current research included measures of overall adiposity (e.g., body figure drawings) or adipose tissue distribution (e.g., waist-to-hip ratio), but not VAT. The weight of evidence indicated that endometriosis was associated with low overall adiposity and with a preponderance of adipose tissue distributed below the waist (peripheral). Endometriosis may be associated with being lean or having peripherally distributed adipose tissue. Well-designed studies with various sampling frameworks and precise measures of adiposity and endometriosis are needed to confirm associations between adiposity measures and endometriosis and delineate potential etiological mechanisms underlying endometriosis.

  11. Overall Adiposity, Adipose Tissue Distribution, and Endometriosis: A Systematic Review

    PubMed Central

    Backonja, Uba; Buck Louis, Germaine M.; Lauver, Diane R.

    2015-01-01

    Background Endometriosis has been associated with a lean body habitus. However, we do not understand whether endometriosis is also associated with other characteristics of adiposity, including adipose tissue distribution and amount of visceral adipose tissue (VAT; adipose tissue lining inner organs). Having these understandings may provide insights on how endometriosis develops—some of the physiologic actions of adipose tissue differ depending on tissue amount and location, and are related to proposed mechanisms of endometriosis development. Objectives To review the literature regarding overall adiposity, adipose tissue distribution and/or VAT, and endometriosis. Methods We reviewed and synthesized studies indexed in PubMed and/or Web of Science. We included studies that had one or more measures of overall adiposity, adipose tissue distribution, and/or VAT, and women with and without endometriosis for comparison. We summarized the findings and commented on the methods used and potential sources of bias. Results Out of 366 identified publications, 19 (5.2%) were eligible. Two additional publications were identified from reference lists. Current research included measures of overall adiposity (e.g., body figure drawings) or adipose tissue distribution (e.g., waist-to-hip ratio), but not VAT. The weight of evidence indicated that endometriosis was associated with low overall adiposity and with a preponderance of adipose tissue distributed below the waist (peripheral). Discussion Endometriosis may be associated with being lean or having peripherally distributed adipose tissue. Well-designed studies with various sampling frameworks and precise measures of adiposity and endometriosis are needed to confirm associations between adiposity measures and endometriosis, and delineate potential etiologic mechanisms underlying endometriosis. PMID:26938364

  12. Pharmacokinetics and brain penetration of carbapenems in mice.

    PubMed

    Matsumoto, Kazuaki; Kurihara, Yuji; Kuroda, Yuko; Hori, Seiji; Kizu, Junko

    2016-05-01

    An adverse effect associated with the administration of carbapenems is central nervous system (CNS) toxicity, with higher brain concentrations of carbapenems being linked to an increased risk of seizures. However, the pharmacokinetics and brain penetration of carbapenems have not yet been examined. Thus, the aim of this in vivo investigation was to determine the pharmacokinetics and brain penetration of carbapenems in mice. Blood samples and brain tissue samples were obtained 10, 20, 30, 60, and 120 min after the subcutaneous administration of carbapenems (91 mg/kg). We obtained the following values for the pharmacokinetic parameters of carbapenems in mice: 1.20-1.71 L/h/kg for CLtotal/F, 1.41-2.03 h(-1) for Ke, 0.34-0.51 h for T1/2, 0.66-0.95 L/kg for Vss/F, 0.49-0.73 h for MRT, 83.46-110.58 μg/mL for Cmax, plasma, and 0.28-0.83 μg/g for Cmax, brain tissue. The AUC0-∞ of the carbapenems tested in plasma were in the following order: doripenem > meropenem > biapenem > imipenem, and in brain tissue were: imipenem > doripenem > meropenem > biapenem. The degrees of brain tissue penetration, defined as the AUC0-∞, brain tissue/fAUC0-∞, plasma ratio, were 0.016 for imipenem, 0.004 for meropenem, 0.002 for biapenem, and 0.008 for doripenem. The results of the present study demonstrated that, of the carbapenems examined, imipenem penetrated brain tissue to the greatest extent. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  13. Cross-species pharmacokinetic comparison from mouse to man of a second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100.

    PubMed

    Yu, Rosie Z; Kim, Tae-Won; Hong, An; Watanabe, Tanya A; Gaus, Hans J; Geary, Richard S

    2007-03-01

    The pharmacokinetics of a 2'-O-(2-methoxyethyl)-modified oligonucleotide, ISIS 301012 [targeting human apolipoprotein B-100 (apoB-100)], was characterized in mouse, rat, monkey, and human. Plasma pharmacokinetics following parental administration was similar across species, exhibiting a rapid distribution phase with t(1/2alpha) of several hours and a prolonged elimination phase with t(1/2beta) of days. The prolonged elimination phase represents equilibrium between tissues and circulating drug due to slow elimination from tissues. Absorption was nearly complete following s.c. injection, with bioavailability ranging from 80 to 100% in monkeys. Plasma clearance scaled well across species as a function of body weight alone, and this correlation was improved when corrected for plasma protein binding. In all of the animal models studied, the highest tissue concentrations of ISIS 301012 were observed in kidney and liver. Urinary excretion was less than 3% in monkeys and human in the first 24 h. ISIS 301012 is highly bound to plasma proteins, probably preventing rapid removal by renal filtration. However, following 25 mg/kg s.c. administration in mouse and 5-mg/kg i.v. bolus administration in rat, plasma concentrations of ISIS 301012 exceeded their respective protein binding capacity. Thus, urinary excretion increased to 16% or greater within the first 24 h. Albeit slow, urinary excretion of ISIS 301012 and its shortened metabolites is the ultimate elimination pathway of this compound, as demonstrated by 32% of dose recovered in total excreta by 14 days in a rat mass balance study. The pharmacokinetics of ISIS 301012 in human is predictable from the pharmacokinetics measured in animals. The pharmacokinetic properties of ISIS 301012 provide guidance for clinical development and support infrequent dose administration.

  14. The effects of wine-processing on ascending and descending: The distribution of flavonoids in rat tissues after oral administration of crude and wine-processed Radix scutellariae.

    PubMed

    Huang, Ping; Tan, Shanzhong; Zhang, Yong-xin; Li, Jun-song; Chai, Chuan; Li, Jin-ji; Cai, Bao-chang

    2014-08-08

    Ascending and descending theory is a core principle of traditional Chinese medicine (TCM) theories. It plays an essential role in TCM clinical applications. Some TCM medicine has specific properties, which could alter the inclination and direction of their actions. The properties of the ascending and floating process of one herbal medicine are affected by means of herb processing. Wine-processing, which is sautéing with rice wine, is one of the most popular technologies of herb processing. Wine-processing increases the inclination and direction of its actions, thereby producing or strengthening their efficacy in cleaning the upper-energizer heat. Radix scutellariae, the dried roots of Scutellaria baicalensis Georgi, is a well-known TCM used for the treatment of inflammation, pyrexia, jaundice, etc. Recently, wine-processed Radix scutellariae was normally applied in clinical studies for the treatment of upper-energizer syndrome. In order to investigate the effects of wine-processing on ascending and descending of Radix scutellariae, the comparative study of distribution of flavonoids in rat tissues of triple energizers (SanJiao-upper, middle, lower jiao) after oral administration of crude and wine-processed Radix scutellariae aqueous extracts was carried out. The rats were randomly assigned to two groups and orally administered with crude and wine-processed Radix scutellariae aqueous extracts, respectively. At different pre-determined time points after administration, the concentrations of compounds in rat tissue homogenate were determined, and the main tissue pharmacokinetic parameters were investigated. Tissue pharmacokinetic parameters including AUC0-t, t1/2, Tmax and Cmax were calculated using DAS 2.0. An unpaired Student t-test was used to compare the differences in tissue pharmacokinetic parameters between the two groups. All the results were expressed as arithmetic mean±S.D. The parameters of Cmax and AUC0-t of some flavonoids in wine-processed Radix

  15. Studies of nontarget-mediated distribution of human full-length IgG1 antibody and its FAb fragment in cardiovascular and metabolic-related tissues.

    PubMed

    Davidsson, Pia; Söderling, Ann-Sofi; Svensson, Lena; Ahnmark, Andrea; Flodin, Christine; Wanag, Ewa; Screpanti-Sundqvist, Valentina; Gennemark, Peter

    2015-05-01

    Tissue distribution and pharmacokinetics (PK) of full-length nontargeted antibody and its antigen-binding fragment (FAb) were evaluated for a range of tissues primarily of interest for cardiovascular and metabolic diseases. Mice were intravenously injected with a dose of 10 mg/kg of either human IgG1or its FAb fragment; perfused tissues were collected at a range of time points over 3 weeks for the human IgG1 antibody and 1 week for the human FAb antibody. Tissues were homogenized and antibody concentrations were measured by specific immunoassays on the Gyros system. Exposure in terms of maximum concentration (Cmax ) and area under the curve was assessed for all nine tissues. Tissue exposure of full-length antibody relative to plasma exposure was found to be between 1% and 10%, except for brain (0.2%). Relative concentrations of FAb antibody were the same, except for kidney tissue, where the antibody concentration was found to be ten times higher than in plasma. However, the absolute tissue uptake of full-length IgG was significantly higher than the absolute tissue uptake of the FAb antibody. This study provides a reference PK state for full-length whole and FAb antibodies in tissues related to cardiovascular and metabolic diseases that do not include antigen or antibody binding. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  16. Rapid Pharmacokinetic and Biodistribution Studies Using Cholorotoxin-Conjugated Iron Oxide Nanoparticles: A Novel Non-Radioactive Method

    PubMed Central

    Lee, Michelle Jeung-Eun; Veiseh, Omid; Bhattarai, Narayan; Sun, Conroy; Hansen, Stacey J.; Ditzler, Sally; Knoblaugh, Sue; Lee, Donghoon; Ellenbogen, Richard; Zhang, Miqin; Olson, James M.

    2010-01-01

    Background Recent advances in nanotechnology have led to the development of biocompatible nanoparticles for in vivo molecular imaging and targeted therapy. Many nanoparticles have undesirable tissue distribution or unacceptably low serum half-lives. Pharmacokinetic (PK) and biodistribution studies can help inform decisions determining particle size, coatings, or other features early in nanoparticle development. Unfortunately, these studies are rarely done in a timely fashion because many nanotechnology labs lack the resources and expertise to synthesize radioactive nanoparticles and evaluate them in mice. Methodology/Principal Findings To address this problem, we developed an economical, radioactivity-free method for assessing serum half-life and tissue distribution of nanoparticles in mice. Iron oxide nanoparticles coated with chitosan and polyethylene glycol that utilize chlorotoxin as a targeting molecule have a serum half-life of 7–8 hours and the particles remain stable for extended periods of time in physiologic fluids and in vivo. Nanoparticles preferentially distribute to spleen and liver, presumably due to reticuloendothelial uptake. Other organs have very low levels of nanoparticles, which is ideal for imaging most cancers in the future. No acute toxicity was attributed to the nanoparticles. Conclusions/Significance We report here a simple near-infrared fluorescence based methodology to assess PK properties of nanoparticles in order to integrate pharmacokinetic data into early nanoparticle design and synthesis. The nanoparticles tested demonstrate properties that are excellent for future clinical imaging strategies and potentially suitable for targeted therapy. PMID:20209054

  17. A model to resolve organochlorine pharmacokinetics in migrating humpback whales.

    PubMed

    Cropp, Roger; Nash, Susan Bengtson; Hawker, Darryl

    2014-07-01

    Humpback whales are iconic mammals at the top of the Antarctic food chain. Their large reserves of lipid-rich tissues such as blubber predispose them to accumulation of lipophilic contaminants throughout their lifetime. Changes in the volume and distribution of lipids in humpback whales, particularly during migration, could play an important role in the pharmacokinetics of lipophilic contaminants such as the organochlorine pesticide hexachlorobenzene (HCB). Previous models have examined constant feeding and nonmigratory scenarios. In the present study, the authors develop a novel heuristic model to investigate HCB dynamics in a humpback whale and its environment by coupling an ecosystem nutrient-phytoplankton-zooplankton-detritus (NPZD) model, a dynamic energy budget (DEB) model, and a physiologically based pharmacokinetic (PBPK) model. The model takes into account the seasonal feeding pattern of whales, their energy requirements, and fluctuating contaminant burdens in the supporting plankton food chain. It is applied to a male whale from weaning to maturity, spanning 20 migration and feeding cycles. The model is initialized with environmental HCB burdens similar to those measured in the Southern Ocean and predicts blubber HCB concentrations consistent with empirical concentrations observed in a southern hemisphere population of male, migrating humpback whales. Results show for the first time some important details of the relationship between energy budgets and organochlorine pharmacokinetics. © 2014 SETAC.

  18. Population pharmacokinetic model of transdermal nicotine delivered from a matrix-type patch.

    PubMed

    Linakis, Matthew W; Rower, Joseph E; Roberts, Jessica K; Miller, Eleanor I; Wilkins, Diana G; Sherwin, Catherine M T

    2017-12-01

    Nicotine addiction is an issue faced by millions of individuals worldwide. As a result, nicotine replacement therapies, such as transdermal nicotine patches, have become widely distributed and used. While the pharmacokinetics of transdermal nicotine have been extensively described using noncompartmental methods, there are few data available describing the between-subject variability in transdermal nicotine pharmacokinetics. The aim of this investigation was to use population pharmacokinetic techniques to describe this variability, particularly as it pertains to the absorption of nicotine from the transdermal patch. A population pharmacokinetic parent-metabolite model was developed using plasma concentrations from 25 participants treated with transdermal nicotine. Covariates tested in this model included: body weight, body mass index, body surface area (calculated using the Mosteller equation) and sex. Nicotine pharmacokinetics were best described with a one-compartment model with absorption based on a Weibull distribution and first-order elimination and a single compartment for the major metabolite, cotinine. Body weight was a significant covariate on apparent volume of distribution of nicotine (exponential scaling factor 1.42). After the inclusion of body weight in the model, no other covariates were significant. This is the first population pharmacokinetic model to describe the absorption and disposition of transdermal nicotine and its metabolism to cotinine and the pharmacokinetic variability between individuals who were administered the patch. © 2017 The British Pharmacological Society.

  19. The Sheep as a Model of Preclinical Safety and Pharmacokinetic Evaluations of Candidate Microbicides

    PubMed Central

    Cameron, David; Dias, Nicola; Holding, Jeremy; Muntendam, Alex; Oostebring, Freddy; Dreier, Peter; Rohan, Lisa; Nuttall, Jeremy

    2015-01-01

    When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. PMID:25845860

  20. The sheep as a model of preclinical safety and pharmacokinetic evaluations of candidate microbicides.

    PubMed

    Holt, Jonathon D S; Cameron, David; Dias, Nicola; Holding, Jeremy; Muntendam, Alex; Oostebring, Freddy; Dreier, Peter; Rohan, Lisa; Nuttall, Jeremy

    2015-07-01

    When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  1. A hybrid design to optimize preparation of lopinavir loaded solid lipid nanoparticles and comparative pharmacokinetic evaluation with marketed lopinavir/ritonavir coformulation.

    PubMed

    Ravi, Punna Rao; Vats, Rahul; Dalal, Vikas; Murthy, Aditya Narasimha

    2014-07-01

    To prepare stearic acid-based lopinavir (LPV) loaded solid lipid nanoparticles (SLNs) using a hybrid design and compare in-vivo performance of optimized formulation with marketed LPV/ritonavir (RTV) coformulation. LPV SLNs were prepared by hot melt emulsion technique and optimized using Plackett-Burman design and Box-Behnken design. Physical characterization studies were conducted for the optimized SLNs. Comparative oral pharmacokinetic studies and tissue distribution studies of optimized SLNs and LPV/RTV coformulation were done in Wistar rats. In-vitro metabolic stability and intestinal permeability studies for LPV SLNs were undertaken to elucidate the mechanism involved in the pharmacokinetic improvement of LPV. Optimized SLNs exhibited nanometeric size (223 nm) with high entrapment efficiency (83%). In-vitro drug release study of SLNs showed biphasic sustained release behaviour. Significant increase in oral bioavailability of LPV from LPV SLNs (5 folds) and LPV/RTV coformulation (3.7 folds) was observed as compared with free LPV. LPV SLNs showed better tissue distribution of LPV in HIV reservoirs than LPV/RTV coformulation. In-vitro studies demonstrated that SLNs provided metabolic protection of LPV and were endocytosized during absorption. SLNs enhanced oral bioavailability and improved distribution profile of LPV to HIV reservoirs and hence could be better alternative to LPV/RTV coformulation. © 2014 Royal Pharmaceutical Society.

  2. Pharmacokinetics of 2,4-di(alpha-methoxyethyl)deuteroporphyrin-IX (dimehin) and its complex with chitosan in mice with tumors

    NASA Astrophysics Data System (ADS)

    Ivanov, Andrei V.; Gradyushko, A. T.; Laptev, V. P.; Panferova, N. G.; Varlamov, V. P.; Klyashchitsky, B. A.; Reshetnickov, Andrei V.; Ponomarev, Gelii V.

    1996-01-01

    The kinetics of photosensitizer distribution and elimination have been studied using fluorescent methods in organs and tumors of A/Snell mice with embriocarcinoma inoculated into their thigh muscles for the porphyrin compound 2,4-di((alpha) -methoxyethyl)deuteroporphyrin-- IX (DMH, `Dimehin') and its complex with polysaccharide chitosan. DMH fluorescence differs in samples of liver and faeces which follows from the spectra comparison. DMH is metabolizable upon passing through liver into a form eliminated by the gastrointestinal tract as our pharmacokinetic data have shown. DMH has been found to be a short-term highly photodynamically efficient photosensitizer judging by combined analysis of our toxicological, pharmacokinetic and photodynamic research data. DMH-chitosan uptake and distribution studies have shown the complex's long-term persistence in blood circulation, high level accumulation in spleen and lungs, whereas there was no complex registered in tumors and other tissues following i.v. administration.

  3. Modeling of electric field distribution in tissues during electroporation

    PubMed Central

    2013-01-01

    Background Electroporation based therapies and treatments (e.g. electrochemotherapy, gene electrotransfer for gene therapy and DNA vaccination, tissue ablation with irreversible electroporation and transdermal drug delivery) require a precise prediction of the therapy or treatment outcome by a personalized treatment planning procedure. Numerical modeling of local electric field distribution within electroporated tissues has become an important tool in treatment planning procedure in both clinical and experimental settings. Recent studies have reported that the uncertainties in electrical properties (i.e. electric conductivity of the treated tissues and the rate of increase in electric conductivity due to electroporation) predefined in numerical models have large effect on electroporation based therapy and treatment effectiveness. The aim of our study was to investigate whether the increase in electric conductivity of tissues needs to be taken into account when modeling tissue response to the electroporation pulses and how it affects the local electric distribution within electroporated tissues. Methods We built 3D numerical models for single tissue (one type of tissue, e.g. liver) and composite tissue (several types of tissues, e.g. subcutaneous tumor). Our computer simulations were performed by using three different modeling approaches that are based on finite element method: inverse analysis, nonlinear parametric and sequential analysis. We compared linear (i.e. tissue conductivity is constant) model and non-linear (i.e. tissue conductivity is electric field dependent) model. By calculating goodness of fit measure we compared the results of our numerical simulations to the results of in vivo measurements. Results The results of our study show that the nonlinear models (i.e. tissue conductivity is electric field dependent: σ(E)) fit experimental data better than linear models (i.e. tissue conductivity is constant). This was found for both single tissue and

  4. [Impact of ECMO on drugs pharmacokinetics].

    PubMed

    Hasni, Nesrine; Lemaitre, Florian; Fernandez, Christine; Combes, Alain; Farinotti, Robert

    2011-01-01

    Extracorporeal membrane oxygenation (ECMO) is a life support system used in the treatment of patients of all ages with severe respiratory or cardiorespiratory failure. Despite the intensive use of drugs in the treatment of patients on ECMO, few studies have been conducted to determine the impact of this device on the pharmacokinetics of drugs. Publications in this field have shown pharmacokinetics changes resulting in an increase in volume of distribution of drugs and/or decreased clearance with consequent increase of their half-life. Reduced plasma concentrations of some drugs due to their adsorption on the different components of the circuit further complicates the determination of pharmacokinetic parameters of patients treated by ECMO. The literature published up to now on the pharmacokinetic changes associated with ECMO provide preliminary support for dosage adjustment. However, more research is needed to identify dosage strategies for this patient population. © 2011 Société Française de Pharmacologie et de Thérapeutique.

  5. On the accuracy of estimation of basic pharmacokinetic parameters by the traditional noncompartmental equations and the prediction of the steady-state volume of distribution in obese patients based upon data derived from normal subjects.

    PubMed

    Berezhkovskiy, Leonid M

    2011-06-01

    The steady-state and terminal volumes of distribution, as well as the mean residence time of drug in the body (V(ss), V(β), and MRT) are the common pharmacokinetic parameters calculated using the drug plasma concentration-time profile C(p) (t) following intravenous (i.v. bolus or constant rate infusion) drug administration. These calculations are valid for the linear pharmacokinetic system with central elimination (i.e., elimination rate being proportional to drug concentration in plasma). Formally, the assumption of central elimination is not normally met because the rate of drug elimination is proportional to the unbound drug concentration at elimination site, although equilibration between systemic circulation and the site of clearance for majority of small molecule drugs is fast. Thus, the assumption of central elimination is practically quite adequate. It appears reasonable to estimate the extent of possible errors in determination of these pharmacokinetic parameters due to the absence of central elimination. The comparison of V(ss), V(β), and MRT calculated by exact equations and the commonly used ones was made considering a simplified physiologically based pharmacokinetic model. It was found that if the drug plasma concentration profile is detected accurately, determination of drug distribution volumes and MRT using the traditional noncompartmental calculations of these parameters from C(p) (t) yields the values very close to that obtained from exact equations. Though in practice, the accurate measurement of C(p) (t), especially its terminal phase, may not always be possible. This is particularly applicable for obtaining the distribution volumes of lipophilic compounds in obese subjects, when the possibility of late terminal phase at low drug concentration is quite likely, specifically for compounds with high clearance. An accurate determination of V(ss) is much needed in clinical practice because it is critical for the proper selection of drug treatment

  6. Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc-Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice.

    PubMed

    Guo, Jianxia; Parise, Robert A; Joseph, Erin; Egorin, Merrill J; Lazo, John S; Prochownik, Edward V; Eiseman, Julie L

    2009-03-01

    c-Myc is commonly activated in many human tumors and is functionally important in cellular proliferation, differentiation, apoptosis and cell cycle progression. The activity of c-Myc requires noncovalent interaction with its client protein Max. In vitro studies indicate the thioxothiazolidinone, 10058-F4, inhibits c-Myc/Max dimerization. In this study, we report the efficacy, pharmacokinetics and metabolism of this novel protein-protein disruptor in mice. SCID mice bearing DU145 or PC-3 human prostate cancer xenografts were treated with either 20 or 30 mg/kg 10058-F4 on a qdx5 schedule for 2 weeks for efficacy studies. For pharmacokinetics and metabolism studies, mice bearing PC-3 or DU145 xenografts were treated with 20 mg/kg of 10058-F4 i.v. Plasma and tissues were collected 5-1440 min after dosing. The concentration of 10058-F4 in plasma and tissues was determined by HPLC, and metabolites were characterized by LC-MS/MS. Following a single iv dose, peak plasma 10058-F4 concentrations of approximately 300 muM were seen at 5 min and declined to below the detection limit at 360 min. Plasma concentration versus time data were best approximated by a two-compartment, open, linear model. The highest tissue concentrations of 10058-F4 were found in fat, lung, liver, and kidney. Peak tumor concentrations of 10058-F4 were at least tenfold lower than peak plasma concentrations. Eight metabolites of 10058-F4 were identified in plasma, liver, and kidney. The terminal half-life of 10058-F4 was approximately 1 h, and the volume of distribution was >200 ml/kg. No significant inhibition of tumor growth was seen after i.v. treatment of mice with either 20 or 30 mg/kg 10058-F4. The lack of significant antitumor activity of 10058-F4 in tumor-bearing mice may have resulted from its rapid metabolism and low concentration in tumors.

  7. [Tetrahydrocannabinol pharmacokinetics; new synthetic cannabinoids; road safety and cannabis].

    PubMed

    Goullé, Jean-Perre; Guerbet, Michel

    2014-03-01

    Delta-9-tetrahydrocannabinol (THC) is the main psychoactive ingredient of cannabis, a drug which is commonly smoked This paper focuses on the pharmacokinetics of THC. The average THC content in cannabis plant material has risen by a factor offour over the past 20 years, from 4% to 16%. This increase has important implications not only for the pharmacokinetics but also for the pharmacology of THC The mean bioavailability of THC in smoked cannabis is about 25%. In a cigarette containing 3.55% of THC, a peak plasma level of about 160 ng/mL occurs approximately 10 min after inhalation. THC is quickly cleared from plasma in a multiphasic manner and is widely distributed to tissues, leading to its pharmacologic effects. Body fat is a long-term storage site. This particular pharmacokinetic behavior explains the lack of correlation between the THC blood level and clinical effects, contrary to ethanol. The main THC metabolites are 11-OH-THC (the only active metabolite) and THC-COOH, which is eliminated in feces and urine over several weeks. Therefore, abstinence can be established by analyzing THC-COOH in urine, while blood THC analysis is used to confirm recent exposure. Cannabis is the main illicit drug found among vehicle drivers. Various traffic safety studies indicate that recent use of this drug at least doubles the risk of causing an accident, and that simultaneous alcohol consumption multiplies this risk by afactor of 14. Since 2009, synthetic cannabinoids have emerged on the illicit drug market. These substances act on the same CB1 receptors as THC, but with higher afinity. Their pharmacokinetics differs from that of THC, as they are metabolized into multiple derivatives, most of which are more active than THC itself.

  8. A Review on Pharmacokinetic Modeling and the Effects of Environmental Stressors on Pharmacokinetics for Operational Medicine: Operational Pharmacokinetics

    DTIC Science & Technology

    2009-09-01

    hypercholesterolemia Two-compartment model Ezzet, Krishna et al. 2001 Antilipemics Statins: simvastatin, rosuvastatin, atorvastatin Treatment of...Pharmacokinetic model* & rosuvastatin Scopus 14 3 PubMed 9 3 Pharmacokinetic model* & atorvastatin Scopus 49 4 Pharmacokinetic model* & zaleplon...Fentanyl & pharmacokinetic & heat 9 2 Fentanyl & pharmacokinetic & cold 4 0 Fentanyl & pharmacokinetic & blood loss 19 5 Atorvastatin

  9. Pharmacokinetics and pharmacodynamics of a novel Acetylcholinesterase Inhibitor, DMNG-3.

    PubMed

    Xin-Guo, Zhang; Kou, Fei; Guo-Di, Ma; Tang, Peng; Zhong-Duo, Yang

    2016-01-01

    DMNG-3(3β-Methyl-[2-(4-nitrophenoxy)ethyl]-amino]con-5-enine), is a new and the potentially most potent acetylcholinesterase inhibitor recently obtained from conessine by N-demethylation and nucleophilic substitution reaction. In the present study, a step-down passive avoidance test was used to investigate whether DMNG-3 could modulate impairment of learning and memory induced by scopolamine, and a high performance liquid chromatography(HPLC) method for the determination of DMNG-3 in biological samples was applied to study its pharmacokinetics and tissues distribution. Separation was achieved on C18 column using a mobile phase consisting methanol-water (70:30, v/v) at a flow rate of 1.0ml/min. The intra- and inter-day precisions were good and the RSD was all lower than 1.30%. The mean absolute recovery of DMNG-3 in plasma ranged from 88.55 to 96.45 %. Our results showed oral administration of DMNG-3(10,25,50 mg/kg/day) can significantly improve the latency and number of errors and had a positive effect of improvement of learning and memory in mice in passive avoidance tests. The elimination half-life (T1/2) was 14.07±1.29, 15.87±1.03h, and the total clearance (CL) values were 0.70±0.11, 0.78±0.13 L/h/kg, respectively. The pharmacokinetic studies showed that DMNG-3 has a slowly clearance and large distribution volume in experimental animals, and its disposition is linear over the range of doses tested. The liver, small intestine, stomach, and large intestine were the major distribution tissues of DMNG-3 in mice. It was found that DMNG-3 could be detected in brain, suggesting that DMNG-3 can cross the blood-brain barrier. The present study shows that DMNG-3 can be possible developed as a new drug for the treatment of Alzheimer's disease in the future.

  10. Physiologically based pharmacokinetic model for quinocetone in pigs and extrapolation to mequindox.

    PubMed

    Zhu, Xudong; Huang, Lingli; Xu, Yamei; Xie, Shuyu; Pan, Yuanhu; Chen, Dongmei; Liu, Zhenli; Yuan, Zonghui

    2017-02-01

    Physiologically based pharmacokinetic (PBPK) models are scientific methods used to predict veterinary drug residues that may occur in food-producing animals, and which have powerful extrapolation ability. Quinocetone (QCT) and mequindox (MEQ) are widely used in China for the prevention of bacterial infections and promoting animal growth, but their abuse causes a potential threat to human health. In this study, a flow-limited PBPK model was developed to simulate simultaneously residue depletion of QCT and its marker residue dideoxyquinocetone (DQCT) in pigs. The model included compartments for blood, liver, kidney, muscle and fat and an extra compartment representing the other tissues. Physiological parameters were obtained from the literature. Plasma protein binding rates, renal clearances and tissue/plasma partition coefficients were determined by in vitro and in vivo experiments. The model was calibrated and validated with several pharmacokinetic and residue-depletion datasets from the literature. Sensitivity analysis and Monte Carlo simulations were incorporated into the PBPK model to estimate individual variation of residual concentrations. The PBPK model for MEQ, the congener compound of QCT, was built through cross-compound extrapolation based on the model for QCT. The QCT model accurately predicted the concentrations of QCT and DQCT in various tissues at most time points, especially the later time points. Correlation coefficients between predicted and measured values for all tissues were greater than 0.9. Monte Carlo simulations showed excellent consistency between estimated concentration distributions and measured data points. The extrapolation model also showed good predictive power. The present models contribute to improve the residue monitoring systems of QCT and MEQ, and provide evidence of the usefulness of PBPK model extrapolation for the same kinds of compounds.

  11. Tissue Distribution Of Chloroaluminium Sulfonated Phthalocyanine In Dogs

    NASA Astrophysics Data System (ADS)

    M. M.; H. C.; Newman

    1989-06-01

    Chloroaluminum sulfonated phthalocyanine (A1PCS) was administered intravenously to clinically normal dogs, and A1PCS levels were determined in tissues using a sensitive assay. A1PCS accumulated to high levels in liver, spleen, bone marrow, kidney, and lung. These tissue levels confirm previous determinations in mice and rats. Only a small amount of dye was retained in skin and very small amounts in muscle and brain. A1PCS was cleared from the blood within 24 h, and excreted primarily by urine. Serum clearance was faster in males than in females. There were also significant tissue distribution differences between the genders, particularly during the first 12 h. The low levels of A1PCS in skin suggest that cutaneous photosensitivity and toxic skin reactions using this photosensitizer in photodynamic therapy of cancer may be eliminated. The difference in tissue distribution between genders is not only intriguing, but indicates that the optimal time window for treatment of various tissue sites may vary by gender.

  12. Pharmacokinetics of tildipirosin in bovine plasma, lung tissue, and bronchial fluid (from live, nonanesthetized cattle).

    PubMed

    Menge, M; Rose, M; Bohland, C; Zschiesche, E; Kilp, S; Metz, W; Allan, M; Röpke, R; Nürnberger, M

    2012-12-01

    The pharmacokinetics of tildipirosin (Zuprevo(®) 180 mg/mL solution for injection for cattle), a novel 16-membered macrolide for treatment, control, and prevention of bovine respiratory disease, were investigated in studies collecting blood plasma, lung tissue, and in vivo samples of bronchial fluid (BF) from cattle. After single subcutaneous (s.c.) injection at 4 mg/kg body weight, maximum plasma concentration (C(max)) was 0.7 μg/mL. T(max) was 23 min. Mean residence time from the time of dosing to the time of last measurable concentration (MRT(last)) and terminal half-life (T(1/2) ) was 6 and 9 days, respectively. A strong dose-response relationship with no significant sex effect was shown for both C(max) and area under the plasma concentration-time curve from time 0 to the last sampling time with a quantifiable drug concentration (AUC(last) ) over the range of doses up to 6 mg/kg. Absolute bioavailability was 78.9%. The volume of distribution based on the terminal phase (V(z)) was 49.4 L/kg, and the plasma clearance was 144 mL/h/kg. The time-concentration profile of tildipirosin in BF and lung far exceeded those in blood plasma. In lung, tildipirosin concentrations reached 9.2 μg/g at 4 h, peaked at 14.8 μg/g at day 1, and slowly declined to 2.0 μg/g at day 28. In BF, the concentration of tildipirosin reached 1.5 and 3.0 μg/g at 4 and 10 h, maintained a plateau of about 3.5 μg/g between day 1 and 3, and slowly declined to 1.0 at day 21. T(1/2) in lung and BF was approximately 10 and 11 days. Tildipirosin is rapidly and extensively distributed to the respiratory tract followed by slow elimination. © 2011 Blackwell Publishing Ltd.

  13. Population Pharmacokinetics and Exposure Response Assessment of CC-292, a Potent BTK Inhibitor, in Patients With Chronic Lymphocytic Leukemia.

    PubMed

    Li, Yan; Ramírez-Valle, Francisco; Xue, Yongjun; Ventura, Judith I; Gouedard, Olivier; Mei, Jay; Takeshita, Kenichi; Palmisano, Maria; Zhou, Simon

    2017-10-01

    CC-292, a potent Bruton tyrosine kinase inhibitor, is under development for the treatment of B-cell malignancies. An analysis was performed to develop a population pharmacokinetic model of CC-292 and assess the influence of demographics and disease-related covariates on CC-292 exposure and to assess the exposure-response (overall response rate) relationship in patients with chronic lymphocytic leukemia. Population pharmacokinetic analysis was based on a 2-compartment base model conducted in NONMEM. Categorical exposure-response analysis was performed using logistic regression in SAS. The population pharmacokinetic analysis results indicated that CC-292 pharmacokinetic disposition is similar between healthy subjects and patients. CC-292 showed a larger central compartment volume of distribution than the peripheral compartment volume of distribution (158 L and 72 L, respectively) and a faster clearance than intercompartmental clearance (134 L/h and 18.7 L/h, respectively), indicating that for CC-292, clearance from blood occurs faster than distribution into deep tissues and organs. CC-292 clearance is not affected by demographics or baseline clinical lab factors, except for sex. Although sex significantly reduced variation of apparent clearance, the sex effect on apparent clearance is unlikely to be clinically relevant. The exposure-response analysis suggested that higher drug exposure is linearly correlated with higher overall response rate. A twice-daily dose regimen showed higher overall response rate as compared to once-daily dosing, consistent with a threshold concentration of approximately 300 ng/mL, above which the probability of overall response rate significantly increases. © 2017, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

  14. Pharmacokinetics and biodegradation of chitosan in rats

    NASA Astrophysics Data System (ADS)

    Li, Hui; Jiang, Zhiwen; Han, Baoqin; Niu, Shuyi; Dong, Wen; Liu, Wanshun

    2015-10-01

    Chitosan, an excellent biomedical material, has received a widespread in vivo application. In contrast, its metabolism and distribution once being implanted were less documented. In this study, the pharmacokinetics and biodegradation of fluorescein isothiocyanate (FITC) labeled and muscle implantation administrated chitosan in rats were investigated with fluorescence spectrophotometry, histological assay and gel chromatography. After implantation, chitosan was degraded gradually during its distribution to diverse organs. Among the tested organs, liver and kidney were found to be the first two highest in chitosan content, which was followed by heart, brain and spleen. Urinary excretion was believed to be the major pathway of chitosan elimination, yet 80% of chitosan administered to rats was not trackable in their urine. This indicated that the majority of chitosan was degraded in tissues. In average, the molecular weight of the degradation products of chitosan in diverse organs and urine was found to be <65 kDa. This further confirmed the in vivo degradation of chitosan. Our findings provided new evidences for the intensive and safe application of chitosan as a biomedical material.

  15. Influence of Dosage Form on the Intravitreal Pharmacokinetics of Diclofenac

    PubMed Central

    Durairaj, Chandrasekar; Kim, Stephen J.; Edelhauser, Henry F.; Shah, Jaymin C.; Kompella, Uday B.

    2009-01-01

    Purpose To prepare a suspension form of diclofenac and compare the influence of the injected form (suspension versus solution) on the intravitreal pharmacokinetics of diclofenac in Dutch belted pigmented rabbits. Methods Diclofenac acid was prepared and characterized in a suspension formulation. Rabbit eyes were injected with either diclofenac sodium solution (0.3 mg) or diclofenac acid suspension (10 mg) prepared in 0.1 mL balanced salt solution. Rabbits were killed at regular time intervals, the eyes enucleated, and drug content quantified in the vitreous humor and retina-choroid tissue by high-performance liquid chromatography. Pharmacokinetic models were developed for both the dosage forms, and simulations were performed for different doses. Results Diclofenac acid with an approximate 5-μm particle size exhibited 3.5-fold lower solubility in vitreous humor, when compared with its sodium salt. The estimated settling velocity of the suspension in the vitreous humor was 3 cm/h. After diclofenac sodium salt solution injection, drug levels declined rapidly with no drug levels detectable after 24 hours in the vitreous humor and 4 hours in the RC. Throughout the assessed time course, drug levels were higher in the vitreous. However, sustained, high drug levels were observed in both the vitreous humor and the retina-choroid even on day 21 after diclofenac acid suspension injection, with retina-choroid drug levels being higher beginning at 0.25 hour. The elimination half-life of diclofenac suspension was 24 and 18 days in vitreous and retina-choroid, respectively, compared to 2.9 and 0.9 hours observed with diclofenac sodium. The pharmacokinetic models developed indicated a slow-release distribution or depot compartment for the diclofenac acid suspension in the posterior segment. Simulations indicated the inability of a 10-mg dose of diclofenac sodium solution to sustain drug levels in the vitreous beyond 11 days. Conclusions By choosing a less soluble form of a drug

  16. Subcellular localization and distribution of the reduced folate carrier in normal rat tissues.

    PubMed

    Hinken, M; Halwachs, S; Kneuer, C; Honscha, W

    2011-01-27

    The reduced folate carrier (Rfc1; Slc19a1) mediated transport of reduced folates and antifolate drugs such as methotrexate (MTX) play an essential role in physiological folate homeostasis and MTX cancer chemotherapy. As no systematic reports are as yet available correlating Rfc1 gene expression and protein levels in all tissues crucial for folate and antifolate uptake, storage or elimination, we investigated gene and protein expression of rat Rfc1 (rRfc1) in selected tissues. This included the generation of a specific anti-rRfc1 antibody. Rabbits were immunised with isolated rRfc1 peptides producing specific anti-rRfc1 antiserum targeted to the intracellular C-terminus of the carrier. Using RT-PCR analysis, high rRfc1 transcript levels were detected in colon, kidney, brain, thymus, and spleen. Moderate rRfc1 gene expression was observed in small intestine, liver, bone marrow, lung, and testes whereas transcript levels were negligible in heart, skeletal muscle or leukocytes. Immunohistochemical analyses revealed strong carrier expression in the apical membrane of tunica mucosa epithelial cells of small intestine and colon, in the brush-border membrane of choroid plexus epithelial cells or in endothelial cells of small vessels in brain and heart. Additionally, high rRfc1 protein levels were localized in the basolateral membrane of renal tubular epithelial cells, in the plasma membrane of periportal hepatocytes, and sertoli cells of the testes. Taken together, our results demonstrated that rRfc1 is expressed almost ubiquitously but to very different levels. The predominant tissue distribution supports the essential role of Rfc1 in physiological folate homeostasis. Moreover, our results may contribute to understand antifolate pharmacokinetics and selected organ toxicity associated with MTX chemotherapy.

  17. Diet-Induced Obesity Alters Vincristine Pharmacokinetics in Blood and Tissues of Mice

    PubMed Central

    Behan, James W.; Avramis, Vassilios I.; Yun, Jason P.; Louie, Stan G.; Mittelman, Steven D.

    2010-01-01

    Obesity is associated with poorer outcome from many cancers, including leukemia. One possible contributor to this could be suboptimal chemotherapy dosing in obese patients. We have previously found that vincristine (VCR) is less effective in obese compared to non-obese mice with leukemia, despite weight-based dosing. In the present study, we administered 3H-VCR to obese and control mice to determine whether obesity would cause suboptimal VCR exposure. Blood VCR concentrations were fitted with a 3-compartment model using pharmacokinetic analysis (two-stage PK) in 3 subsets of VCR concentrations vs. time method. Tissue and blood VCR concentrations were also analyzed using non-compartmental modeling. Blood VCR concentrations showed a triexponential decay and tended to be slightly higher in the obese mice at all time-points. However, the t½β and t½γ were shorter in the obese mice (9.7 vs. 44.5 minutes and 60.3 vs. 85.6 hours, respectively), resulting in a lower AUC0→∞ (13,099 vs. 15,384 ng/ml*hr). Had the dose of VCR been “capped”, as is done in clinical practice, the AUC0→∞ would have been 36% lower in the obese mice than the controls. Tissue disposition of VCR revealed a biexponential decay from spleen, liver, and adipose. Interestingly, VCR slowly accumulated in the bone marrow of control mice, but had a slow decay from the marrow in the obese mice. Thus, obesity alters VCR PK, causing a lower overall exposure in circulation and bone marrow. Given the high prevalence of obesity, additional PK studies should be performed in obese subjects to optimize chemotherapy dosing regimens. PMID:20083201

  18. Enantioselective Tissue Distribution of Ketorolac and its Enantiomers in Rats.

    PubMed

    Dubey, S K; Anand, A; Saha, R N

    2015-08-01

    The difference in tissue distribution of Ketorolac and its enantiomers were investigated in wistar rats. Separate high performance liquid chromatographic method was developed and validated for determination of Ketorolac and its enantiomers. Oyster BDS (150 × 4.6 mm id., 5 μm particle size) column was used for determination of concentration of Ketorolac. Ketorolac enantiomers were determined using Chiral-AGP column (100 × 4.0 mm I.D., particle size 5 μ, Chrom tech Ltd, Sweden). Detection was done at wavelength of 322 nm using an ultraviolet detector in the analytical system. Ketorolac enantiomers exhibit difference in their disposition in Wistar rats. In kidney, there was a significant difference in pharmacokinetic parameters. The Cmax was nearly 4 times and AUC 0-∞ was found to be more than double for S (-) Ketorolac than that of R (+) Ketorolac. MRT, Ke and t1/2 differ significantly in kidney. In liver, Cmax was found to be approximately 69% higher for S (-) Ketorolac compared to R (+) Ketorolac. AUC 0-∞ did not differ significantly for the enantiomers in liver. In liver, S (-) Ketorolac eliminated very fast in comparison to R (+) Ketorolac having t1/2 (one third) in comparison to R (+) Ketorolac. In lungs, there was no difference observed for Cmax and other parameters but AUC 0-∞ was found to be marginally higher for S (-) ketorolac. © Georg Thieme Verlag KG Stuttgart · New York.

  19. Propofol pharmacokinetics in a dwarfism patient.

    PubMed

    Tsubokawa, T; Yamamoto, K; Komuro, A; Ishizuka, S; Kobayashi, T

    2003-04-01

    Pharmacokinetic information is important to control anesthetic depth. However, there are few available pharmacokinetic data of propofol in dwarfism patients. We anesthetized a dwarfism patient who underwent spinal decompression, and investigated the pharmacokinetics of propofol. The patient was a 40-year-old man suffering from muscle weakness and numbness in the arms. The operation consisted of two stages; anterior approach in the supine position and posterior approach in the prone position. We also obtained arterial blood for pharmacokinetic analysis. Distribution volume at steady-state and clearance in the supine position was 180 and 0.92 l min- 1, respectively, and in the prone position 127 and 0.74 l min- 1, respectively, in spite of a continuous infusion of dopamine. The data in the supine position were well predicted by Gepts' parameters (used in Diprifusor Zeneca Ltd, Cheshire, UK), which means the target-controlled infusion (TCI) technique can be available in the supine position, while attention is necessary to avoid overdosing when a patient is placed in the prone position.

  20. A physiologically based pharmacokinetic model for developmental exposure to BDE-47 in rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Emond, Claude, E-mail: claude.emond@umontreal.c; BioSimulation Consulting Inc., Newark, DE 19711; Raymer, James H.

    2010-02-01

    Polybrominated diphenyl ethers (PBDEs) are used commercially as additive flame retardants and have been shown to transfer into environmental compartments, where they have the potential to bioaccumulate in wildlife and humans. Of the 209 possible PBDEs, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is usually the dominant congener found in human blood and milk samples. BDE-47 has been shown to have endocrine activity and produce developmental, reproductive, and neurotoxic effects. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for BDE-47 in male and female (pregnant and non-pregnant) adult rats to facilitate investigations of developmental exposure. This model consistsmore » of eight compartments: liver, brain, adipose tissue, kidney, placenta, fetus, blood, and the rest of the body. Concentrations of BDE-47 from the literature and from maternal-fetal pharmacokinetic studies conducted at RTI International were used to parameterize and evaluate the model. The results showed that the model simulated BDE-47 tissue concentrations in adult male, maternal, and fetal compartments within the standard deviations of the experimental data. The model's ability to estimate BDE-47 concentrations in the fetus after maternal exposure will be useful to design in utero exposure/effect studies. This PBPK model is the first one designed for any PBDE pharmaco/toxicokinetic description. The next steps will be to expand this model to simulate BDE-47 pharmacokinetics and distributions across species (mice), and then extrapolate it to humans. After mouse and human model development, additional PBDE congeners will be incorporated into the model and simulated as a mixture.« less

  1. Host pharmacokinetics and drug accumulation of anthelmintics within target helminth parasites of ruminants.

    PubMed

    Lifschitz, A; Lanusse, C; Alvarez, L

    2017-07-01

    Anthelmintic drugs require effective concentrations to be attained at the site of parasite location for a certain period to assure their efficacy. The processes of absorption, distribution, metabolism and excretion (pharmacokinetic phase) directly influence drug concentrations attained at the site of action and the resultant pharmacological effect. The aim of the current review article was to provide an overview of the relationship between the pharmacokinetic features of different anthelmintic drugs, their availability in host tissues, accumulation within target helminths and resulting therapeutic efficacy. It focuses on the anthelmintics used in cattle and sheep for which published information on the overall topic is available; benzimidazoles, macrocyclic lactones and monepantel. Physicochemical properties, such as water solubility and dissolution rate, determine the ability of anthelmintic compounds to accumulate in the target parasites and consequently final clinical efficacy. The transcuticular absorption process is the main route of penetration for different drugs in nematodes and cestodes. However, oral ingestion is a main route of drug entry into adult liver flukes. Among other factors, the route of administration may substantially affect the pharmacokinetic behaviour of anthelmintic molecules and modify their efficacy. Oral administration improves drug efficacy against nematodes located in the gastroinestinal tract especially if parasites have a reduced susceptibility. Partitioning of the drug between gastrointestinal contents, mucosal tissue and the target parasite is important to enhance the drug exposure of the nematodes located in the lumen of the abomasum and/or small intestine. On the other hand, large inter-animal variability in drug exposure and subsequent high variability in efficacy is observed after topical administration of anthelmintic compounds. As it has been extensively demonstrated under experimental and field conditions, understanding

  2. Development of a Physiologically Based Pharmacokinetic Model for Triadimefon and its Metabolite Triandimenol in Rats and Humans

    EPA Science Inventory

    physiologically based pharmacokinetic (PBPK) model was developed for the conazole fungicide triadimefon and its primary metabolite, triadimenol. Rat tissue:blood partition coefficients and metabolic constants were measured in vitro for both compounds. Pharmacokinetic data for par...

  3. Cell-size distribution in epithelial tissue formation and homeostasis

    PubMed Central

    Primo, Luca; Celani, Antonio

    2017-01-01

    How cell growth and proliferation are orchestrated in living tissues to achieve a given biological function is a central problem in biology. During development, tissue regeneration and homeostasis, cell proliferation must be coordinated by spatial cues in order for cells to attain the correct size and shape. Biological tissues also feature a notable homogeneity of cell size, which, in specific cases, represents a physiological need. Here, we study the temporal evolution of the cell-size distribution by applying the theory of kinetic fragmentation to tissue development and homeostasis. Our theory predicts self-similar probability density function (PDF) of cell size and explains how division times and redistribution ensure cell size homogeneity across the tissue. Theoretical predictions and numerical simulations of confluent non-homeostatic tissue cultures show that cell size distribution is self-similar. Our experimental data confirm predictions and reveal that, as assumed in the theory, cell division times scale like a power-law of the cell size. We find that in homeostatic conditions there is a stationary distribution with lognormal tails, consistently with our experimental data. Our theoretical predictions and numerical simulations show that the shape of the PDF depends on how the space inherited by apoptotic cells is redistributed and that apoptotic cell rates might also depend on size. PMID:28330988

  4. Pharmacokinetics of differently designed immunoliposome formulations in rats with or without hepatic colon cancer metastases.

    PubMed

    Koning, G A; Morselt, H W; Gorter, A; Allen, T M; Zalipsky, S; Kamps, J A; Scherphof, G L

    2001-09-01

    Compare pharmacokinetics of tumor-directed immunoliposomes in healthy and tumor-bearing rats (hepatic colon cancer metastases). A tumor cell-specific monoclonal antibody was attached to polyethyleneglycol-stabilized liposomes, either in a random orientation via a lipid anchor (MPB-PEG-liposomes) or uniformly oriented at the distal end of the PEG chains (Hz-PEG-liposomes). Pharmacokinetics and tissue distribution were determined using [3H]cholesteryloleylether or bilayer-anchored 5-fluoro[3H]deoxyuridine-dipalmitate ([3H]FUdR-dP) as a marker. In healthy animals clearance of PEG-(immuno)liposomes was almost log-linear and only slightly affected by antibody attachment; in tumor-bearing animals all liposomes displayed biphasic clearance. In normal and tumor animals blood elimination increased with increasing antibody density; particularly for the Hz-PEG-liposomes, and was accompanied by increased hepatic uptake, probably due to increased numbers of macrophages induced by tumor growth. The presence of antibodies on the liposomes enhanced tumor accumulation: uptake per gram tumor tissue (2-4% of dose) was similar to that of liver. Remarkably, this applied to tumor-specific and irrelevant antibody. Increased immunoliposome uptake by trypsin-treated Kupffer cells implicated involvement of high-affinity Fc-receptors on activated macrophages. Tumor growth and immunoliposome characteristics (antibody density and orientation) determine immunoliposome pharmacokinetics. Although with a long-circulating immunoliposome formulation, efficiently retaining the prodrug FUdR-dP, we achieved enhanced uptake by hepatic metastases, this was probably not mediated by specific interaction with the tumor cells, but rather by tumor-associated macrophages.

  5. Population pharmacokinetics of phenytoin in critically ill children.

    PubMed

    Hennig, Stefanie; Norris, Ross; Tu, Quyen; van Breda, Karin; Riney, Kate; Foster, Kelly; Lister, Bruce; Charles, Bruce

    2015-03-01

    The objective was to study the population pharmacokinetics of bound and unbound phenytoin in critically ill children, including influences on the protein binding profile. A population pharmacokinetic approach was used to analyze paired protein-unbound and total phenytoin plasma concentrations (n = 146 each) from 32 critically ill children (0.08-17 years of age) who were admitted to a pediatric hospital, primarily intensive care unit. The pharmacokinetics of unbound and bound phenytoin and the influence of possible influential covariates were modeled and evaluated using visual predictive checks and bootstrapping. The pharmacokinetics of protein-unbound phenytoin was described satisfactorily by a 1-compartment model with first-order absorption in conjunction with a linear partition coefficient parameter to describe the binding of phenytoin to albumin. The partitioning coefficient describing protein binding and distribution to bound phenytoin was estimated to be 8.22. Nonlinear elimination of unbound phenytoin was not supported in this patient group. Weight, allometrically scaled for clearance and volume of distribution for the unbound and bound compartments, and albumin concentration significantly influenced the partition coefficient for protein binding of phenytoin. The population model can be applied to estimate the fraction of unbound phenytoin in critically ill children given an individual's albumin concentration. © 2014, The American College of Clinical Pharmacology.

  6. Tissue compatibility and pharmacokinetics of three potential subcutaneous injectables for low-pH drug solutions.

    PubMed

    Wu, Zimei; Tucker, Ian G; Razzak, Majid; McSporran, Keith; Medlicott, Natalie J

    2010-07-01

    The aim of the study was to investigate the tissue tolerance and bioavailability of four formulations containing 5% ricobendazole solubilised at low pH, following subcutaneous injection in sheep. Formulations were: a water-in-oil emulsion, a microemulsion, a hydroxypropyl-beta-cyclodextrin (HP-beta-CD, 20%) drug solution, and a low-pH drug solution (reference). In-vitro cytotoxicity of the formulations was investigated in L929 fibroblasts using MTS viability and lactate dehydrogenase leakage assays. Each formulation and respective vehicle was injected into either side of the back of a sheep to investigate the tissue tolerance and pharmacokinetics. In-vitro studies suggested that both the emulsion and the microemulsion are unlikely to give a burst release of the low-pH drug solution in aqueous media. The microemulsion showed the greatest in-vitro cytotoxic effect but no significant difference was observed between the other formulations. In sheep, the three new formulations and vehicles caused little or no injection-site reactions compared with a marked response to the reference formulation. Bioavailabilities of HP-beta-CD formulation, emulsion and microemulsion formulations, relative to the reference formulation, were 194, 155 and 115%, respectively. The three new subcutaneous injectables showed promise for reducing irritation of low-pH solubilised ricobendazole. HP-beta-CD significantly enhanced the drug absorption. Controlling the burst release of the low-pH drug solution may improve tissue tolerance and minimise post-injection precipitation, and hence increase drug bioavailability. The in-vitro cytotoxicity studies did not predict the in-vivo irritation effects.

  7. Explicit Pharmacokinetic Modeling: Tools for Documentation, Verification, and Portability

    EPA Science Inventory

    Quantitative estimates of tissue dosimetry of environmental chemicals due to multiple exposure pathways require the use of complex mathematical models, such as physiologically-based pharmacokinetic (PBPK) models. The process of translating the abstract mathematics of a PBPK mode...

  8. The influence of labour on the pharmacokinetics of intravenously administered amoxicillin in pregnant women

    PubMed Central

    Muller, Anouk E; Dörr, P Joep; Mouton, Johan W; De Jongh, Joost; Oostvogel, Paul M; Steegers, Eric A P; Voskuyl, Rob A; Danhof, Meindert

    2008-01-01

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTExamples exist that pharmacokinetics of drugs in pregnant women can differ from that in non-pregnant individuals.In pregnant women before the onset of labour, the pharmacokinetics of amoxicillin is similar to that in non-pregnant individuals, but for women during labour this is unknown. WHAT THIS STUDY ADDSLabour influences the pharmacokinetics of amoxicillin.During labour and even more in the immediate postpartum period, the peripheral volume of distribution was decreased compared with pregnant women before the onset of labour.The volume of distribution increases with an increasing amount of oedema. AIMS Many physiological changes take place during pregnancy and labour. These might change the pharmacokinetics of amoxicillin, necessitating adjustment of the dose for prevention of neonatal infections. We investigated the influence of labour on the pharmacokinetics of amoxicillin. METHODS Pregnant women before and during labour were recruited and treated with amoxicillin intravenously. A postpartum dose was offered. Blood samples were obtained and amoxicillin concentrations were determined using high-pressure liquid chromatography. The pharmacokinetics were characterized by nonlinear mixed-effects modelling using NONMEM. RESULTS The pharmacokinetics of amoxicillin in 34 patients was best described by a three-compartment model. Moderate interindividual variability was identified in CL, central and peripheral volumes of distribution. The volume of distribution (V) increased with an increasing amount of oedema. Labour influenced the parameter estimate of peripheral volume of distribution (V2). V2 was decreased during labour, and even more in the immediate postpartum period. For all patients the population estimates (mean ± SE) for CL and V were 21.1 ± 4.1 l h−1 (CL), 8.7 ± 6.6 l (V1), 11.8 ± 7.7 l (V2) and 20.5 ± 15.4 l (V3) respectively. CONCLUSIONS The peripheral distribution volume of amoxicillin in pregnant women during

  9. Evaluation of Pharmacokinetic Assumptions Using a 443 ...

    EPA Pesticide Factsheets

    With the increasing availability of high-throughput and in vitro data for untested chemicals, there is a need for pharmacokinetic (PK) models for in vitro to in vivo extrapolation (IVIVE). Though some PBPK models have been created for individual compounds using in vivo data, we are now able to rapidly parameterize generic PBPK models using in vitro data to allow IVIVE for chemicals tested for bioactivity via high-throughput screening. However, these new models are expected to have limited accuracy due to their simplicity and generalization of assumptions. We evaluated the assumptions and performance of a generic PBPK model (R package “httk”) parameterized by a library of in vitro PK data for 443 chemicals. We evaluate and calibrate Schmitt’s method by comparing the predicted volume of distribution (Vd) and tissue partition coefficients to in vivo measurements. The partition coefficients are initially over predicted, likely due to overestimation of partitioning into phospholipids in tissues and the lack of lipid partitioning in the in vitro measurements of the fraction unbound in plasma. Correcting for phospholipids and plasma binding improved the predictive ability (R2 to 0.52 for partition coefficients and 0.32 for Vd). We lacked enough data to evaluate the accuracy of changing the model structure to include tissue blood volumes and/or separate compartments for richly/poorly perfused tissues, therefore we evaluated the impact of these changes on model

  10. Model selection for clustering of pharmacokinetic responses.

    PubMed

    Guerra, Rui P; Carvalho, Alexandra M; Mateus, Paulo

    2018-08-01

    Pharmacokinetics comprises the study of drug absorption, distribution, metabolism and excretion over time. Clinical pharmacokinetics, focusing on therapeutic management, offers important insights towards personalised medicine through the study of efficacy and toxicity of drug therapies. This study is hampered by subject's high variability in drug blood concentration, when starting a therapy with the same drug dosage. Clustering of pharmacokinetics responses has been addressed recently as a way to stratify subjects and provide different drug doses for each stratum. This clustering method, however, is not able to automatically determine the correct number of clusters, using an user-defined parameter for collapsing clusters that are closer than a given heuristic threshold. We aim to use information-theoretical approaches to address parameter-free model selection. We propose two model selection criteria for clustering pharmacokinetics responses, founded on the Minimum Description Length and on the Normalised Maximum Likelihood. Experimental results show the ability of model selection schemes to unveil the correct number of clusters underlying the mixture of pharmacokinetics responses. In this work we were able to devise two model selection criteria to determine the number of clusters in a mixture of pharmacokinetics curves, advancing over previous works. A cost-efficient parallel implementation in Java of the proposed method is publicly available for the community. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Cell-size distribution in epithelial tissue formation and homeostasis.

    PubMed

    Puliafito, Alberto; Primo, Luca; Celani, Antonio

    2017-03-01

    How cell growth and proliferation are orchestrated in living tissues to achieve a given biological function is a central problem in biology. During development, tissue regeneration and homeostasis, cell proliferation must be coordinated by spatial cues in order for cells to attain the correct size and shape. Biological tissues also feature a notable homogeneity of cell size, which, in specific cases, represents a physiological need. Here, we study the temporal evolution of the cell-size distribution by applying the theory of kinetic fragmentation to tissue development and homeostasis. Our theory predicts self-similar probability density function (PDF) of cell size and explains how division times and redistribution ensure cell size homogeneity across the tissue. Theoretical predictions and numerical simulations of confluent non-homeostatic tissue cultures show that cell size distribution is self-similar. Our experimental data confirm predictions and reveal that, as assumed in the theory, cell division times scale like a power-law of the cell size. We find that in homeostatic conditions there is a stationary distribution with lognormal tails, consistently with our experimental data. Our theoretical predictions and numerical simulations show that the shape of the PDF depends on how the space inherited by apoptotic cells is redistributed and that apoptotic cell rates might also depend on size. © 2017 The Author(s).

  12. Population Pharmacokinetics of Intranasal Scopolamine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Chow, D. S. L.; Putcha, L.

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

  13. Diet-induced obesity alters vincristine pharmacokinetics in blood and tissues of mice.

    PubMed

    Behan, James W; Avramis, Vassilios I; Yun, Jason P; Louie, Stan G; Mittelman, Steven D

    2010-05-01

    Obesity is associated with poorer outcome from many cancers, including leukemia. One possible contributor to this could be suboptimal chemotherapy dosing in obese patients. We have previously found that vincristine (VCR) is less effective in obese compared to non-obese mice with leukemia, despite weight-based dosing. In the present study, we administered (3)H-VCR to obese and control mice to determine whether obesity would cause suboptimal VCR exposure. Blood VCR concentrations were fitted with a three-compartment model using pharmacokinetic analysis (two-stage PK) in three subsets of VCR concentrations vs. time method. Tissue and blood VCR concentrations were also analyzed using non-compartmental modeling. Blood VCR concentrations showed a triexponential decay and tended to be slightly higher in the obese mice at all time-points. However, the t(1/2,beta) and t(1/2,gamma) were shorter in the obese mice (9.7 min vs. 44.5 min and 60.3h vs. 85.6h, respectively), resulting in a lower AUC(0-infinity) (13,099 ng/m Lh vs. 15,384 ng/mL h). Had the dose of VCR been "capped", as is done in clinical practice, the AUC(0-infinity) would have been 36% lower in the obese mice than the controls. Tissue disposition of VCR revealed a biexponential decay from spleen, liver, and adipose. Interestingly, VCR slowly accumulated in the bone marrow of control mice, but had a slow decay from the marrow in the obese mice. Thus, obesity alters VCR PK, causing a lower overall exposure in circulation and bone marrow. Given the high prevalence of obesity, additional PK studies should be performed in obese subjects to optimize chemotherapy dosing regimens. (c) 2010 Elsevier Ltd. All rights reserved.

  14. Pediatric Obesity: Pharmacokinetic Alterations and Effects on Antimicrobial Dosing.

    PubMed

    Natale, Stephanie; Bradley, John; Nguyen, William Huy; Tran, Tri; Ny, Pamela; La, Kirsten; Vivian, Eva; Le, Jennifer

    2017-03-01

    Limited data exist for appropriate drug dosing in obese children. This comprehensive review summarizes pharmacokinetic (PK) alterations that occur with age and obesity, and these effects on antimicrobial dosing. A thorough comparison of different measures of body weight and specific antimicrobial agents including cefazolin, cefepime, ceftazidime, daptomycin, doripenem, gentamicin, linezolid, meropenem, piperacillin-tazobactam, tobramycin, vancomycin, and voriconazole is presented. PubMed (1966-July 2015) and Cochrane Library searches were performed using these key terms: children, pharmacokinetic, obesity, overweight, body mass index, ideal body weight, lean body weight, body composition, and specific antimicrobial drugs. PK studies in obese children and, if necessary, data from adult studies were summarized. Knowledge of PK alterations stemming from physiologic changes that occur with age from the neonate to adolescent, as well as those that result from increased body fat, become an essential first step toward optimizing drug dosing in obese children. Excessive amounts of adipose tissue contribute significantly to body size, total body water content, and organ size and function that may modify drug distribution and clearance. PK studies that evaluated antimicrobial dosing primarily used total (or actual) body weight (TBW) for loading doses and TBW or adjusted body weight for maintenance doses, depending on the drugs' properties and dosing units. PK studies in obese children are imperative to elucidate drug distribution, clearance, and, consequently, the dose required for effective therapy in these children. Future studies should evaluate the effects of both age and obesity on drug dosing because the incidence of obesity is increasing in pediatric patients. © 2017 Pharmacotherapy Publications, Inc.

  15. High Throughput Pharmacokinetics for Environmental Chemicals (FutureToxII)

    EPA Science Inventory

    Pharmacokinetic (PK) models are critical to determine whether chemical exposures produce potentially hazardous tissue concentrations. For bioactivity identified in vitro (e.g. ToxCast) – hazardous or not – PK models can forecast exposure thresholds, below which no significant bio...

  16. Pharmacokinetics of Snake Venom

    PubMed Central

    Sanhajariya, Suchaya; Duffull, Stephen B.

    2018-01-01

    Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974–present) and Medline (1946–present). For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, the disposition of snake venom was described by a two-compartment model consisting of a rapid distribution phase and a slow elimination phase, with half-lives of 5 to 48 min and 0.8 to 28 h, respectively, following rapid intravenous injection of the venoms or toxins. When the venoms or toxins were administered intramuscularly or subcutaneously, an initial absorption phase and slow elimination phase were observed. The bioavailability of venoms or toxins ranged from 4 to 81.5% following intramuscular administration and 60% following subcutaneous administration. The volume of distribution and the clearance varied between snake species. For humans, 24 out of 666 initially identified publications contained sufficient information and timed venom concentrations in the absence of antivenom therapy for data extraction. The data were extracted and modelled in NONMEM. A one-compartment model provided the best fit, with an elimination half-life of 9.71 ± 1.29 h. It is intended that the quantitative information provided in this review will provide a useful basis for future studies that address the pharmacokinetics of snakebite in humans. PMID:29414889

  17. A Permeability-Limited Physiologically Based Pharmacokinetic (PBPK) Model for Perfluorooctanoic acid (PFOA) in Male Rats.

    PubMed

    Cheng, Weixiao; Ng, Carla A

    2017-09-05

    Physiologically based pharmacokinetic (PBPK) modeling is a powerful in silico tool that can be used to simulate the toxicokinetics and tissue distribution of xenobiotic substances, such as perfluorooctanoic acid (PFOA), in organisms. However, most existing PBPK models have been based on the flow-limited assumption and largely rely on in vivo data for parametrization. In this study, we propose a permeability-limited PBPK model to estimate the toxicokinetics and tissue distribution of PFOA in male rats. Our model considers the cellular uptake and efflux of PFOA via both passive diffusion and transport facilitated by various membrane transporters, association with serum albumin in circulatory and extracellular spaces, and association with intracellular proteins in liver and kidney. Model performance is assessed using seven experimental data sets extracted from three different studies. Comparing model predictions with these experimental data, our model successfully predicts the toxicokinetics and tissue distribution of PFOA in rats following exposure via both IV and oral routes. More importantly, rather than requiring in vivo data fitting, all PFOA-related parameters were obtained from in vitro assays. Our model thus provides an effective framework to test in vitro-in vivo extrapolation and holds great promise for predicting toxicokinetics of per- and polyfluorinated alkyl substances in humans.

  18. Dose Assessment of Cefquinome by Pharmacokinetic/Pharmacodynamic Modeling in Mouse Model of Staphylococcus aureus Mastitis

    PubMed Central

    Yu, Yang; Zhou, Yu-Feng; Li, Xiao; Chen, Mei-Ren; Qiao, Gui-Lin; Sun, Jian; Liao, Xiao-Ping; Liu, Ya-Hong

    2016-01-01

    This work aimed to characterize the mammary gland pharmacokinetics of cefquinome after an intramammary administration and integrate pharmacokinetic/pharmacodynamic model. The pharmacokinetic profiles of cefquinome in gland tissue were measured using high performance liquid chromatograph. Therapeutic regimens covered various dosages ranging from 25 to 800 μg/gland and multiple dosing intervals of 8, 12, and 24 h. The in vivo bacterial killing activity elevated when dosage increased or when dosing intervals were shortened. The best antibacterial effect was demonstrated by a mean 1.5 log10CFU/gland visible count reduction. On the other hand, the results showed that the percentage of time duration of drug concentration exceeding the MIC during a dose interval (%T > MIC) was generally 100% because of the influence of drug distribution caused by the blood-milk barrier. Therefore, pharmacokinetic/pharmacodynamic parameter of the ratio of area under the concentration-time curve over 24 h to the MIC (AUC0-24/MIC) was used to describe the efficacy of cefquinome instead of %T > MIC. When the magnitude of AUC0-24/MIC exceeding 16571.55 h⋅mL/g, considerable activity of about 1.5 log10CFU/g gland bacterial count reduction was observed in vivo. Based on the Monte Carlo simulation, the clinical recommended regimen of three infusions of 75 mg per quarter every 12 h can achieve a 76.67% cure rate in clinical treatment of bovine mastitis caused by Staphylococcus aureus infection. PMID:27774090

  19. Pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of monoclonal antibodies in children.

    PubMed

    Edlund, Helena; Melin, Johanna; Parra-Guillen, Zinnia P; Kloft, Charlotte

    2015-01-01

    Monoclonal antibodies (mAbs) constitute a therapeutically and economically important drug class with increasing use in both adult and paediatric patients. The rather complex pharmacokinetic and pharmacodynamic properties of mAbs have been extensively reviewed in adults. In children, however, limited information is currently available. This paper aims to comprehensively review published pharmacokinetic and pharmacokinetic-pharmacodynamic studies of mAbs in children. The current status of mAbs in the USA and in Europe is outlined, including a critical discussion of the dosing strategies of approved mAbs. The pharmacokinetic properties of mAbs in children are exhaustively summarised along with comparisons to reports in adults: for each pharmacokinetic process, we discuss the general principles and mechanisms of the pharmacokinetic/pharmacodynamic characteristics of mAbs, as well as key growth and maturational processes in children that might impact these characteristics. Throughout this review, considerable knowledge gaps are identified, especially regarding children-specific properties that influence pharmacokinetics, pharmacodynamics and immunogenicity. Furthermore, the large heterogeneity in the presentation of pharmacokinetic/pharmacodynamic data limited clinical inferences in many aspects of paediatric mAb therapy. Overall, further studies are needed to fully understand the impact of body size and maturational changes on drug exposure and response. To maximise future knowledge gain, we propose a 'Guideline for Best Practice' on how to report pharmacokinetic and pharmacokinetic-pharmacodynamic results from mAb studies in children which also facilitates comparisons. Finally, we advocate the use of more sophisticated modelling strategies (population analysis, physiology-based approaches) to appropriately characterise pharmacokinetic-pharmacodynamic relationships of mAbs and, thus, allow for a more rational use of mAb in the paediatric population.

  20. [Project to enhance bone bank tissue storage and distribution procedures].

    PubMed

    Huang, Jui-Chen; Wu, Chiung-Lan; Chen, Chun-Chuan; Chen, Shu-Hua

    2011-10-01

    Organ and tissue transplantation are now commonly preformed procedures. Improper organ bank handling procedures may increase infection risks. Execution accuracy in terms of tissue storage and distribution at our bone bank was 80%. We thus proposed an execution improvement project to enhance procedures in order to fulfill the intent of donors and ensure recipient safety. This project was designed to raise nurse professionalism, and ensure patient safety through enhanced tissue storage and distribution procedures. Education programs developed for this project focus on teaching standard operating procedures for bone and ligament storage and distribution, bone bank facility maintenance, trouble shooting and solutions, and periodic inspection systems. Cognition of proper storage and distribution procedures rose from 81% to 100%; Execution accuracy also rose from 80% to 100%. The project successfully conveyed concepts essential to the correct execution of organ storage and distribution procedures and proper organ bank facility management. Achieving and maintaining procedural and management standards is crucial to continued organ donations and the recipient safety.

  1. Pharmacokinetics Application in Biophysics Experiments

    NASA Astrophysics Data System (ADS)

    Millet, Philippe; Lemoigne, Yves

    Among the available computerised tomography devices, the Positron Emission Tomography (PET) has the advantage to be sensitive to pico-molar concentrations of radiotracers inside living matter. Devices adapted to small animal imaging are now commercially available and allow us to study the function rather than the structure of living tissues by in vivo analysis. PET methodology, from the physics of electron-positron annihilation to the biophysics involved in tracers, is treated by other authors in this book. The basics of coincidence detection, image reconstruction, spatial resolution and sensitivity are discussed in the paper by R. Ott. The use of compartment analysis combined with pharmacokinetics is described here to illustrate an application to neuroimaging and to show how parametric imaging can bring insight on the in vivo bio-distribution of a radioactive tracer with small animal PET scanners. After reporting on the use of an intracerebral β+ radiosensitive probe (βP), we describe a small animal PET experiment used to measure the density of 5HT 1 a receptors in rat brain.

  2. [Microbiological and pharmacokinetic studies on flomoxef in ophthalmologic field].

    PubMed

    Ooishi, M; Sakaue, F; Oomomo, A; Tazawa, H

    1989-05-01

    Microbiological and pharmacokinetic studies were carried out on flomoxef (FMOX, 6315-S), a new oxacephem parenteral antibiotic, in the ophthalmologic field. The results obtained are summarized as follows. FMOX has a broad antimicrobial activity spectrum against Gram-positive and Gram-negative bacteria. The MIC distribution against Staphylococcus aureus isolated from clinical cases was less than or equal to 0.20 - greater than or equal to 100 micrograms/ml with the peak value of 0.39 micrograms/ml. Concentrations of FMOX in aqueous humor and ocular tissues were determined after intravenous injection of 50 mg/kg to rabbits. FMOX showed a peak level of 2.2 micrograms/ml in the aqueous humor at 1/2 hour after administration with the ratio to serum level of 3.4%. Levels of FMOX in external and internal ocular tissues were 12.7 - 76.5 micrograms/g, less than 0.8 - 34.4 micrograms/g (ml) at 1/2 hour after administration, respectively. From these results, we concluded that FMOX may be expected to be a useful and valuable agent against infections in the ophthalmologic field.

  3. Steady-state pharmacokinetics and pharmacodynamics of cysteamine bitartrate in paediatric nephropathic cystinosis patients.

    PubMed

    Belldina, Eric B; Huang, Mei Y; Schneider, Jerry A; Brundage, Richard C; Tracy, Timothy S

    2003-11-01

    Cysteamine is used to reduce tissue cystine content in patients suffering from nephropathic cystinosis. The objectives of the current study were to investigate pharmacokinetics and pharmacodynamics of cysteamine bitartrate in children and young adults with nephropathic cystinosis. Cysteamine bitartrate was administered to 11 cystinosis patients at their regular dose level in a single-dose, open-label, steady-state study. Blood samples were collected and analysed for plasma cysteamine and white blood cell cystine content and pharmacokinetic and pharmacodynamic parameters estimated by NONMEM analysis using a linked pharmacokinetic-pharmacodynamic model. Cysteamine was rapidly cleared from the plasma (mean CL/F = 32.3 ml min(-1) kg(-1), range = 17.3-52.2), appeared to be extensively distributed (mean Vss/F = 15.1 l, range 2.7-32.3) and exhibited a mean Tmax of 1.4 h. White blood cell cystine content post-dosing was significantly decreased compared with pre- and post-dose values (average decrement approximately 47%). A counter-clockwise hysteresis was noted in all patients, suggestive of a lag time (mean Tlag = 0.44 h, range 0.22-0.92) between drug concentration and effect. The results of this study establish that cysteamine is rapidly cleared from the plasma but that an every 6 h dosing interval adequately maintains white blood cell cystine content below the target of 1 nmol cystine per mg protein.

  4. Pharmacokinetics of Lidocaine With Epinephrine Following Local Anesthesia Reversal With Phentolamine Mesylate

    PubMed Central

    Moore, Paul A; Hersh, Elliot V; Papas, Athena S; Goodson, J. Max; Yagiela, John A; Rutherford, Bruce; Rogy, Seigried; Navalta, Laura

    2008-01-01

    Phentolamine mesylate accelerates recovery from oral soft tissue anesthesia in patients who have received local anesthetic injections containing a vasoconstrictor. The proposed mechanism is that phentolamine, an alpha-adrenergic antagonist, blocks the vasoconstriction associated with the epinephrine used in dental anesthetic formulations, thus enhancing the systemic absorption of the local anesthetic from the injection site. Assessments of the pharmacokinetics of lidocaine and phentolamine, and the impact of phentolamine on the pharmacokinetics of lidocaine with epinephrine were performed to characterize this potentially valuable strategy. The blood levels of phentolamine were determined following its administration intraorally and intravenously. Additionally, the effects of phentolamine mesylate on the pharmacokinetics of intraoral injections of lidocaine with epinephrine were evaluated. Sixteen subjects were enrolled in this phase 1 trial, each receiving 4 drug treatments: 1 cartridge lidocaine/epinephrine followed after 30 minutes by 1 cartridge phentolamine (1L1P), 1 cartridge phentolamine administered intravenously (1Piv), 4 cartridges lidocaine/epinephrine followed after 30 minutes by 2 cartridges phentolamine (4L2P), and 4 cartridges lidocaine/epinephrine followed by no phentolamine (4L). Pharmacokinetic parameters estimated for phentolamine, lidocaine, and epinephrine included peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve from 0 to the last time point (AUClast) or from time 0 to infinity (AUCinf), elimination half-life (t1/2), clearance (CL), and volume of distribution (Vd). The phentolamine Tmax occurred earlier following the intravenous administration of 1Piv (7 minutes than following its submucosal administration in treatment 1L1P (15 minutes) or 4L2P (11 minutes). The phentolamine t1/2, CL, and Vd values were similar for 1L1P, 1Piv, and 4L2P. The Tmax for lidocaine occurred

  5. [Pharmacokinetics of domestic actoprotector drug Metaprot in healthy volunteers].

    PubMed

    Kibal'chich, D A; Belolipetskaia, V G; Blagodatskikh, S V; Martsevich, S Iu; Rudenko, L I; Iatsuk, V R

    2011-01-01

    Pharmacokinetics of the actoprotector Metaprot, an original Russian drug, has been studied in a group of healthy adult volunteers. Metaprot in capsules was administrated orally as a single dose of 250 mg. The concentration of the active substance (ethylthiobenzimidazole) in the blood serum was determined by high-performance liquid chromatography (HPLC) with UV detection. The pharmacokinetic parameters were calculated by the model-independent method. The peak concentration of ethylthiobenzimidazole in plasma was Cmax = 0.91 +/- 1.05 microg/ml and the average time to peak concentration was t(max) = 1.06 +/- 0.16 h. A polymodal character of the distribution of pharmacokinetic parameters in the test group was revealed.

  6. Microcomputer-Based Programs for Pharmacokinetic Simulations.

    ERIC Educational Resources Information Center

    Li, Ronald C.; And Others

    1995-01-01

    Microcomputer software that simulates drug-concentration time profiles based on user-assigned pharmacokinetic parameters such as central volume of distribution, elimination rate constant, absorption rate constant, dosing regimens, and compartmental transfer rate constants is described. The software is recommended for use in undergraduate…

  7. Pharmacokinetics and dosimetry of the antiandrogen vinclozolin after oral administration in the rat.

    PubMed

    Sierra-Santoyo, Adolfo; Castañeda-Hernández, Gilberto; Harrison, Randy A; Barton, Hugh A; Hughes, Michael F

    2008-11-01

    Vinclozolin (V) is a fungicide with antiandrogenic properties. To determine the pharmacokinetics and dosimetry of V, adult male rats were administered an oral dose of V (100 mg/kg) in corn oil and sacrificed over time after dosing. V and its metabolites were analyzed in serum and tissues by high performance liquid chromatography/diode array detector/mass spectrometer. V, 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (M1), and 3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2), and five other metabolites were detected in serum and tissues. One metabolite was identified as 3',5'-dichloro-2,3,4-trihydroxy-2-methylbutylanilide (M5). The mean serum concentration data for V were fitted to a one-compartment model for kinetic analysis. At 2 h, V serum concentration peaked; whereas only trace levels were detected at 24 h (t(1/2 elim) = 3.6 h). V was detected in all tissues and preferentially accumulated in fat. M1 serum levels increased until 8 h, being at least 2-fold higher than those of V at this time, and then declined with a t(1/2) = 3.3 h. M5 was the main metabolite in serum and tissues. Serum M5 levels were 5-fold higher than V and 2-fold greater than M1 at all times. At 48 h, M5 remained the main metabolite (t(1/2 elim) = 13.1 h). Liver and kidney exhibited the highest levels of M5, V, and M1. M2 and 3,5-dichloroaniline had the lowest levels of V metabolites in serum and tissues. V is well absorbed, extensively metabolized and widely distributed. M5, the most abundant V metabolite, may be used as an exposure biomarker for pharmacokinetic modeling. These results may clarify the relationship between toxicity and tissue dose of V and its metabolites.

  8. Improvement of the Pharmacokinetics and In Vivo Antibacterial Efficacy of a Novel Type IIa Topoisomerase Inhibitor by Formulation in Liposomes

    PubMed Central

    Newman, Joseph; Goteti, Kosalaram; Beaudoin, Marie-Eve; Harrison, Rane; Hopkins, Sussie; Agrawal, Nikunj; Rivin, Olga

    2013-01-01

    Several useful properties of liposome-based formulations of various existing antibacterial drugs have been reported. These properties include lower MICs, improved pharmacokinetics, lower toxicity, selective distribution to infected tissues, and enhanced in vivo efficacy. Here we report in vivo studies of a liposomal formulation of a member of a novel class of antibacterial type II topoisomerase inhibitors, others of which have progressed to early phases of clinical trials. The free (i.e., nonliposomal) compound has broad-spectrum MICs but suboptimal pharmacokinetics in rats and mice, characterized by a high volume of distribution and rapid clearance. The liposomal formulation of the compound had essentially unchanged MICs but greatly reduced volume of distribution and clearance in rats and mice. In an in vivo mouse model of Staphylococcus aureus infection of one thigh, the liposomal compound localized preferentially to the infected thigh, whereas the free compound showed no preference for the infected versus the uninfected thigh. Most importantly, the liposomal compound had enhanced efficacy at clearing the infection compared with the free compound. Delivery of this class of compounds as liposomal formulations may offer clinical advantages compared with free compounds. PMID:23877679

  9. Chiral Pesticide Pharmacokinetics: A Range of Values

    EPA Science Inventory

    Approximately 30% of pesticides are chiral and used as mixtures of two or more stereoisomers. In biological systems, these stereoisomers can exhibit significantly different pharmacokinetics (absorption, distribution, metabolism, and elimination). In spite of these differences, th...

  10. Expression and distribution of endocan in human tissues.

    PubMed

    Zhang, S M; Zuo, L; Zhou, Q; Gui, S Y; Shi, R; Wu, Q; Wei, W; Wang, Y

    2012-04-01

    Endocan is a novel human endothelial cell specific molecule. Its expression is regulated by cytokines and vascular endothelial growth factor (VEGF). The distribution of endocan in normal human tissues, however, remains unclear. We examined the expression of endocan in normal human tissue using immunohistochemical stains. Endocan was expressed in actively proliferative or neogeneic tissues and cells such as glandular tissues, endothelium of neovasculature, bronchial epithelium, germinal centers of lymph nodes etc. Endocan was not present in silent or resting tissues or cells such as endothelium of great arteries and spleen etc. Our findings suggest that endocan may act as a marker for angiogenesis or oncogenesis and could be regarded as a candidate gene for inflammatory tissue, neoplasia, tumor development and metastasis. The expression level of endocan may assist early diagnosis and prognosis of some tumors.

  11. Moxidectin: a review of chemistry, pharmacokinetics and use in horses

    PubMed Central

    Cobb, Rami; Boeckh, Albert

    2009-01-01

    This article reviews the current knowledge of the use of moxidectin (MOX) in horses, including its mode of action, pharmacokinetic and pharmacodynamic properties, efficacy, safety and resistance profile. Moxidectin is a second generation macrocyclic lactone (ML) with potent endectocide activity. It is used for parasite control in horses in an oral gel formulation. The principal mode of action of MOX and of other MLs is binding to gamma-aminobutyric (GABA) and glutamate-gated chloride channels. Moxidectin is different from other MLs in that it is a poor substrate for P-glycoproteins (P-gps) and therefore less susceptible to elimination from parasite cells through this mechanism. Due to its unique physicochemical and pharmacokinetic characteristics, MOX provides broad distribution into tissues, long half-life, significant residual antiparasitic activity, and high efficacy against encysted cyathostomin larvae. These characteristics allow for high efficacy and longer treatment interval against all important nematodes, when compared to other equine anthelmintics. A combination of MOX with praziquantel provides expanded spectrum of activity by adding activity against cestodes. Appropriate use of MOX allows for the development of strategic anthelmintic programmes that are different from those with conventional anthelmintics. Fewer treatments are required over a period of time, and therefore impose less frequent selection pressure for resistance. PMID:19778466

  12. Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part I: Program Implementation and Lessons Learned

    PubMed Central

    Dorman, David C.; Andersen, Melvin E.; Roper, Jerry M.; Taylor, Michael D.

    2012-01-01

    Concerns have been raised regarding environmental manganese exposure since high exposures have been associated with neurological disorders. The USA Environmental Protection Agency most recent human health risk assessment of inhaled manganese conducted in 1993 identified specific areas of uncertainty regarding manganese pharmacokinetics. This led to the development of a test rule under the USA Clean Air Act that required the generation of pharmacokinetic information on the inorganic manganese combustion products of the organometallic fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT). The Alternative Tier 2 testing program for MMT, described in this paper, has yielded substantial pharmacokinetic data and has enabled the generation of physiologically based pharmacokinetic (PBPK) models for manganese. These models are capable of predicting tissue manganese concentrations across a variety of dose routes, levels, and durations while accounting for factors such as age, gender, and reproductive status, enabling the consideration of tissue dosimetry in future risk assessments. PMID:22545047

  13. A Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin methanesulfonate (CMS) in Rat.

    PubMed

    Bouchene, Salim; Marchand, Sandrine; Couet, William; Friberg, Lena E; Gobin, Patrice; Lamarche, Isabelle; Grégoire, Nicolas; Björkman, Sven; Karlsson, Mats O

    2018-04-17

    Colistin is a polymyxin antibiotic used to treat patients infected with multidrug-resistant Gram negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model to predict tissue distribution of colistin in rat. The distribution of a drug in a tissue is commonly characterized by its tissue-to-plasma partition coefficient, K p . Colistin and its prodrug, colistin methanesulfonate (CMS) K p priors were measured experimentally from rat tissue homogenates or predicted in silico. The PK parameters of both compounds were estimated fitting in vivo their plasma concentration-time profiles from six rats receiving an i.v. bolus of CMS. The variability in the data was quantified by applying a non-linear mixed effect (NLME) modelling approach. A WB-PBPK model was developed assuming a well-stirred and perfusion-limited distribution in tissue compartments. Prior information on tissue distribution of colistin and CMS was investigated following three scenarios: K p were estimated using in silico K p priors (I) or K p were estimated using experimental K p priors (II) or K p were fixed to the experimental values (III). The WB-PBPK model best described colistun and CMS plasma concentration-time profiles in scenario II. Colistin predicted concentrations in kidneys in scenario II were higher than in other tissues, which was consistent with its large experimental K p prior. This might be explained by a high affinity of colistin for renal parenchyma and active reabsorption into the proximal tubular cells. In contrast, renal accumulation of colistin was not predicted in scenario I. Colistin and CMS clearance estimates were in agreement with published values. The developed model suggests using experimental priors over in silico K p priors for kidneys to provide a better prediction of colistin renal distribution. Such models might serve in drug development for interspecies scaling and investigating the impact of

  14. Fast deep-tissue multispectral optoacoustic tomography (MSOT) for preclinical imaging of cancer and cardiovascular disease

    NASA Astrophysics Data System (ADS)

    Taruttis, Adrian; Razansky, Daniel; Ntziachristos, Vasilis

    2012-02-01

    Optoacoustic imaging has enabled the visualization of optical contrast at high resolutions in deep tissue. Our Multispectral optoacoustic tomography (MSOT) imaging results reveal internal tissue heterogeneity, where the underlying distribution of specific endogenous and exogenous sources of absorption can be resolved in detail. Technical advances in cardiac imaging allow motion-resolved multispectral measurements of the heart, opening the way for studies of cardiovascular disease. We further demonstrate the fast characterization of the pharmacokinetic profiles of lightabsorbing agents. Overall, our MSOT findings indicate new possibilities in high resolution imaging of functional and molecular parameters.

  15. Pharmacokinetics of vephylline--a new N-substituted theophylline derivative.

    PubMed

    Staneva, D; Mihailova, D; Astroug, H; Prodanova, K; Micheva, M

    1988-01-01

    Vephylline (7,2-bis-2-hydroxyethylamino-1, 3-dimethylxanthine tartarate) is a xanthine derivative with high bronchodilating activity, low toxicity, and weak effects on the central nervous system. The aim of this study is to determine the pharmacokinetic parameters of vephylline after intravenous and oral (in solution and in tablets) administration to rabbits. Vephylline (dose 50 mg/kg b.w. intravenousely and orally in solution and dose 53.5 mg/kg b.w. in the form of tablets) is administered to the rabbits in an autocontrol crossover design at 7-days intervals. After the intravenous administration the distribution is relatively fast (t1/2 alpha = 3.28h). High values of the apparent volume of distribution--12.15 1/kg suggest tissue accumulation. Elimination is considerably slower (t1/2 beta = 19,00 h) than distribution. After oral administration of the drug in solution the absorption half-life is short and the bioavailability is relatively high. Peak plasma levels are attained at the first hour. The differences in the distribution and elimination patterns for vephylline and theophyline could determine a longer effect for the new bronchodilating drug. The results are discussed in regard to the future clinical application of vephylline.

  16. Population pharmacokinetic (PK) analysis of laromustine, an emerging alkylating agent, in cancer patients.

    PubMed

    Nassar, Ala F; Wisnewski, Adam V; King, Ivan

    2017-05-01

    1. Alkylating agents are capable of introducing an alkyl group into nucleophilic sites on DNA or RNA through covalent bond. Laromustine is an active member of a relatively new class of sulfonylhydrazine prodrugs under development as antineoplastic alkylating agents, and displays significant single-agent activity. 2. This is the first report of the population pharmacokinetic analysis of laromustine, 106 patients, 66 with hematologic malignancies and 40 with solid tumors, participated in five clinical trials worldwide. Of these, 104 patients were included in the final NONMEM analysis. 3. The population estimates for total clearance (CL) and volume of distribution of the central compartment (V 1 ) were 96.3 L/h and 45.9 L, associated with high inter-patient variability of 52.9% and 79.8% and inter-occasion variability of 26.7% and 49.3%, respectively. The population estimates for Q and V 2 were 73.2 L/h and 29.9 L, and inter-patient variability in V 2 was 63.1%, respectively. 4. The estimate of V ss (75.8 L) exceeds total body water, indicating that laromustine is distributed to tissues. The half-life is short, less than 1 h, reflecting rapid clearance. Population PK analysis showed laromustine pharmacokinetics to be independent of dose and organ function with no effect on subsequent dosing cycles.

  17. Adipose tissue content and distribution in children and adolescents with bronchial asthma.

    PubMed

    Umławska, Wioleta

    2015-02-01

    The excess of adipose tissue and the pattern of adipose tissue distribution in the body seem to play an important role in the complicated dependencies between obesity and risk of developing asthma. The aim of the present study was to determine nutritional status in children and adolescents with bronchial asthma with special emphasis on adipose tissue distribution evaluated on the basis of skin-fold thicknesses, and to determine the relationships between patterns of adipose tissue distribution and the course of the disease. Anthropometric data on height, weight, circumferences and skin-fold thicknesses were extracted from the medical histories of 261 children diagnosed with asthma bronchitis. Values for children with asthma were compared to Polish national growth reference charts. Distribution of subcutaneous adipose tissue was evaluated using principal components analysis (PCA). Multivariate linear regression analyses tested the effect of three factors on subcutaneous adipose tissue distribution: type of asthma, the severity of the disease and the duration of the disease. Mean body height in the children examined in this study was lower than in their healthy peers. Mean BMI and skin-fold thicknesses were significantly higher and lean body mass was lower in the study group. Excess body fat was noted, especially in girls. Adipose tissue was preferentially deposited in the trunk in girls with severe asthma, as well as in those who had been suffering from asthma for a longer time. The type of asthma, atopic or non-atopic, had no observable effect on subcutaneous adipose tissue distribution in children examined. The data suggest that long-treated subjects and those with severe bronchial asthma accumulate more adipose tissue on the trunk. It is important to regularly monitor nutritional status in children with asthma, especially in those receiving high doses of systemic or inhaled glucocorticosteroids, and long-term treatment as well. Copyright © 2014 Elsevier Ltd. All

  18. Tissue distribution of human acetylcholinesterase and butyrylcholinesterase messenger RNA

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Jbilo, O.; Barteles, C.F.; Chatonnet, A.

    1994-12-31

    Tissue distribution of human acetyicholinesterase and butyryicholinesterase messenger RNA. 1 Cholinesterase inhibitors occur naturally in the calabar bean (eserine), green potatoes (solanine), insect-resistant crab apples, the coca plant (cocaine) and snake venom (fasciculin). There are also synthetic cholinesterase inhibitors, for example man-made insecticides. These inhibitors inactivate acetyicholinesterase and butyrylcholinesterase as well as other targets. From a study of the tissue distribution of acetylcholinesterase and butyrylcholinesterase mRNA by Northern blot analysis, we have found the highest levels of butyrylcholinesterase mRNA in the liver and lungs, tissues known as the principal detoxication sites of the human body. These results indicate that butyrylcholinesterasemore » may be a first line of defense against poisons that are eaten or inhaled.« less

  19. Three-Dimensional Optical Mapping of Nanoparticle Distribution in Intact Tissues.

    PubMed

    Sindhwani, Shrey; Syed, Abdullah Muhammad; Wilhelm, Stefan; Glancy, Dylan R; Chen, Yih Yang; Dobosz, Michael; Chan, Warren C W

    2016-05-24

    The role of tissue architecture in mediating nanoparticle transport, targeting, and biological effects is unknown due to the lack of tools for imaging nanomaterials in whole organs. Here, we developed a rapid optical mapping technique to image nanomaterials in intact organs ex vivo and in three-dimensions (3D). We engineered a high-throughput electrophoretic flow device to simultaneously transform up to 48 tissues into optically transparent structures, allowing subcellular imaging of nanomaterials more than 1 mm deep into tissues which is 25-fold greater than current techniques. A key finding is that nanomaterials can be retained in the processed tissue by chemical cross-linking of surface adsorbed serum proteins to the tissue matrix, which enables nanomaterials to be imaged with respect to cells, blood vessels, and other structures. We developed a computational algorithm to analyze and quantitatively map nanomaterial distribution. This method can be universally applied to visualize the distribution and interactions of materials in whole tissues and animals including such applications as the imaging of nanomaterials, tissue engineered constructs, and biosensors within their intact biological environment.

  20. Effects of imposed acid-base derangement on the cardiovascular effects and pharmacokinetics of bupivacaine and thiopental.

    PubMed

    Mather, Laurence E; Ladd, Leigh A; Copeland, Susan E; Chang, Dennis H-T

    2004-06-01

    By changing physicochemical properties such as effective lipophilicity, changes in blood pH could alter the distribution, elimination, and effects of weakly ionizing drugs. The authors examined the outcome of imposed acid-base derangement on cardiovascular effects and myocardial and whole body pharmacokinetics of bupivacaine, a weak base, and thiopental, a weak acid. Intravenous infusions of rac-bupivacaine HCl (37.5 mg) or rac-thiopental sodium (250 mg, subanesthetic dose) were administered over 3 min to previously instrumented conscious ewes with normal blood pH, acidemia imposed by lactic acid infusion, or alkalemia imposed by bicarbonate infusion. Hemodynamic and electrocardiographic effects were recorded; arterial and coronary sinus drug blood concentrations were analyzed by chiral high-performance liquid chromatography. Bupivacaine decreased myocardial contractility, coronary perfusion, heart rate, and cardiac output; however, cardiac output and stroke volume were not as affected by bupivacaine with acidemia. Thiopental decreased myocardial contractility and stroke volume and increased heart rate; acidemia enhanced the tachycardia and produced a greater decrease in stroke volume than with alkalemia. Taken as a whole, the cardiovascular changes were not systematically modified by acid-base derangement. Overall, the tissue distribution of bupivacaine was favored by alkalemia, but thiopental pharmacokinetics were essentially unaffected by acid-base derangement. Acid-base derangement did not influence the kinetics of either drug enantioselectively. At the doses used, the hemodynamic and electrocardiographic effects of bupivacaine and thiopental were not systematically modified by acid-base derangement, nor were there changes in regional or whole body pharmacokinetics of either drug that were clearly related to acid-base status.

  1. Pharmacokinetics of the dipeptidyl peptidase 4 inhibitor saxagliptin in rats, dogs, and monkeys and clinical projections.

    PubMed

    Fura, Aberra; Khanna, Ashish; Vyas, Viral; Koplowitz, Barry; Chang, Shu-Ying; Caporuscio, Christian; Boulton, David W; Christopher, Lisa J; Chadwick, Kristina D; Hamann, Lawrence G; Humphreys, W Griffith; Kirby, Mark

    2009-06-01

    Saxagliptin is a potent, selective, reversible dipeptidyl peptidase 4 (DPP4) inhibitor specifically designed for extended inhibition of the DPP4 enzyme and is currently under development for the treatment of type-2 diabetes. The pharmacokinetics of saxagliptin were evaluated in rats, dogs, and monkeys and used to predict its human pharmacokinetics. Saxagliptin was rapidly absorbed and had good bioavailability (50-75%) in the species tested. The plasma clearance of saxagliptin was higher in rats (115 ml/min/kg) than in dogs (9.3 ml/min/kg) and monkeys (14.5 ml/min/kg) and was predicted to be low to moderate in humans. The plasma elimination half-life was between 2.1 and 4.4 h in rats, dogs, and monkeys, and both metabolism and renal excretion contributed to the overall elimination. The primary metabolic clearance pathway involved the formation of a significant circulating, pharmacologically active hydroxylated metabolite, M2. The volume of distribution values observed in rats, dogs, and monkeys (1.3-5.2 l/kg) and predicted for humans (2.7 l/kg) were greater than those for total body water, indicating extravascular distribution. The in vitro serum protein binding was low (< or =30%) in rats, dogs, monkeys, and humans. After intra-arterial administration of saxagliptin to Sprague-Dawley and Zucker diabetic fatty rats, higher levels of saxagliptin and M2 were observed in the intestine (a proposed major site of drug action) relative to that in plasma. Saxagliptin has prolonged pharmacodynamic properties relative to its plasma pharmacokinetic profile, presumably due to additional contributions from M2, distribution of saxagliptin and M2 to the intestinal tissue, and prolonged dissociation of both saxagliptin and M2 from DPP4.

  2. A comparative review of the pharmacokinetics of boric acid in rodents and humans.

    PubMed

    Murray, F J

    1998-01-01

    The pharmacokinetics of boric acid (BA) have been studied in animals and humans. Orally administered BA is readily and completely absorbed in rats, rabbits, and humans, as well as other animal species. In animals and humans, absorbed BA appears to be rapidly distributed throughout the body water via passive diffusion. Following administration of BA, the ratio of blood: soft tissue concentrations of boron (B) is approx 1.0 in rats and humans; in contrast, concentrations of B in bone exceed those in blood by a factor of approx 4 in both rats and humans. In rats, adipose tissue concentrations of B are only 20% of the levels found in blood and soft tissues; however, human data on adipose tissue levels are not available. BA does not appear to be metabolized in either animals or humans owing to the excessive energy required to break the B-O bond. BA has an affinity for cis-hydroxy groups, and it has been hypothesized to elicit its biological activity through this mechanism. The elimination kinetics of BA also appear to be similar for rodents and humans. BA is eliminated unchanged in the urine. The kinetics of elimination were evaluated in human volunteers given BA orally or intravenously; the half-life for elimination was essentially the same (approx 21 h) by either route of exposure. In rats, blood and tissue levels of B reached steady-state after 3-4 d of oral administration of BA; assuming first-order kinetics, a half-life of 14-19 h may be calculated. The lack of metabolism of BA eliminates metabolic clearance as a potential source of interspecies variation. Accordingly, in the absence of differences in metabolic clearance, renal clearance is expected to be the major determinant of interspecies variation in pharmacokinetics. Because glomerular filtration rates are slightly higher in rats than in humans, the slight difference in half-lives may be readily explained. The most sensitive toxicity end point for BA appears to be developmental toxicity in rats, with a No

  3. The influence of Actinobacillus pleuropneumoniae infection on tulathromycin pharmacokinetics and lung tissue disposition in pigs.

    PubMed

    Gajda, A; Bladek, T; Jablonski, A; Posyniak, A

    2016-04-01

    A tulathromycin concentration and pharmacokinetic parameters in plasma and lung tissue from healthy pigs and Actinobacillus pleuropneumoniae (App)-infected pigs were compared. Tulathromycin was administered intramuscularly (i.m.) to all pigs at a single dose of 2.5 mg/kg. Blood and lung tissue samples were collected during 33 days postdrug application. Tulathromycin concentration in plasma and lung was determined by high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. The mean maximum plasma concentration (Cmax ) in healthy pigs was 586 ± 71 ng/mL, reached by 0.5 h, while the mean value for Cmax of tulathromycin in infected pigs was 386 ± 97 ng/mL after 0.5 h. The mean maximum tulathromycin concentration in lung of healthy group was calculated as 3412 ± 748 ng/g, detected at 12 h, while in pigs with App, the highest concentration in lung was 3337 ± 937 ng/g, determined at 48 h postdosing. The higher plasma and lung concentrations in pigs with no pulmonary inflammation were observed at the first time points sampling after tulathromycin administration, but slower elimination with elimination half-life t1/2el  = 126 h in plasma and t1/2el  = 165 h in lung, as well as longer drug persistent in infected pigs, was found. © 2015 John Wiley & Sons Ltd.

  4. Pharmacokinetics of Mequindox and Its Marker Residue 1,4-Bisdesoxymequindox in Swine Following Multiple Oral Gavage and Intramuscular Administration: An Experimental Study Coupled with Population Physiologically Based Pharmacokinetic Modeling.

    PubMed

    Zeng, Dongping; Lin, Zhoumeng; Fang, Binghu; Li, Miao; Gehring, Ronette; Riviere, Jim E; Zeng, Zhenling

    2017-07-19

    Mequindox (MEQ) is a quinoxaline-N,N-dioxide antibiotic used in food-producing animals. MEQ residue in animal-derived foods is a food safety concern. The tissue distribution of MEQ and its marker residue 1,4-bisdesoxymequindox (M1) were determined in swine following oral gavage or intramuscular injection twice daily for 3 days. The experimental data were used to construct a flow-limited physiologically based pharmacokinetic (PBPK) model. The model predictions correlated with available data well. Monte Carlo analysis showed that the times needed for M1 concentrations to fall below limit of detection (5 μg/kg) in liver for the 99th percentile of the population were 27 and 34 days after oral gavage and intramuscular administration twice daily for 3 days, respectively. This population PBPK model can be used to predict depletion kinetic profiles and tissue residues of MEQ's marker residue M1 in swine and as a foundation for scaling to other quinoxaline-N,N-dioxide antibiotics and to other animal species.

  5. Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in non-anesthetized rat.

    PubMed

    Wong, Yin Cheong; Ilkova, Trayana; van Wijk, Rob C; Hartman, Robin; de Lange, Elizabeth C M

    2018-01-01

    Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to occupy the available D2 receptors and antagonize the action of dopamine or drugs on D2 in preclinical studies. The aims of this study were to comprehensively evaluate its pharmacokinetic (PK) profiles in different brain compartments and to establish a PK-RO model that could predict the brain distribution and RO of raclopride in the freely moving rat using a LC-MS based approach. Rats (n=24) received a 10-min IV infusion of non-radiolabeled raclopride (1.61μmol/kg, i.e. 0.56mg/kg). Plasma and the brain tissues of striatum (with high density of D2 receptors) and cerebellum (with negligible amount of D2 receptors) were collected. Additional microdialysis experiments were performed in some rats (n=7) to measure the free drug concentration in the extracellular fluid of the striatum and cerebellum. Raclopride concentrations in all samples were analyzed by LC-MS. A population PK-RO model was constructed in NONMEM to describe the concentration-time profiles in the unbound plasma, brain extracellular fluid and brain tissue compartments and to estimate the RO based on raclopride-D2 receptor binding kinetics. In plasma raclopride showed a rapid distribution phase followed by a slower elimination phase. The striatum tissue concentrations were consistently higher than that of cerebellum tissue throughout the whole experimental period (10-h) due to higher non-specific tissue binding and D2 receptor binding in the striatum. Model-based simulations accurately predicted the literature data on rat plasma PK, brain tissue PK and D2 RO at different time points after intravenous or subcutaneous administration of raclopride at tracer dose (RO <10%), sub-pharmacological dose (RO 10%-30%) and pharmacological

  6. Comparative Kinetics and Distribution to Target Tissues of Organophosphates Using Physiologically - Based Pharmacokinetic Modeling

    DTIC Science & Technology

    2008-03-01

    throughout history where nerve agents have been used on human populations, such as the subway bombing in Tokyo and Matsumoto, Japan. Data can be...kidney, fat, diaphragm, arterial blood, venous blood, bronchial passages, and the skin. The remaining tissues will be lumped together as either slowly...were then further developed as a weapon, whose primary effect is on the central nervous system. These agents are tabun, sarin, soman, and VX. They

  7. A PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODEL FOR intravenous and ingested DIMETHYLARSINIC ACID (DMAV) IN MICE.

    EPA Science Inventory

    A physiologically based pharmacokinetic (PBPK) model for the organoarsenical dimethylarsinic acid (DMA(V)) was developed in mice. The model was calibrated using tissue time course data from multiple tissues in mice administered DMA(V) intravenously. The final model structure was ...

  8. Population pharmacokinetic modelling of non-linear brain distribution of morphine: influence of active saturable influx and P-glycoprotein mediated efflux

    PubMed Central

    Groenendaal, D; Freijer, J; de Mik, D; Bouw, M R; Danhof, M; de Lange, E C M

    2007-01-01

    Background and purpose: Biophase equilibration must be considered to gain insight into the mechanisms underlying the pharmacokinetic-pharmacodynamic (PK-PD) correlations of opioids. The objective was to characterise in a quantitative manner the non-linear distribution kinetics of morphine in brain. Experimental approach: Male rats received a 10-min infusion of 4 mg kg−1 of morphine, combined with a continuous infusion of the P-glycoprotein (Pgp) inhibitor GF120918 or vehicle, or 40 mg kg−1 morphine alone. Unbound extracellular fluid (ECF) concentrations obtained by intracerebral microdialysis and total blood concentrations were analysed using a population modelling approach. Key results: Blood pharmacokinetics of morphine was best described with a three-compartment model and was not influenced by GF120918. Non-linear distribution kinetics in brain ECF was observed with increasing dose. A one compartment distribution model was developed, with separate expressions for passive diffusion, active saturable influx and active efflux by Pgp. The passive diffusion rate constant was 0.0014 min−1. The active efflux rate constant decreased from 0.0195 min−1 to 0.0113 min−1 in the presence of GF120918. The active influx was insensitive to GF120918 and had a maximum transport (Nmax/Vecf) of 0.66 ng min−1 ml−1 and was saturated at low concentrations of morphine (C50=9.9 ng ml−1). Conclusions and implications: Brain distribution of morphine is determined by three factors: limited passive diffusion; active efflux, reduced by 42% by Pgp inhibition; low capacity active uptake. This implies blood concentration-dependency and sensitivity to drug-drug interactions. These factors should be taken into account in further investigations on PK-PD correlations of morphine. PMID:17471182

  9. Pharmacokinetic assessment of dapivirine vaginal microbicide gel in healthy, HIV-negative women.

    PubMed

    Nel, Annalene M; Coplan, Paul; Smythe, Shanique C; McCord, Karen; Mitchnick, Mark; Kaptur, Paulina E; Romano, Joseph

    2010-11-01

    To assess the pharmacokinetics of dapivirine in plasma and dapivirine concentrations in cervicovaginal fluids (CVF) and cervicovaginal tissues following vaginal administration of dapivirine microbicide gel in healthy, HIV-negative women for 10 days. A randomized, double-blind, phase I study was conducted at a single research center in South Africa. A total of 18 women used dapivirine gel (0.001%, 0.005%, or 0.02%) once daily on Days 1 and 10 and twice daily on Days 2-9. Pharmacokinetics of dapivirine were assessed in plasma on Days 1 and 10. Dapivirine concentrations were measured in CVF on Days 1 and 10 and in cervicovaginal tissues on Day 10. Safety was evaluated through laboratory tests (hematology, clinical chemistry, and urinalysis), physical examinations, and assessment of adverse events. Plasma concentrations of dapivirine increased over time with gel dose and were greater on Day 10 (C(max) 31 to 471 pg/ml) than Day 1 (C(max) 23 to 80 pg/ml). T(max) was 10-12 h on Day 1, and 9 h on Day 10. Concentrations in CVF generally increased with dose but were highly variable among participants. Mean peak values ranged from 4.6-8.3 × 10(6) pg/ml on Day 1 and from 2.3-20.7 × 10(6) pg/ml on Day 10 across dose groups. Dapivirine was detectable in all tissue biopsies on Day 10 at concentrations of 1.0-356 × 10(3) pg/mg. Dapivirine was widely distributed throughout the lower genital tract with low systemic absorption when administered in a vaginal gel formulation for 10 consecutive days. The gel was safe and well tolerated.

  10. Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach.

    PubMed

    Marsot, Amélie; Brevaut-Malaty, Véronique; Vialet, Renaud; Boulamery, Audrey; Bruguerolle, Bernard; Simon, Nicolas

    2014-08-01

    Phenobarbital is widely used for treatment of neonatal seizures. Its optimal use in neonates and young infants requires information regarding pharmacokinetics. The objective of this study is to characterize the absolute bioavailability of phenobarbital in neonates and young infants, a pharmacokinetic parameter which has not yet been investigated. Routine clinical pharmacokinetic data were retrospectively collected from 48 neonates and infants (weight: 0.7-10 kg; patient's postnatal age: 0-206 days; GA: 27-42 weeks) treated with phenobarbital, who were administered as intravenous or suspension by oral routes and hospitalized in a paediatric intensive care unit. Total mean dose of 4.6 mg/kg (3.1-10.6 mg/kg) per day was administered by 30-min infusion or by oral route. Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model software). Data were modelled with an allometric pharmacokinetic model, using three-fourths scaling exponent for clearance (CL). The population typical mean [per cent relative standard error (%RSE)] values for CL, apparent volume of distribution (Vd ) and bioavailability (F) were 0.0054 L/H/kg (7%), 0.64 L/kg (15%) and 48.9% (22%), respectively. The interindividual variability of CL, Vd , F (%RSE) and residual variability (%RSE) was 17% (31%), 50% (27%), 39% (27%) and 7.2 mg/L (29%), respectively. The absolute bioavailability of phenobarbital in neonates and infants was estimated. The dose should be increased when switching from intravenous to oral administration. © 2013 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.

  11. Analytical Techniques and Pharmacokinetics of Gastrodia elata Blume and Its Constituents.

    PubMed

    Wu, Jinyi; Wu, Bingchu; Tang, Chunlan; Zhao, Jinshun

    2017-07-08

    Gastrodia elata Blume ( G. elata ), commonly called Tianma in Chinese, is an important and notable traditional Chinese medicine (TCM), which has been used in China as an anticonvulsant, analgesic, sedative, anti-asthma, anti-immune drug since ancient times. The aim of this review is to provide an overview of the abundant efforts of scientists in developing analytical techniques and performing pharmacokinetic studies of G. elata and its constituents, including sample pretreatment methods, analytical techniques, absorption, distribution, metabolism, excretion (ADME) and influence factors to its pharmacokinetics. Based on the reported pharmacokinetic property data of G. elata and its constituents, it is hoped that more studies will focus on the development of rapid and sensitive analytical techniques, discovering new therapeutic uses and understanding the specific in vivo mechanisms of action of G. elata and its constituents from the pharmacokinetic viewpoint in the near future. The present review discusses analytical techniques and pharmacokinetics of G. elata and its constituents reported from 1985 onwards.

  12. Pharmacokinetics of pirfenidone after topical administration in rabbit eye

    PubMed Central

    Sun, Guoying; Lin, Xianchai; Zhong, Hua; Yang, Yangfan; Qiu, Xuan; Ye, Chengtian; Wu, Kaili

    2011-01-01

    Purpose Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) is a new, broad-spectrum agent that has an inhibition effect on the proliferation, migration, and collagen contraction of human Tenon’s fibroblasts, and thus modulating the wound healing process of glaucoma filtering surgical site. This study investigated the pharmacokinetics of topically administered pirfenidone (0.5%) in rabbit eyes. Methods Pirfenidone solution (50 μl) was instilled into the rabbit’s conjunctival sac. The rabbits were quickly sacrificed at 2, 5, 8, 10, 15, 20, 30, 60, 90, and 120 min after the administration and ocular tissues were obtained. The concentrations of pirfenidone in conjunctiva, sclera, cornea, aqueous humor, and vitreous were determined by high performance liquid chromatography. Results After topical administration, there was wide distribution and fast clearance of pirfenidone among the various ocular tissues. The mean maximum concentrations (Cmax) of pirfenidone in cornea, conjunctiva, sclera, aqueous humor, and vitreous were 9.64 mg/g, 9.62 mg/g, 2.13 mg/g, 34.88 mg/l and 0.52 mg/l, respectively. The half-life for these tissues was 18.26, 34.16, 15.71, 70.91, and 39.48 min, respectively. Conclusions Measurable concentrations of pirfenidone are achieved in ocular tissues after topical application in rabbit model. Topical administration of pirfenidone may be an effective approach for modulation of wound healing responses in glaucoma filtration surgical site. PMID:21866212

  13. Modeling Single and Repeated Dose Pharmacokinetics of PFOA in Mice (J)

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA) displays complicated pharmacokinetics in that serum concentrations indicate long half-lives despite which steady state appears to be achieved rapidly. In this study, serum and tissue concentration time-courses were obtained for male and female CD1 m...

  14. Physiologically based pharmacokinetic modeling of PLGA nanoparticles with varied mPEG content

    PubMed Central

    Li, Mingguang; Panagi, Zoi; Avgoustakis, Konstantinos; Reineke, Joshua

    2012-01-01

    Biodistribution of nanoparticles is dependent on their physicochemical properties (such as size, surface charge, and surface hydrophilicity). Clear and systematic understanding of nanoparticle properties’ effects on their in vivo performance is of fundamental significance in nanoparticle design, development and optimization for medical applications, and toxicity evaluation. In the present study, a physiologically based pharmacokinetic model was utilized to interpret the effects of nanoparticle properties on previously published biodistribution data. Biodistribution data for five poly(lactic-co-glycolic) acid (PLGA) nanoparticle formulations prepared with varied content of monomethoxypoly (ethyleneglycol) (mPEG) (PLGA, PLGA-mPEG256, PLGA-mPEG153, PLGA-mPEG51, PLGA-mPEG34) were collected in mice after intravenous injection. A physiologically based pharmacokinetic model was developed and evaluated to simulate the mass-time profiles of nanoparticle distribution in tissues. In anticipation that the biodistribution of new nanoparticle formulations could be predicted from the physiologically based pharmacokinetic model, multivariate regression analysis was performed to build the relationship between nanoparticle properties (size, zeta potential, and number of PEG molecules per unit surface area) and biodistribution parameters. Based on these relationships, characterized physicochemical properties of PLGA-mPEG495 nanoparticles (a sixth formulation) were used to calculate (predict) biodistribution profiles. For all five initial formulations, the developed model adequately simulates the experimental data indicating that the model is suitable for description of PLGA-mPEG nanoparticle biodistribution. Further, the predicted biodistribution profiles of PLGA-mPEG495 were close to experimental data, reflecting properly developed property–biodistribution relationships. PMID:22419876

  15. Population Pharmacokinetics of Bevacizumab in Children with Osteosarcoma: Implications for Dosing

    PubMed Central

    Turner, David C.; Navid, Fariba; Daw, Najat C.; Mao, Shenghua; Wu, Jianrong; Santana, Victor M.; Neel, Michael; Rao, Bhaskar; Willert, Jennifer Reikes; Loeb, David M.; Harstead, K. Elaine; Throm, Stacy L.; Freeman, Burgess B.; Stewart, Clinton F.

    2014-01-01

    Purpose To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Experimental Design Prior to tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age 12.2 years) enrolled on a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Results Bevacizumab concentration-time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space,49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure as body mass index percentile was significantly (p<0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure prior to primary tumor resection was associated with increased risk of major wound healing complications after surgery (p<0.05). Conclusion A population pharmacokinetic model for bevacizumab was developed which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications. PMID:24637635

  16. Identification of intestinal loss of a drug through physiologically based pharmacokinetic simulation of plasma concentration-time profiles.

    PubMed

    Peters, Sheila Annie

    2008-01-01

    Despite recent advances in understanding of the role of the gut as a metabolizing organ, recognition of gut wall metabolism and/or other factors contributing to intestinal loss of a compound has been a challenging task due to the lack of well characterized methods to distinguish it from first-pass hepatic extraction. The implications of identifying intestinal loss of a compound in drug discovery and development can be enormous. Physiologically based pharmacokinetic (PBPK) simulations of pharmacokinetic profiles provide a simple, reliable and cost-effective way to understand the mechanisms underlying pharmacokinetic processes. The purpose of this article is to demonstrate the application of PBPK simulations in bringing to light intestinal loss of orally administered drugs, using two example compounds: verapamil and an in-house compound that is no longer in development (referred to as compound A in this article). A generic PBPK model, built in-house using MATLAB software and incorporating absorption, metabolism, distribution, biliary and renal elimination models, was employed for simulation of concentration-time profiles. Modulation of intrinsic hepatic clearance and tissue distribution parameters in the generic PBPK model was done to achieve a good fit to the observed intravenous pharmacokinetic profiles of the compounds studied. These optimized clearance and distribution parameters are expected to be invariant across different routes of administration, as long as the kinetics are linear, and were therefore employed to simulate the oral profiles of the compounds. For compounds with reasonably good solubility and permeability, an area under the concentration-time curve for the simulated oral profile that far exceeded the observed would indicate some kind of loss in the intestine. PBPK simulations applied to compound A showed substantial loss of the compound in the gastrointestinal tract in humans but not in rats. This accounted for the lower bioavailability of the

  17. Transferrin receptors in human tissues: their distribution and possible clinical relevance.

    PubMed

    Gatter, K C; Brown, G; Trowbridge, I S; Woolston, R E; Mason, D Y

    1983-05-01

    The distribution of transferrin receptors (TR) has been studied in a range of normal and malignant tissues using four monoclonal antibodies, BK19.9, B3/25, T56/14 and T58/1. In normal tissues TR was found in a limited number of sites, notably basal epidermis, the endocrine pancreas, hepatocytes, Kupffer cells, testis and pituitary. This restricted pattern of distribution may be relevant to the characteristic pattern of iron deposition in primary haemachromatosis. In contrast to this limited pattern of expression in normal tissue, the receptor was widely distributed in carcinomas, sarcomas and in samples from cases of Hodgkin's disease. This malignancy-associated expression of the receptor may play a role in the anaemia of advanced malignancy by competing with the bone marrow for serum iron.

  18. Transferrin receptors in human tissues: their distribution and possible clinical relevance.

    PubMed Central

    Gatter, K C; Brown, G; Trowbridge, I S; Woolston, R E; Mason, D Y

    1983-01-01

    The distribution of transferrin receptors (TR) has been studied in a range of normal and malignant tissues using four monoclonal antibodies, BK19.9, B3/25, T56/14 and T58/1. In normal tissues TR was found in a limited number of sites, notably basal epidermis, the endocrine pancreas, hepatocytes, Kupffer cells, testis and pituitary. This restricted pattern of distribution may be relevant to the characteristic pattern of iron deposition in primary haemachromatosis. In contrast to this limited pattern of expression in normal tissue, the receptor was widely distributed in carcinomas, sarcomas and in samples from cases of Hodgkin's disease. This malignancy-associated expression of the receptor may play a role in the anaemia of advanced malignancy by competing with the bone marrow for serum iron. Images PMID:6302135

  19. Metabolic pathways and pharmacokinetics of natural medicines with low permeability.

    PubMed

    Zeng, Mei; Yang, Lan; He, Dan; Li, Yao; Shi, Mingxin; Zhang, Jingqing

    2017-11-01

    Drug metabolism plays an important role in the drug disposal process. Differences in pharmacokinetics among individuals are the basis for personalized medicine. Natural medicines, formed by long-term evolution of nature, prioritize the action of a target protein with a drug. Natural medicines are valued for structural diversity, low toxicity, low cost, and definite biological activities. Metabolic pathway and pharmacokinetic research of natural medicines is highly beneficial for clinical dose adjustment and the development of personalized medicine. This review was performed using a systematic search of all available literature. It provides an overview and discussion of metabolic pathways and the pharmacokinetics of natural medicines with low permeability. The related enzymes and factors affecting them are analyzed. The series of metabolic reactions, including phase I reactions(oxidation hydrolysis, and reduction reactions) and phase II reactions (binding reactions), catalyzed by intracellular metabolic enzymes (such as CYP450, esterase, SULT, and UGT enzymes) in tissues (such as liver and gastro-intestinal tract) or in the body fluid environment were examined. The administration route, drug dose, and delivery system had a large influence on absorption, metabolism, and pharmacokinetics. Natural medicines with low permeability had distinctive metabolisms and pharmacokinetics. The metabolic and in vivo kinetic properties were favorably modified by choosing suitable drug delivery systems, administration routes and drug doses, among other variables. This study provides valuable information for clinicians and pharmacists to guide patients safe, effective, and rational drug use. The research of metabolism and pharmacokinetics is significant in guiding personalized clinical medicine.

  20. Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine.

    PubMed

    Hartmanshenn, Clara; Scherholz, Megerle; Androulakis, Ioannis P

    2016-10-01

    Personalized medicine strives to deliver the 'right drug at the right dose' by considering inter-person variability, one of the causes for therapeutic failure in specialized populations of patients. Physiologically-based pharmacokinetic (PBPK) modeling is a key tool in the advancement of personalized medicine to evaluate complex clinical scenarios, making use of physiological information as well as physicochemical data to simulate various physiological states to predict the distribution of pharmacokinetic responses. The increased dependency on PBPK models to address regulatory questions is aligned with the ability of PBPK models to minimize ethical and technical difficulties associated with pharmacokinetic and toxicology experiments for special patient populations. Subpopulation modeling can be achieved through an iterative and integrative approach using an adopt, adapt, develop, assess, amend, and deliver methodology. PBPK modeling has two valuable applications in personalized medicine: (1) determining the importance of certain subpopulations within a distribution of pharmacokinetic responses for a given drug formulation and (2) establishing the formulation design space needed to attain a targeted drug plasma concentration profile. This review article focuses on model development for physiological differences associated with sex (male vs. female), age (pediatric vs. young adults vs. elderly), disease state (healthy vs. unhealthy), and temporal variation (influence of biological rhythms), connecting them to drug product formulation development within the quality by design framework. Although PBPK modeling has come a long way, there is still a lengthy road before it can be fully accepted by pharmacologists, clinicians, and the broader industry.

  1. Pharmacokinetic profile of Mitoguazone (MGBG) in patients with AIDS related non-Hodgkin's lymphoma.

    PubMed

    Rizzo, J; Levine, A M; Weiss, G R; Pearce, T; Kraynak, M; Mueck, R; Smith, S; Von Hoff, D D; Kuhn, J G

    1996-01-01

    Mitoguazone is a unique chemotherapeutic agent whose activity is believed to result primarily from the competitive inhibition of S-adenosyl-methionine decarboxylase leading to a disruption in polyamine biosynthesis. Initial clinical trials demonstrated that the dose-limiting toxicities (mucositis and myelosuppression) of Mitoguazone were both dose and schedule dependent. Early pharmacokinetic studies of Mitoguazone in man revealed a prolonged half-life. Concurrent with a recent Phase II trial of Mitoguazone in patients with AIDS related non-Hodgkin's lymphoma, the single dose pharmacokinetics of Mitoguazone were characterized. Twelve patients received 600 mg/m2 of intravenous Mitoguazone over 30 minutes on an intermittent every 2 week schedule. Blood, urine, cerebrospinal fluid (CSF), pleural fluid and tissue samples were collected and analyzed by HPLC. Mitoguazone was cleared from the plasma triexponentially with a harmonic mean terminal half-life of 175 hours and a mean residence time of 192 hours. Peak plasma levels occurred immediately post-infusion, ranged from 6.47 to 42.8 micrograms/ml, and remained (for an extended period) well above the reported concentration for inhibition of polyamine biosynthesis. Plasma clearance averaged 4.73 l/hr/m2 with a relatively large apparent volume of distribution at steady-state of 1012 l/m2 indicating tissue sequestration. Renal excretion of unchanged Mitoguazone accounted for an average of 15.8% of the dose within 48 to 72 hours post-administration. Detectable levels of drug were present in random voided samples eight days post-dose. Mitoguazone levels in CSF ranged from 22 to 186 ng/ml post-dose with CSF/plasma ratios ranging from 0.6% to 7%. The pleural fluid/plasma ratio was approximately 1. Tissue levels of Mitoguazone were highest in the liver followed by lymph node, spleen and the brain.

  2. Pharmacokinetics of pyropheophorbide-a-hexyl ether in the dog.

    PubMed

    Payne, J T; McCaw, D L; Casteel, S W; Frazier, D; Rogers, K; Tompson, R V

    1996-01-01

    Pyropheophorbide-a-hexyl ether (HPPH) is a new compound being investigated for use as a photosensitizer for photodynamic therapy; however, the pharmacokinetics are not known for any of the target species likely to be treated with this drug. The objective of this study was to determine the pharmacokinetic parameters of this drug prior to institution of a clinical trial in canine patients with various cancers. HPPH (0.3mg/kg i.v.) was administered to 12 dogs and blood samples were drawn at intervals for 24 hours and plasma HPPH concentrations were determined. Pharmacokinetic parameters were calculated for each dog. No evidence of toxicity was noted in any dog. The mean half-life was calculated to be 26.98 +/- 2.35 hrs. The mean clearance was 5.061 +/- 0.214 ml/hr/kg. The mean volume of distribution of the central compartment was 0.069 +/- 0.003 L/kg, and the mean steady state volume of distribution was 4.47 +/- 0.25 L/kg. The conclusion is that 0.3 mg/kg HPPH injected intravenously resulted in measurable plasma levels for 24 hrs, and resulted in no detectable adverse reactions.

  3. Pharmacokinetics and transplacental distribution of fentanyl in epidural anesthesia for normal pregnant women.

    PubMed

    Moisés, Elaine Christine Dantas; de Barros Duarte, Luciana; de Carvalho Cavalli, Ricardo; Lanchote, Vera Lúcia; Duarte, Geraldo; da Cunha, Sérgio Pereira

    2005-08-01

    Fentanyl is an opioid drug widely used as a co-adjuvant in abdominal delivery, a fact that justifies its pharmacokinetic study under these conditions. Our objective was to investigate the pharmacokinetics and placental transfer of fentanyl in parturients whose pregnancies were resolved by cesarian section with epidural anesthesia. Ten clinically normal parturients who delivered at term received 5 ml of 2% lidocaine hydrochloride without a vasoconstrictor for skin and subcutaneous blockade, followed by epidural injection of 2 ml fentanyl citrate (0.05 mg/ml), 15 ml 0.5% bupivacaine hydrochloride with 1:200,000 epinephrine, and 10 ml 2% lidocaine hydrochloride without a vasoconstrictor. Maternal blood samples were collected at various times after injection (1--840 min), and the fentanyl plasma concentrations were determined by gas chromatography-mass spectrometry. Pharmacokinetic analysis was performed using the bi- or tri-compartmental model. The fetal/maternal ratio of the plasma fentanyl was determined at birth. The values of the pharmacokinetic parameters were: t(1/2)alpha=13.5 min, t(1/2)beta=192.5 min, t(1/2)gamma=620 min, AUC(0-infinity)=137.404 ng.min per milliliter, C(l)/f=464.984 ml/min, V(d)/f=299.974 l, C(l)/f/kg=6.875 ml/min per kilogram, and V(d)/f/kg=4.441 l/kg. The latency between drug administration and birth was 28.5 min, with a maternal and fetal plasma concentration of 0.310 and 0.245 ng/ml, respectively, at a median fetal/maternal ratio of 0.892. The study demonstrated a rapid passage of fentanyl from the epidural space to maternal blood and a significant transplacental transfer of maternal fentanyl of about 90%, which should serve as an alert to obstetricians.

  4. Determination of the neuropharmacological drug nodakenin in rat plasma and brain tissues by liquid chromatography tandem mass spectrometry: Application to pharmacokinetic studies.

    PubMed

    Song, Yingshi; Yan, Huiyu; Xu, Jingbo; Ma, Hongxi

    2017-09-01

    A rapid and sensitive liquid chromatography tandem mass spectrometry detection using selected reaction monitoring in positive ionization mode was developed and validated for the quantification of nodakenin in rat plasma and brain. Pareruptorin A was used as internal standard. A single step liquid-liquid extraction was used for plasma and brain sample preparation. The method was validated with respect to selectivity, precision, accuracy, linearity, limit of quantification, recovery, matrix effect and stability. Lower limit of quantification of nodakenin was 2.0 ng/mL in plasma and brain tissue homogenates. Linear calibration curves were obtained over concentration ranges of 2.0-1000 ng/mL in plasma and brain tissue homogenates for nodakenin. Intra-day and inter-day precisions (relative standard deviation, RSD) were <15% in both biological media. This assay was successfully applied to plasma and brain pharmacokinetic studies of nodakenin in rats after intravenous administration. Copyright © 2017 John Wiley & Sons, Ltd.

  5. The inclusion of capillary distribution in the adiabatic tissue homogeneity model of blood flow

    NASA Astrophysics Data System (ADS)

    Koh, T. S.; Zeman, V.; Darko, J.; Lee, T.-Y.; Milosevic, M. F.; Haider, M.; Warde, P.; Yeung, I. W. T.

    2001-05-01

    We have developed a non-invasive imaging tracer kinetic model for blood flow which takes into account the distribution of capillaries in tissue. Each individual capillary is assumed to follow the adiabatic tissue homogeneity model. The main strength of our new model is in its ability to quantify the functional distribution of capillaries by the standard deviation in the time taken by blood to pass through the tissue. We have applied our model to the human prostate and have tested two different types of distribution functions. Both distribution functions yielded very similar predictions for the various model parameters, and in particular for the standard deviation in transit time. Our motivation for developing this model is the fact that the capillary distribution in cancerous tissue is drastically different from in normal tissue. We believe that there is great potential for our model to be used as a prognostic tool in cancer treatment. For example, an accurate knowledge of the distribution in transit times might result in an accurate estimate of the degree of tumour hypoxia, which is crucial to the success of radiation therapy.

  6. Development of ex vivo model for determining temperature distribution in tumor tissue during photothermal therapy

    NASA Astrophysics Data System (ADS)

    Liu, Shaojie; Doughty, Austin; Mesiya, Sana; Pettitt, Alex; Zhou, Feifan; Chen, Wei R.

    2017-02-01

    Temperature distribution in tissue is a crucial factor in determining the outcome of photothermal therapy in cancer treatment. In order to investigate the temperature distribution in tumor tissue during laser irradiation, we developed a novel ex vivo device to simulate the photothermal therapy on tumors. A 35°C, a thermostatic incubator was used to provide a simulation environment for body temperature of live animals. Different biological tissues (chicken breast and bovine liver) were buried inside a tissue-simulating gel and considered as tumor tissues. An 805-nm laser was used to irradiate the target tissue. A fiber with an interstitial cylindrical diffuser (10 mm) was directly inserted in the center of the tissue, and the needle probes of a thermocouple were inserted into the tissue paralleling the laser fiber at different distances to measure the temperature distribution. All of the procedures were performed in the incubator. Based on the results of this study, the temperature distribution in bovine liver is similar to that of tumor tissue under photothermal therapy with the same doses. Therefore, the developed model using bovine liver for determining temperature distribution can be used during interstitial photothermal therapy.

  7. High Throughput pharmacokinetic modeling using computationally predicted parameter values: dissociation constants (TDS)

    EPA Science Inventory

    Estimates of the ionization association and dissociation constant (pKa) are vital to modeling the pharmacokinetic behavior of chemicals in vivo. Methodologies for the prediction of compound sequestration in specific tissues using partition coefficients require a parameter that ch...

  8. [Distribution of variant alleles association with warfarin pharmacokinetics and pharmacodynamics in the Han population in China].

    PubMed

    Liu, Yuan; Zhong, Shi-long; Yang, Min; Tan, Hong-hong; Fei, Hong-wen; Chen, Ji-yan; Yu, Xi-yong; Lin, Shu-guang

    2011-12-18

    To investigate distribution of CYP2C9, CYP3A4, VKORC1 and GGCX gene polymorphisms in the Han population of Guangdong. The subjects included were 970 Chinese Han patients who received long-term warfarin anticoagulant therapy orally after valve replacement in Guangdong General Hospital between 2000 and 2008. By selecting and analyzing the 12 single nucleotide polymorphisms (SNPs) loci, rs12572351 G>A, rs9332146 G>A, rs4917639 G>T, rs1057910 A>C (CYP2C9*3), rs1934967 G>T, rs1934968 G>A, rs2242480 T>C, rs2246709 G>A, rs9923231 C>T (VKORC1-1639 G>A), rs2359612 G>A (VKORC1*2), rs10871454 C>T, and rs699664 T>C, in 4 genes including CYP2C9, CYP3A4, VKORC1 and GGCX that were possibly correlated with warfarin pharmacodynamics and pharmacokinetics through literature retrieval, the distribution of mutation frequencies of the 12 SNPs loci in Chinese Han population were obtained systematically. SNaPshot technique was used to detect gene SNPs, Hardy-Weinberg genetic equilibrium test was used to test population representativeness. The allelic mutation frequency at CYP2C9 gene rs12572351 G>A, rs9332146 G>A, rs4917639 C>A, rs1057910 A>C (*3), rs1934967 G>T and rs1934968 G>A loci was 32.53%, 2.16%, 8.25%, 3.61%, 19.18% and 37.37%, respectively; the allelic mutation frequency at CYP3A4 gene rs2242480 T>C and rs2246709 G>A loci was 29.07% and 40.41%, respectively; the allelic mutation frequency at VKORC1 gene rs9923231 C>T, rs2359612 G>A and rs10871454 C>T SNPs loci was 87.99%, 87.94% and 91.34%, respectively; the allelic mutation frequency at GGCX gene rs699664 T>C locus was 31.86%. It is of important clinical significance in individualized warfarin therapy to systematically study distribution of mutation frequencies at 12 polymorphisms loci in 4 genes including CYP2C9, CYP3A4 , VKORC1 and GGCX related to warfarin pharmacodynamics and pharmacokinetics in the Chinese Han population receiving valve replacement.

  9. Clinical Pharmacokinetics in Kidney Disease: Fundamental Principles.

    PubMed

    Lea-Henry, Tom N; Carland, Jane E; Stocker, Sophie L; Sevastos, Jacob; Roberts, Darren M

    2018-06-22

    Kidney disease is an increasingly common comorbidity that alters the pharmacokinetics of many drugs. Prescribing to patients with kidney disease requires knowledge about the drug, the extent of the patient's altered physiology, and pharmacokinetic principles that influence the design of dosing regimens. There are multiple physiologic effects of impaired kidney function, and the extent to which they occur in an individual at any given time can be difficult to define. Although some guidelines are available for dosing in kidney disease, they may be on the basis of limited data or not widely applicable, and therefore, an understanding of pharmacokinetic principles and how to apply them is important to the practicing clinician. Whether kidney disease is acute or chronic, drug clearance decreases, and the volume of distribution may remain the same or increase. Although in CKD, these changes progress relatively slowly, they are dynamic in AKI, and recovery is possible depending on the etiology and treatments. This, and the use of kidney replacement therapies further complicate attempts to quantify drug clearance at the time of prescribing and dosing in AKI. The required change in the dosing regimen can be estimated or even quantitated in certain instances through the application of pharmacokinetic principles to guide rational drug dosing. This offers an opportunity to provide personalized medical care and minimizes adverse drug events from either under- or overdosing. We discuss the principles of pharmacokinetics that are fundamental for the design of an appropriate dosing regimen in this review. Copyright © 2018 by the American Society of Nephrology.

  10. Development of a physiologically based pharmacokinetic model for flunixin in cattle (Bos taurus).

    PubMed

    Leavens, Teresa L; Tell, Lisa A; Kissell, Lindsey W; Smith, Geoffrey W; Smith, David J; Wagner, Sarah A; Shelver, Weilin L; Wu, Huali; Baynes, Ronald E; Riviere, Jim E

    2014-01-01

    Frequent violation of flunixin residues in tissues from cattle has been attributed to non-compliance with the USFDA-approved route of administration and withdrawal time. However, the effect of administration route and physiological differences among animals on tissue depletion has not been determined. The objective of this work was to develop a physiologically based pharmacokinetic (PBPK) model to predict plasma, liver and milk concentrations of flunixin in cattle following intravenous (i.v.), intramuscular (i.m.) or subcutaneous (s.c.) administration for use as a tool to determine factors that may affect the withdrawal time. The PBPK model included blood flow-limited distribution in all tissues and elimination in the liver, kidney and milk. Regeneration of parent flunixin due to enterohepatic recirculation and hydrolysis of conjugated metabolites was incorporated in the liver compartment. Values for physiological parameters were obtained from the literature, and partition coefficients for all tissues but liver and kidney were derived empirically. Liver and kidney partition coefficients and elimination parameters were estimated for 14 pharmacokinetic studies (including five crossover studies) from the literature or government sources in which flunixin was administered i.v., i.m. or s.c. Model simulations compared well with data for the matrices following all routes of administration. Influential model parameters included those that may be age or disease-dependent, such as clearance and rate of milk production. Based on the model, route of administration would not affect the estimated days to reach the tolerance concentration (0.125 mg kg(-1)) in the liver of treated cattle. The majority of USDA-reported violative residues in liver were below the upper uncertainty predictions based on estimated parameters, which suggests the need to consider variability due to disease and age in establishing withdrawal intervals for drugs used in food animals. The model predicted

  11. Applications of a Pharmacokinetic Simulation Program in Pharmacy Courses.

    ERIC Educational Resources Information Center

    Ingram, D.; And Others

    1979-01-01

    Presents a multicompartment model which illustrates aspects of drug absorption, distribution, and elimination in the human body for a course in pharmacokinetics. The course work consists of the interpretation of computer generated simulated data. (Author/CMV)

  12. Distribution of cyclosporine A in ocular tissues after topical administration of cyclosporine A cationic emulsions to pigmented rabbits.

    PubMed

    Daull, Philippe; Lallemand, Frédéric; Philips, Betty; Lambert, Grégory; Buggage, Ronald; Garrigue, Jean-Sébastien

    2013-03-01

    The aim of this study was to compare the ocular and systemic distribution of cyclosporine A (CsA) in rabbits after the instillation of preservative-free CsA cationic and anionic emulsions. For the single-dose pharmacokinetic (PK) study, rabbits were instilled with 50 μL of the test material. For the multiple-dose PK study, rabbits were instilled twice daily with Restasis or once daily with NOVA22007 for 10 days. At each time point, the cornea, conjunctiva, and whole blood were harvested for CsA quantification. Ocular and systemic distribution were determined after 4 times daily instillations with 50 μL of 3H-CsA cationic and anionic emulsions for 7 days. Restasis was used as a reference in all studies. Single-dose PK data demonstrated that NOVA22007 0.1% and 0.05% delivered higher CsA concentrations to the cornea than Restasis [concentration maximum (C max): 2692, 1372, and 748 ng/g, respectively] and have a better exposition (area under the curve). Conjunctival Cmax values were 1914, 696, and 849 ng/g and area under the curve values were 3984, 2796, and 2515 ng/g · h, for either dose of the cationic emulsions and Restasis, respectively. The multiple-dose PK and the 3H-CsA distribution data demonstrated that the systemic distribution after repeated instillations was low and comparable for all emulsions. These data demonstrate that the CsA cationic emulsions were more effective than Restasis at delivering CsA to target tissues, thus confirming the potential advantage of cationic emulsions over anionic emulsions as vehicle for ocular drug delivery for the treatment of ocular surface diseases.

  13. Population Pharmacokinetic Modeling of Diltiazem in Chinese Renal Transplant Recipients.

    PubMed

    Guan, Xiao-Feng; Li, Dai-Yang; Yin, Wen-Jun; Ding, Jun-Jie; Zhou, Ling-Yun; Wang, Jiang-Lin; Ma, Rong-Rong; Zuo, Xiao-Cong

    2018-02-01

    Diltiazem is a benzothiazepine calcium blocker and widely used in renal transplant patients since it improves the level of tacrolimus or cyclosporine A concentration. Several population pharmacokinetic (PopPK) models had been established for cyclosporine A and tacrolimus but no specific PopPK model was established for diltiazem. The aim of the study is to develop a PopPK model for diltiazem in renal transplant recipients and provide relevant pharmacokinetic parameters of diltiazem for further pharmacokinetic interaction study. Patients received tacrolimus as primary immunosuppressant agent after renal transplant and started administration of diltiazem 90 mg twice daily on 5th day. The concentration of diltiazem at 0, 0.5, 1, 2, 8, and 12 h was measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Genotyping for CYP3A4*1G, CYP3A5*3, and MDR1 3435 was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). 25 covariates were considered in the stepwise covariate model (SCM) building procedure. One-compartment structural pharmacokinetic model with first-order absorption and elimination was used to describe the pharmacokinetic characteristics of diltiazem. Total bilirubin (TBIL) influenced apparent volume of distribution (V/F) of diltiazem in the forward selection. The absorption rate constant (K a ), V/F, and apparent oral clearance (CL/F) of the final population pharmacokinetic (PopPK) model of diltiazem were 1.96/h, 3550 L, and 92.4 L/h, respectively. A PopPK model of diltiazem is established in Chinese renal transplant recipients and it will provide relevant pharmacokinetic parameters of diltiazem for further pharmacokinetic interaction study.

  14. Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design.

    PubMed

    Leroux, Stéphanie; Turner, Mark A; Guellec, Chantal Barin-Le; Hill, Helen; van den Anker, Johannes N; Kearns, Gregory L; Jacqz-Aigrain, Evelyne; Zhao, Wei

    2015-12-01

    The use of an opportunistic (also called scavenged) sampling strategy in a prospective pharmacokinetic study combined with population pharmacokinetic modelling has been proposed as an alternative strategy to conventional methods for accomplishing pharmacokinetic studies in neonates. However, the reliability of this approach in this particular paediatric population has not been evaluated. The objective of the present study was to evaluate the performance of an opportunistic sampling strategy for a population pharmacokinetic estimation, as well as dose prediction, and compare this strategy with a predetermined pharmacokinetic sampling approach. Three population pharmacokinetic models were derived for ciprofloxacin from opportunistic blood samples (SC model), predetermined (i.e. scheduled) samples (TR model) and all samples (full model used to previously characterize ciprofloxacin pharmacokinetics), using NONMEM software. The predictive performance of developed models was evaluated in an independent group of patients. Pharmacokinetic data from 60 newborns were obtained with a total of 430 samples available for analysis; 265 collected at predetermined times and 165 that were scavenged from those obtained as part of clinical care. All datasets were fit using a two-compartment model with first-order elimination. The SC model could identify the most significant covariates and provided reasonable estimates of population pharmacokinetic parameters (clearance and steady-state volume of distribution) compared with the TR and full models. Their predictive performances were further confirmed in an external validation by Bayesian estimation, and showed similar results. Monte Carlo simulation based on area under the concentration-time curve from zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) using either the SC or the TR model gave similar dose prediction for ciprofloxacin. Blood samples scavenged in the course of caring for neonates can be used to estimate

  15. [Population pharmacokinetics applied to optimising cisplatin doses in cancer patients].

    PubMed

    Ramón-López, A; Escudero-Ortiz, V; Carbonell, V; Pérez-Ruixo, J J; Valenzuela, B

    2012-01-01

    To develop and internally validate a population pharmacokinetics model for cisplatin and assess its prediction capacity for personalising doses in cancer patients. Cisplatin plasma concentrations in forty-six cancer patients were used to determine the pharmacokinetic parameters of a two-compartment pharmacokinetic model implemented in NONMEN VI software. Pharmacokinetic parameter identification capacity was assessed using the parametric bootstrap method and the model was validated using the nonparametric bootstrap method and standardised visual and numerical predictive checks. The final model's prediction capacity was evaluated in terms of accuracy and precision during the first (a priori) and second (a posteriori) chemotherapy cycles. Mean population cisplatin clearance is 1.03 L/h with an interpatient variability of 78.0%. Estimated distribution volume at steady state was 48.3 L, with inter- and intrapatient variabilities of 31,3% and 11,7%, respectively. Internal validation confirmed that the population pharmacokinetics model is appropriate to describe changes over time in cisplatin plasma concentrations, as well as its variability in the study population. The accuracy and precision of a posteriori prediction of cisplatin concentrations improved by 21% and 54% compared to a priori prediction. The population pharmacokinetic model developed adequately described the changes in cisplatin plasma concentrations in cancer patients and can be used to optimise cisplatin dosing regimes accurately and precisely. Copyright © 2011 SEFH. Published by Elsevier Espana. All rights reserved.

  16. Pharmacokinetic modeling of 4,4'-methylenedianiline released from reused polyurethane dialyzer potting materials.

    PubMed

    Do Luu, H M; Hutter, J C

    2000-01-01

    4, 4'-Methylenedianiline (MDA) is a hydrolysis degradation product that can be released from polyurethanes commonly used in medical device applications. MDA is mutagenic and carcinogenic in animals. In humans, it is hepatotoxic, a known contact and respiratory allergen, and a suspected carcinogen. A physiologically based pharmacokinetic (PBPK) model was developed to estimate the absorption, distribution, metabolism, and excretion of MDA in patients exposed to MDA leached from the potting materials of hemodialyzers. A worst-case reuse situation and a single use case were investigated. The PBPK model included five tissue compartments: liver, kidney, gastrointestinal tract, slowly perfused tissues, and richly perfused tissues. Physiological and chemical parameters of a healthy individual used in the model were obtained from the literature. The model was calibrated using previously published kinetic studies of IV administered doses of (14) C-MDA to rats. The model was validated using independent data published for MDA-exposed workers. The PBPK results indicated that dialysis patients who are exposed to MDA released from dialyzers (new or reused) could accumulate low levels of MDA and metabolites (total MDA) over time. Copyright 2000 John Wiley & Sons, Inc.

  17. Use of Markov Chain Monte Carlo analysis with a physiologically-based pharmacokinetic model of methylmercury to estimate exposures in US women of childbearing age.

    PubMed

    Allen, Bruce C; Hack, C Eric; Clewell, Harvey J

    2007-08-01

    A Bayesian approach, implemented using Markov Chain Monte Carlo (MCMC) analysis, was applied with a physiologically-based pharmacokinetic (PBPK) model of methylmercury (MeHg) to evaluate the variability of MeHg exposure in women of childbearing age in the U.S. population. The analysis made use of the newly available National Health and Nutrition Survey (NHANES) blood and hair mercury concentration data for women of age 16-49 years (sample size, 1,582). Bayesian analysis was performed to estimate the population variability in MeHg exposure (daily ingestion rate) implied by the variation in blood and hair concentrations of mercury in the NHANES database. The measured variability in the NHANES blood and hair data represents the result of a process that includes interindividual variation in exposure to MeHg and interindividual variation in the pharmacokinetics (distribution, clearance) of MeHg. The PBPK model includes a number of pharmacokinetic parameters (e.g., tissue volumes, partition coefficients, rate constants for metabolism and elimination) that can vary from individual to individual within the subpopulation of interest. Using MCMC analysis, it was possible to combine prior distributions of the PBPK model parameters with the NHANES blood and hair data, as well as with kinetic data from controlled human exposures to MeHg, to derive posterior distributions that refine the estimates of both the population exposure distribution and the pharmacokinetic parameters. In general, based on the populations surveyed by NHANES, the results of the MCMC analysis indicate that a small fraction, less than 1%, of the U.S. population of women of childbearing age may have mercury exposures greater than the EPA RfD for MeHg of 0.1 microg/kg/day, and that there are few, if any, exposures greater than the ATSDR MRL of 0.3 microg/kg/day. The analysis also indicates that typical exposures may be greater than previously estimated from food consumption surveys, but that the variability

  18. Pregnancy-related pharmacokinetic changes.

    PubMed

    Tasnif, Y; Morado, J; Hebert, M F

    2016-07-01

    The pharmacokinetics of many drugs are altered by pregnancy. Drug distribution and protein binding are changed by pregnancy. While some drug metabolizing enzymes have an apparent increase in activity, others have an apparent decrease in activity. Not only is drug metabolism affected by pregnancy, but renal filtration is also increased. In addition, pregnancy alters the apparent activities of multiple drug transporters resulting in changes in the net renal secretion of drugs. © 2016 American Society for Clinical Pharmacology and Therapeutics.

  19. Population Pharmacokinetics of Elagolix in Healthy Women and Women with Endometriosis.

    PubMed

    Winzenborg, Insa; Nader, Ahmed; Polepally, Akshanth R; Liu, Mohan; Degner, Jacob; Klein, Cheri E; Mostafa, Nael M; Noertersheuser, Peter; Ng, Juki

    2018-02-23

    Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH) receptor antagonist in development for the management of endometriosis with associated pain and heavy menstrual bleeding due to uterine fibroids. The pharmacokinetics of elagolix have been well-characterized in phase I studies; however, elagolix population pharmacokinetics have not been previously reported. Therefore, a robust model was developed to describe elagolix population pharmacokinetics and to evaluate factors affecting elagolix pharmacokinetic parameters. The data from nine clinical studies (a total of 1624 women) were included in the analysis: five phase I studies in healthy, premenopausal women and four phase III studies in premenopausal women with endometriosis. Elagolix population pharmacokinetics were best described by a two-compartment model with a lag time in absorption. Of the 15 covariates tested for effect on elagolix apparent clearance (CL/F) and/or volume of distribution only one covariate, organic anion transporting polypeptide (OATP) 1B1 genotype status, had a statistically significant, but not clinically meaningful, effect on elagolix CL/F. Elagolix pharmacokinetics were not affected by patient demographics and were similar between healthy women and women with endometriosis. Clinical Trial Registration Numbers NCT01403038, NCT01620528, NCT01760954, NCT01931670, NCT02143713.

  20. A population pharmacokinetic model of valproic acid in pediatric patients with epilepsy: a non-linear pharmacokinetic model based on protein-binding saturation.

    PubMed

    Ding, Junjie; Wang, Yi; Lin, Weiwei; Wang, Changlian; Zhao, Limei; Li, Xingang; Zhao, Zhigang; Miao, Liyan; Jiao, Zheng

    2015-03-01

    Valproic acid (VPA) follows a non-linear pharmacokinetic profile in terms of protein-binding saturation. The total daily dose regarding VPA clearance is a simple power function, which may partially explain the non-linearity of the pharmacokinetic profile; however, it may be confounded by the therapeutic drug monitoring effect. The aim of this study was to develop a population pharmacokinetic model for VPA based on protein-binding saturation in pediatric patients with epilepsy. A total of 1,107 VPA serum trough concentrations at steady state were collected from 902 epileptic pediatric patients aged from 3 weeks to 14 years at three hospitals. The population pharmacokinetic model was developed using NONMEM(®) software. The ability of three candidate models (the simple power exponent model, the dose-dependent maximum effect [DDE] model, and the protein-binding model) to describe the non-linear pharmacokinetic profile of VPA was investigated, and potential covariates were screened using a stepwise approach. Bootstrap, normalized prediction distribution errors and external evaluations from two independent studies were performed to determine the stability and predictive performance of the candidate models. The age-dependent exponent model described the effects of body weight and age on the clearance well. Co-medication with carbamazepine was identified as a significant covariate. The DDE model best fitted the aim of this study, although there were no obvious differences in the predictive performances. The condition number was less than 500, and the precision of the parameter estimates was less than 30 %, indicating stability and validity of the final model. The DDE model successfully described the non-linear pharmacokinetics of VPA. Furthermore, the proposed population pharmacokinetic model of VPA can be used to design rational dosage regimens to achieve desirable serum concentrations.

  1. Pharmacokinetic study of gallocatechin-7-gallate from Pithecellobium clypearia Benth. in rats.

    PubMed

    Li, Chao; Song, Xiaowei; Song, Junke; Pang, Xiaocong; Wang, Zhe; Zhao, Ying; Lian, Wenwen; Liu, Ailin; Du, Guanhua

    2016-01-01

    The pharmacokinetic profile of gallocatechin-7-gallate (J10688) was studied in rats after intravenous administration. Male and female Sprague-Dawley (SD) rats received 1, 3, and 10 mg/kg (i.v.) of J10688 and plasma drug concentrations were determined by a high performance liquid chromatography-mass spectrometry (LC-MS) method. The pharmacokinetic software Data Analysis System (Version 3.0) was used to calculate the pharmacokinetic parameters. For different i.v. doses of J10688, the mean peak plasma concentration (C 0) values ranged from 11.26 to 50.82 mg/L, and mean area under the concentration-time curve (AUC0-t ) values ranged from 1.75 to 11.80 (mg·h/L). J10688 lacked dose-dependent pharmacokinetic properties within doses between 1 and 10 mg/kg, based on the power model. The method developed in this study was sensitive, precise, and stable. The pharmacokinetic properties of J10688 in SD rats were shown to have rapid distribution and clearance values. These pharmacokinetic results may contribute to an improved understanding of the pharmacological actions of J10688.

  2. Visualisation of the distributions of melanin and indocyanine green in biological tissues

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Genina, E A; Fedosov, I V; Bashkatov, A N

    2008-03-31

    A double-wavelength laser scanning microphotometer with the high spectral and spatial resolutions is developed for studying the distribution of endogenic and exogenic dyes in biological tissues. Samples of hair and skin biopsy with hair follicles stained with indocyanine green are studied. The spatial distribution of indocyanine green and melanin in the biological tissue is determined from the measured optical transmittance. (laser biology)

  3. Propagation of population pharmacokinetic information using a Bayesian approach: comparison with meta-analysis.

    PubMed

    Dokoumetzidis, Aristides; Aarons, Leon

    2005-08-01

    We investigated the propagation of population pharmacokinetic information across clinical studies by applying Bayesian techniques. The aim was to summarize the population pharmacokinetic estimates of a study in appropriate statistical distributions in order to use them as Bayesian priors in consequent population pharmacokinetic analyses. Various data sets of simulated and real clinical data were fitted with WinBUGS, with and without informative priors. The posterior estimates of fittings with non-informative priors were used to build parametric informative priors and the whole procedure was carried on in a consecutive manner. The posterior distributions of the fittings with informative priors where compared to those of the meta-analysis fittings of the respective combinations of data sets. Good agreement was found, for the simulated and experimental datasets when the populations were exchangeable, with the posterior distribution from the fittings with the prior to be nearly identical to the ones estimated with meta-analysis. However, when populations were not exchangeble an alternative parametric form for the prior, the natural conjugate prior, had to be used in order to have consistent results. In conclusion, the results of a population pharmacokinetic analysis may be summarized in Bayesian prior distributions that can be used consecutively with other analyses. The procedure is an alternative to meta-analysis and gives comparable results. It has the advantage that it is faster than the meta-analysis, due to the large datasets used with the latter and can be performed when the data included in the prior are not actually available.

  4. Comparison of Dapivirine Vaginal Gel and Film Formulation Pharmacokinetics and Pharmacodynamics (FAME 02B).

    PubMed

    Robinson, Jennifer A; Marzinke, Mark A; Bakshi, Rahul P; Fuchs, Edward J; Radebaugh, Christine L; Aung, Wutyi; Spiegel, Hans M L; Coleman, Jenell S; Rohan, Lisa C; Hendrix, Craig W

    2017-04-01

    While preexposure prophylaxis with oral tenofovir/emtricitabine reduces HIV acquisition rates, poor adherence to and acceptability of vaginal gels and the potential for evolving drug resistance have led to development of vaginal film formulations and other antiretroviral drugs, respectively, including the non-nucleoside reverse transcriptase inhibitor dapivirine. In this two-arm crossover study of a novel fast-dissolving dapivirine film and a previously studied semisolid dapivirine gel, 10 healthy women received a single 1.25 mg vaginal dose of each study product; one withdrew after the first dose. Clinical, pharmacokinetic, and antiviral pharmacodynamic assessments (ex vivo HIV-BaL challenge of tissue explants) were performed over 168 h postdose. Six of ten participants experienced mild to moderate adverse effects, similar between products, with no severe adverse events or adverse events attributed to study products. There were no statistically significant differences in plasma, cervicovaginal fluid (CVF), or cervical tissue dapivirine concentrations between the gel and film (all p > .05). CVF dapivirine concentrations were 1.5 and 6 log 10 greater than tissue and plasma concentrations, respectively (p < .001). Both film and gel demonstrated reduced cervical tissue infectivity after ex vivo HIV challenge 5 h postdose, compared to baseline and 72-h postdose biopsies (p < .05 for gel, p = .06 for film). There was no difference in ex vivo explant HIV challenge between gel and film. The dapivirine film and gel performed similarly in terms of tolerability, pharmacokinetics, and antiviral effect. Dapivirine film may provide an alternative to pharmacokinetically comparable dapivirine gel formulations. Effectiveness remains to be tested.

  5. Probabilistic pharmacokinetic models of decompression sickness in humans, part 1: Coupled perfusion-limited compartments.

    PubMed

    Murphy, F Gregory; Hada, Ethan A; Doolette, David J; Howle, Laurens E

    2017-07-01

    Decompression sickness (DCS) is a disease caused by gas bubbles forming in body tissues following a reduction in ambient pressure, such as occurs in scuba diving. Probabilistic models for quantifying the risk of DCS are typically composed of a collection of independent, perfusion-limited theoretical tissue compartments which describe gas content or bubble volume within these compartments. It has been previously shown that 'pharmacokinetic' gas content models, with compartments coupled in series, show promise as predictors of the incidence of DCS. The mechanism of coupling can be through perfusion or diffusion. This work examines the application of five novel pharmacokinetic structures with compartments coupled by perfusion to the prediction of the probability and time of onset of DCS in humans. We optimize these models against a training set of human dive trial data consisting of 4335 exposures with 223 DCS cases. Further, we examine the extrapolation quality of the models on an additional set of human dive trial data consisting of 3140 exposures with 147 DCS cases. We find that pharmacokinetic models describe the incidence of DCS for single air bounce dives better than a single-compartment, perfusion-limited model. We further find the U.S. Navy LEM-NMRI98 is a better predictor of DCS risk for the entire training set than any of our pharmacokinetic models. However, one of the pharmacokinetic models we consider, the CS2T3 model, is a better predictor of DCS risk for single air bounce dives and oxygen decompression dives. Additionally, we find that LEM-NMRI98 outperforms CS2T3 on the extrapolation data. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Comparison of normal tissue pharmacokinetics with {sup 111}In/{sup 9}Y monoclonal antibody m170 for breast and prostate cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lehmann, Joerg; Department of Radiodiagnosis and Therapy, Division of Hematology/Oncology, University of California Davis School of Medicine, Sacramento, CA; DeNardo, Gerald L.

    Purpose: Radioactivity deposition in normal tissues limits the dose deliverable by radiopharmaceuticals (RP) in radioimmunotherapy (RIT). This study investigated the absorbed radiation dose in normal tissues for prostate cancer patients in comparison to breast cancer patients for 2 RPs using the monoclonal antibody (MAb) m170. Methods and Materials: {sup 111}In-DOTA-glycylglycylglycyl-L-p-isothiocyanatophenylalanine amide (GGGF)-m170 and {sup 111}In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) 2-iminothiolane (2IT)-m170, representing the same MAb and chelate with and without a cleavable linkage, were studied in 13 breast cancer and 26 prostate cancer patients. Dosimetry for {sup 9}Y was calculated using {sup 111}In MAb pharmacokinetics from the initial imaging study for eachmore » patient, using reference man- and patient-specific masses. Results: The reference man-specific radiation doses (cGy/MBq) were not significantly different for the breast and the prostate cancer patients for both RPs in all but one tissue-RP combination (liver, DOTA-2IT). The patient-specific doses had differences between the groups most of which can be related to weight differences. Conclusions: Similar normal tissue doses were calculated for two groups of patients having different cancers and genders. This similarity combined with continued careful analysis of the imaging data might allow the use of higher starting doses in early phase RIT studies.« less

  7. Prediction of human pharmacokinetics using physiologically based modeling: a retrospective analysis of 26 clinically tested drugs.

    PubMed

    De Buck, Stefan S; Sinha, Vikash K; Fenu, Luca A; Nijsen, Marjoleen J; Mackie, Claire E; Gilissen, Ron A H J

    2007-10-01

    The aim of this study was to evaluate different physiologically based modeling strategies for the prediction of human pharmacokinetics. Plasma profiles after intravenous and oral dosing were simulated for 26 clinically tested drugs. Two mechanism-based predictions of human tissue-to-plasma partitioning (P(tp)) from physicochemical input (method Vd1) were evaluated for their ability to describe human volume of distribution at steady state (V(ss)). This method was compared with a strategy that combined predicted and experimentally determined in vivo rat P(tp) data (method Vd2). Best V(ss) predictions were obtained using method Vd2, providing that rat P(tp) input was corrected for interspecies differences in plasma protein binding (84% within 2-fold). V(ss) predictions from physicochemical input alone were poor (32% within 2-fold). Total body clearance (CL) was predicted as the sum of scaled rat renal clearance and hepatic clearance projected from in vitro metabolism data. Best CL predictions were obtained by disregarding both blood and microsomal or hepatocyte binding (method CL2, 74% within 2-fold), whereas strong bias was seen using both blood and microsomal or hepatocyte binding (method CL1, 53% within 2-fold). The physiologically based pharmacokinetics (PBPK) model, which combined methods Vd2 and CL2 yielded the most accurate predictions of in vivo terminal half-life (69% within 2-fold). The Gastroplus advanced compartmental absorption and transit model was used to construct an absorption-disposition model and provided accurate predictions of area under the plasma concentration-time profile, oral apparent volume of distribution, and maximum plasma concentration after oral dosing, with 74%, 70%, and 65% within 2-fold, respectively. This evaluation demonstrates that PBPK models can lead to reasonable predictions of human pharmacokinetics.

  8. Population Pharmacokinetic Modeling of Olmesartan, the Active Metabolite of Olmesartan Medoxomil, in Patients with Hypertension.

    PubMed

    Kodati, Devender; Kotakonda, Harish Kaushik; Yellu, Narsimhareddy

    2017-08-01

    Olmesartan medoxomil is an orally given angiotensin II receptor antagonist indicated for the treatment of hypertension. The aim of the study was to establish a population pharmacokinetic model for olmesartan, the active metabolite of olmesartan medoxomil, in Indian hypertensive patients, and to evaluate effects of covariates on the volume of distribution (V/F) and oral clearance (CL/F) of olmesartan. The population pharmacokinetic model for olmesartan was developed using Phoenix NLME 1.3 with a non-linear mixed-effect model. Bootstrap and visual predictive check were used simultaneously to validate the final population pharmacokinetic models. The covariates included age, sex, body surface area (BSA), bodyweight, height, creatinine clearance (CL CR ) as an index of renal function and liver parameters as indices of hepatic function. A total of 205 olmesartan plasma sample concentrations from 69 patients with hypertension were collected in this study. The pharmacokinetic data of olmesartan was well described by a two-compartment linear pharmacokinetic model with first-order absorption and an absorption lag-time. The mean values of CL/F and V/F of olmesartan in the patients were 0.31565 L/h and 44.5162 L, respectively. Analysis of covariates showed that age and CL CR were factors influencing the clearance of olmesartan and the volume of distribution of olmesartan was dependent on age and BSA. The final population pharmacokinetic model was demonstrated to be appropriate and effective and it can be used to assess the pharmacokinetic parameters of olmesartan in Indian patients with hypertension.

  9. A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin: a step towards predicting bacterial killing at sites of infection.

    PubMed

    Sadiq, Muhammad W; Nielsen, Elisabet I; Khachman, Dalia; Conil, Jean-Marie; Georges, Bernard; Houin, Georges; Laffont, Celine M; Karlsson, Mats O; Friberg, Lena E

    2017-04-01

    The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors. The developed WB-PBPK model successfully characterized both the typical trends and variability of the available ciprofloxacin plasma concentration data. The WB-PBPK model was thereafter combined with a pharmacokinetic-pharmacodynamic (PKPD) model, developed based on in vitro time-kill data of ciprofloxacin and Escherichia coli to illustrate the potential of this type of approach to predict the time-course of bacterial killing at different sites of infection. The predicted unbound concentration-time profile in extracellular tissue was driving the bacterial killing in the PKPD model and the rate and extent of take-over of mutant bacteria in different tissues were explored. The bacterial killing was predicted to be most efficient in lung and kidney, which correspond well to ciprofloxacin's indications pneumonia and urinary tract infections. Furthermore, a function based on available information on bacterial killing by the immune system in vivo was incorporated. This work demonstrates the development and application of a WB-PBPK-PD model to compare killing of bacteria with different antibiotic susceptibility, of value for drug development and the optimal use of antibiotics .

  10. Histone Deacetylase Inhibitor MS-275 Exhibits Poor Brain Penetration: Pharmacokinetic Studies of [11C]MS-275 using Positron Emission Tomography

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hooker, J.M.; Hooker, J.M.; Kim, S.W.

    2009-10-01

    MS-275 (entinostat) is a histone deacetylase (HDAC) inhibitor currently in clinical trials for the treatment of several types of cancer. Recent reports have noted that MS-275 can cross the blood-brain barrier (BBB) and cause region-specific changes in rodent brain histone acetylation. To characterize the pharmacokinetics and distribution of MS-275 in the brain using positron emission tomography (PET), we labeled the carbamate carbon of MS-275 with carbon-11. Using PET, we determined that [{sup 11}C]MS-275 has low uptake in brain tissue when administered intravenously to nonhuman primates. In rodent studies, we observed that pharmacokinetics and brain accumulation of [{sup 11}C]MS-275 were notmore » changed by the coadministration of large doses of unlabeled MS-275. These results, which both highlight the poor brain penetration of MS-275, clearly suggest its limitation as a therapeutic agent for the central nervous system (CNS). Moreover, our study demonstrates the effectiveness of PET at providing brain pharmacokinetic data for HDAC inhibitors. These data are important not only for the development of new compounds for peripheral cancer treatment (where CNS exclusion is often advantageous) but also for the treatment of neurological disorders (where CNS penetration is critical).« less

  11. Biodistribution and pharmacokinetics of recombinant α1-microglobulin and its potential use in radioprotection of kidneys

    PubMed Central

    Ahlstedt, Jonas; Tran, Thuy A; Strand, Filip; Holmqvist, Bo; Strand, Sven-Erik; Gram, Magnus; Åkerström, Bo

    2015-01-01

    Peptide-receptor radionuclide therapy (PRRT) is a systemically administrated molecular targeted radiation therapy for treatment of neuroendocrine tumors. Fifteen years of clinical use show that renal toxicity, due to glomerular filtration of the peptides followed by local generation of highly reactive free radicals, is the main side-effect that limits the maximum activity that can be administrated for efficient therapy. α1-microglobulin (A1M) is an endogenous radical scavenger shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. An important feature of A1M is that, following distribution to the blood, it is equilibrated to the extravascular compartments and filtrated in the kidneys. Aiming at developing renal protection against toxic side-effects of PRRT, we have characterized the pharmacokinetics and biodistribution of intravenously (i.v.) injected 125I- and non-labelled recombinant human A1M and the 111In- and fluorescence-labelled somatostatin analogue octreotide. Both molecules were predominantly localized to the kidneys, displaying a prevailing distribution in the cortex. A maximum of 76% of the injected A1M and 46% of the injected octreotide were present per gram kidney tissue at 10 to 20 minutes, respectively, after i.v. injection. Immunohistochemistry and fluorescence microscopy revealed a dominating co-existence of the two substances in proximal tubules, with a cellular co-localization in the epithelial cells. Importantly, analysis of kidney extracts displayed an intact, full-length A1M at least up to 60 minutes post-injection (p.i.). In summary, the results show a highly similar pharmacokinetics and biodistribution of A1M and octreotide, thus enabling the use of A1M to protect the kidneys tissue during PRRT. PMID:26269772

  12. The pharmacokinetics of JS-38, a novel antineoplastic drug, in rats.

    PubMed

    Ng, Hong Zha; Fang, Yu; Li, Ying; Fan, Ting-Ting; Qin, Yan; Liu, Quan-Hai

    2008-01-01

    To evaluate the pre-clinical pharmacokinetics of JS-38(C22H1404N2S2F6, MW: 548), a study was conducted in Wistar rats (3 female, 2 male: 200-250 g about 6 or 7 months). The concentration-time curve of JS-38 in rats demonstrated the pharmacokinetic (PK) characteristics of a two-compartmental model. The area under the concentration-time curve from zero to infinity (AUC(0-infinity)) for the low, middle and high dosage (i.e., 20, 50 and 125 mg x kg(-1)) amounted to 46.850 +/- 19.946, 161.101 +/- 58.877 and 312.565 +/- 187.273 mg/L x h respectively; a positive correlation was demonstrated between the AUC(0-infinity). and the dosages in question (r = 0.99). The average time to reach maximum concentration (Tmax) was 3.( RSD: 20.4% and the half-life (t(1/2)) was 11.4 h( RSD: 8.8% P > 0.05. For the low, middle and high dosage, the maximum concentration (Cmax) was 4.882, 11.248, and 13.431 microg x mL(-1) respectively. After the administration of JS-38, except for the brain and spinal marrow, the drug distribution in the different body tissues varied, in particular in the liver, intestine and thyroid gland. A significant distribution of JS-38 was detected in cancerous tissues, and its concentrations demonstrated a tendency increase over time. There was a certain degree of distribution in the bone marrow. The urine samples showed that JS-38 nearly was practically not eliminated in its original form. The amount eliminated after 72h via the bile was only 1.03 +/- 0.1% of the administered dose. In the rat model, most of the JS-38 in its original form (53.58 +/- 22.28%) was excreted via the feces. When the intragastric administration of doses of 20, 50 and 125 mg x kg(-1) was compared with i.v. administered JS-38 (1 mg x kg(-1)), the absolute bioavailability amounted to 22.2 +/- 9.5%, 30.4 +/- 14.5% and 23.6 +/- 11.3% respectively. It was found that this compound is well absorbed in to the system and that it shows favorable PK properties. The outcome of this early pre

  13. Enhanced distribution and extended elimination of glycyrrhetinic acid in mice liver by mPEG-PLA modified (mPEGylated) liposome.

    PubMed

    Li, Juan; Yu, Hua; Li, Shuai; Wang, Guang Ji

    2010-04-06

    A rapid and simple method of high-performance liquid chromatography with UV detector for the quantification of glycyrrhetinic acid (GA) in mice plasma and tissues has been developed and validated. With the established assay method, the pharmacokinetic profiles and tissue distribution of GA in different formulations are compared in mice after intravenous administration of the drug (25mg/kg). The results showed that mPEG-PLA modified (mPEGylated) GA liposome (PL-GA) significantly prolonged the mean residence time (MRT) of GA in mice plasma and liver (MRT: 0.43+/-0.13 and 1.72+/-0.11h, respectively) than the normal GA liposome (L-GA) (MRT: 0.23+/-0.01 and 1.07+/-0.31h, respectively) and GA sodium injection (S-GA) (MRT: 0.13+/-0.01 and 0.95+/-0.08h, respectively). Moreover, PL-GA specifically increased GA uptake in liver (AUC(0-infinity,)(liver) value of 1.6-fold and 1.3-fold higher than that for S-GA and L-GA, respectively) and reduced its distribution into other tissues after dosing. Due to these pharmacokinetic properties, it may be promising to develop PL-GA further as a new pharmaceutical preparation for GA on the treatment of various chronic hepatic diseases. Copyright 2009. Published by Elsevier B.V.

  14. Plasma pharmacokinetics and synovial concentrations of S-flurbiprofen plaster in humans.

    PubMed

    Yataba, Ikuko; Otsuka, Noboru; Matsushita, Isao; Kamezawa, Miho; Yamada, Ichimaro; Sasaki, Sigeru; Uebaba, Kazuo; Matsumoto, Hideo; Hoshino, Yuichi

    2016-01-01

    The purpose of this study is to investigate the pharmacokinetics and deep tissue penetration capability of the newly developed S-flurbiprofen plaster (SFPP) in humans. Study 1: SFPP tape-type patch (2-60 mg) was applied to the lower back for 24 h in healthy adult volunteers. S-flurbiprofen (SFP) plasma concentration was measured over time to examine SFP pharmacokinetics. Study 2: SFPP (20 mg) was applied for 12 h to the affected knee of osteoarthritis (OA) patients who were scheduled for total knee arthroplasty. Deep tissues (synovial tissue and synovial fluid) were collected during surgery to compare SFP concentrations after application of SFPP or a commercially available flurbiprofen (FP) gel-type patch. Study 1: The plasma concentration of SFP was sustained during 24-h topical application of the SFPP, showing a high percutaneous absorption ratio of 51.4-72.2 %. Cmax and AUC0-∞ were dose-proportional. Study 2: After application of the SFPP for 12 h, SFP concentrations in the synovial tissue and synovial fluid were 14.8-fold (p = 0.002) and 32.7-fold (p < 0.001) higher, respectively, than those achieved by the FP patch. Sustained plasma concentration of SFP and high percutaneous absorption ratio was observed after 24-h topical application of the SFPP. Compared to the FP patch, the SFPP showed superior percutaneous absorption and greater tissue penetration of SFP into the synovial tissue. Greater tissue penetration of the SFPP seemed to be primarily due to its formulation. Thus, SFPP is expected to show higher efficacy for the treatment of knee OA.

  15. Clinical Pharmacokinetics and Pharmacodynamics of Febuxostat.

    PubMed

    Kamel, Bishoy; Graham, Garry G; Williams, Kenneth M; Pile, Kevin D; Day, Richard O

    2017-05-01

    Febuxostat is a xanthine oxidoreductase inhibitor that has been developed to treat chronic gout. In healthy subjects, the pharmacokinetic parameters of febuxostat after multiple oral dose administration include an oral availability of about 85 %, an apparent oral clearance (CL/F) of 10.5 ± 3.4 L/h and an apparent volume of distribution at steady state (V ss /F) of 48 ± 23 L. The time course of plasma concentrations follows a two-compartment model. The initial half-life (t ½ ) is approximately 2 h and the terminal t ½ determined at daily doses of 40 mg or more is 9.4 ± 4.9 h. Febuxostat is administered once daily. The maximum (peak) plasma concentrations are approximately 100-fold greater than the trough concentrations. Consequently, there is no significant accumulation of the drug during multiple dose administration. There are few data on the pharmacokinetics of febuxostat in patients with gout. While the pharmacokinetic parameters are not affected by mild to moderate hepatic impairment, there is no consensus on whether renal impairment has any effect on the pharmacokinetics of febuxostat. Febuxostat is extensively metabolised by oxidation (approximately 35 %) and acyl glucuronidation (up to 40 %); febuxostat acyl glucuronides are cleared by the kidney. In healthy subjects treated with multiple doses of febuxostat 10-240 mg, the concentrations of serum urate are reduced by a maximum of about 80 %. The percentage reduction in the concentrations of serum urate is slightly less in gouty patients than in healthy subjects.

  16. Pharmacokinetics of doxycycline in laying hens after intravenous and oral administration.

    PubMed

    Yang, F; Si, H B; Wang, Y Q; Zhao, Z S; Zhou, B H; Hao, X Q

    2016-08-01

    The pharmacokinetics of doxycycline in laying hens was investigated after a single intravenous (IV) or an oral (PO) dose at 20 mg/kg body weight. The concentrations of doxycycline in plasma samples were determined by high-performance liquid chromatography with an ultraviolet detector, and pharmacokinetic parameters were calculated using a compartmental model method. The disposition of doxycycline after one single IV injection was best described by a two-compartment open model and the main pharmacokinetic parameters were as follows: volume of distribution (Vd) was 865.15 ± 127.64 ml/kg, distribution rate constant (α) was (2.28 ± 0.38) 1/h, elimination rate constant (β) was 0.08 ± 0.02 1/h and total body clearance (Cl) was104.11 ± 18.32 ml/h/kg, while after PO administration, the concentration versus time curve was best described by a one-compartment open model and absorption rate constant (Ka), peak concentration (Cmax), time to reach Cmax (tmax) and absolute bioavailability (F) were 2.55 ± 1.40 1/h, 5.88 ± 0.70 μg/ml, 1.73 ± 0.75 h and 52.33%, respectively. The profile of doxycycline exhibited favourable pharmacokinetic characteristics in laying hens, such as quick absorption and slow distribution and elimination, though oral bioavailability was relatively low. A multiple-dosing regimen (a dose of 20 mg/kg/d for 3 consecutive days) of doxycycline was recommended to treat infections in laying hens. But a further study should be conducted to determine the withdrawal time of doxycycline in eggs.

  17. Tissue temperature distribution measurement by MRI and laser immunology for cancer treatment

    NASA Astrophysics Data System (ADS)

    Chen, Yichao; Gnyawali, Surya C.; Wu, Feng; Liu, Hong; Tesiram, Yasvir A.; Abbott, Andrew; Towner, Rheal A.; Chen, Wei R.

    2007-02-01

    In cancer treatment and immune response enhancement research, Magnetic Resonance Imaging (MRI) is an ideal method for non-invasive, three-dimensional temperature measurement. We used a 7.1-Tesla magnetic resonance imager for ex vivo tissues and small animal to determine temperature distribution of target tissue during laser irradiation. The feasibility of imaging is approved with high spatial resolution and high signal-noise- ratio. Tissue-simulating gel phantom gel, biological tissues, and tumor-bearing animals were used in the experiments for laser treatment and MR imaging. Thermal couple measurement of temperature in target samples was used for system calibration. An 805-nm laser was used to irradiate the samples with a laser power in the range of 1 to 2.5 watts. Using the MRI system and a specially developed processing algorithm, a clear temperature distribution matrix in the target tissue and surrounding tissue was obtained. The temperature profiles show that the selective laser photothermal effect could result in tissue temperature elevation in a range of 10 to 45 °C. The temperature resolution of the measurement was about 0.37°C including the total system error. The spatial resolution was 0.4 mm (128x128 pixels with field of view of 5.5x5.5 cm). The temperature distribution provided in vivo thermal information and future reference for optimizing dye concentration and irradiation parameters to achieve optimal thermal effects in cancer treatment.

  18. Requirements for pharmacokinetic evaluation of antibiotics in phase I studies.

    PubMed

    Bergan, T

    1986-01-01

    Initial pharmacokinetic studies usually include healthy volunteers to minimize variation generated by diseases. Ethical aspects of initial studies are paramount. The guidelines of the Helsinki Declaration should be followed or even extended. Thorough toxicologic screening in animals is a prerequisite. The use of radioisotopes for pharmacokinetic studies should be limited. The basic design of studies includes cross-over administration of intravenous and oral doses of several sizes. Bioavailability, total area under the serum concentration curve, serum half-life, amount eliminated in urine as active drug, and metabolism are the most important data. The fate of the parent compound and of its possible metabolites in both healthy persons and ill individuals (including those with renal or hepatic dysfunction) should be monitored. Diet may have consequences with regard to recommended dosage schedules. When possible, tissue penetration of antibiotics should be assessed, preferably through the analysis of peripheral human lymph and of suction-blister and peritoneal fluids. Theoretical dosage schedules based on pharmacokinetic assessments in healthy persons should be tested in patients with infectious disease, particularly in those with reduced renal and/or hepatic function.

  19. Single-cell and subcellular pharmacokinetic imaging allows insight into drug action in vivo.

    PubMed

    Thurber, Greg M; Yang, Katy S; Reiner, Thomas; Kohler, Rainer H; Sorger, Peter; Mitchison, Tim; Weissleder, Ralph

    2013-01-01

    Pharmacokinetic analysis at the organ level provides insight into how drugs distribute throughout the body, but cannot explain how drugs work at the cellular level. Here we demonstrate in vivo single-cell pharmacokinetic imaging of PARP-1 inhibitors and model drug behaviour under varying conditions. We visualize intracellular kinetics of the PARP-1 inhibitor distribution in real time, showing that PARP-1 inhibitors reach their cellular target compartment, the nucleus, within minutes in vivo both in cancer and normal cells in various cancer models. We also use these data to validate predictive finite element modelling. Our theoretical and experimental data indicate that tumour cells are exposed to sufficiently high PARP-1 inhibitor concentrations in vivo and suggest that drug inefficiency is likely related to proteomic heterogeneity or insensitivity of cancer cells to DNA-repair inhibition. This suggests that single-cell pharmacokinetic imaging and derived modelling improve our understanding of drug action at single-cell resolution in vivo.

  20. Pharmacokinetic and Pharmacodynamic Modeling of Anidulafungin (LY303366): Reappraisal of Its Efficacy in Neutropenic Animal Models of Opportunistic Mycoses Using Optimal Plasma Sampling

    PubMed Central

    Groll, Andreas H.; Mickiene, Diana; Petraitiene, Ruta; Petraitis, Vidmantas; Lyman, Caron A.; Bacher, John S.; Piscitelli, Stephen C.; Walsh, Thomas J.

    2001-01-01

    The compartmental pharmacokinetics of anidulafungin (VER-002; formerly LY303366) in plasma were characterized with normal rabbits, and the relationships between drug concentrations and antifungal efficacy were assessed in clinically applicable infection models in persistently neutropenic animals. At intravenous dosages ranging from 0.1 to 20 mg/kg of body weight, anidulafungin demonstrated linear plasma pharmacokinetics that fitted best to a three-compartment open pharmacokinetic model. Following administration over 7 days, the mean (± standard error of the mean) peak plasma concentration (Cmax) increased from 0.46 ± 0.02 μg/ml at 0.1 mg/kg to 63.02 ± 2.93 μg/ml at 20 mg/kg, and the mean area under the concentration-time curve from 0 h to infinity (AUC0–∞) rose from 0.71 ± 0.04 to 208.80 ± 24.21 μg · h/ml. The mean apparent volume of distribution at steady state (Vss) ranged from 0.953 ± 0.05 to 1.636 ± 0.22 liter/kg (nonsignificant [NS]), and clearance ranged from 0.107 ± 0.01 to 0.149 ± 0.00 liter/kg/h (NS). Except for a significant prolongation of the terminal half-life and a trend toward an increased Vss at the higher end of the dosage range after multiple doses, no significant differences in pharmacokinetic parameters were noted in comparison to single-dose administration. Concentrations in tissue at trough after multiple dosing (0.1 to 10 mg/kg/day) were highest in lung and liver (0.85 ± 0.16 to 32.64 ± 2.03 and 0.32 ± 0.05 to 43.76 ± 1.62 μg/g, respectively), followed by spleen and kidney (0.24 ± 0.65 to 21.74 ± 1.86 and <0.20 to 16.92 ± 0.56, respectively). Measurable concentrations in brain tissue were found at dosages of ≥0.5 mg/kg (0.24 ± 0.02 to 3.90 ± 0.25). Implementation of optimal plasma sampling in persistently neutropenic rabbit infection models of disseminated candidiasis and pulmonary aspergillosis based on the Bayesian approach and model parameters from normal animals as priors revealed a significantly slower

  1. Tracking Antibody Distribution with Near-Infrared Fluorescent Dyes: Impact of Dye Structure and Degree of Labeling on Plasma Clearance.

    PubMed

    Cilliers, Cornelius; Nessler, Ian; Christodolu, Nikolas; Thurber, Greg M

    2017-05-01

    Monoclonal antibodies labeled with near-infrared (NIR) fluorophores have potential use in disease detection, intraoperative imaging, and pharmacokinetic characterization of therapeutic antibodies in both the preclinical and clinical setting. Recent work has shown conjugation of NIR fluorophores to antibodies can potentially alter antibody disposition at a sufficiently high degree of labeling (DoL); however, other reports show minimal impact after labeling with NIR fluorophores. In this work, we label two clinically approved antibodies, Herceptin (trastuzumab) and Avastin (bevacizumab), with NIR dyes IRDye 800CW (800CW) or Alexa Fluor 680 (AF680), at 1.2 and 0.3 dyes/antibody and examine the impact of fluorophore conjugation on antibody plasma clearance and tissue distribution. At 0.3 DoL, AF680 conjugates exhibited similar clearance to unlabeled antibody over 17 days while 800CW conjugates diverged after 4 days, suggesting AF680 is a more suitable choice for long-term pharmacokinetic studies. At the 1.2 DoL, 800CW conjugates cleared faster than unlabeled antibodies after several hours, in agreement with other published reports. The tissue biodistribution for bevacizumab-800CW and -AF680 conjugates agreed well with literature reported biodistributions using radiolabels. However, the greater tissue autofluorescence at 680 nm resulted in limited detection above background at low (∼2 mg/kg) doses and 0.3 DoL for AF680, indicating that 800CW is more appropriate for short-term biodistribution measurements and intraoperative imaging. Overall, our work shows a DoL of 0.3 or less for non-site-specifically labeled antibodies (with a Poisson distribution) is ideal for limiting the impact of NIR fluorophores on antibody pharmacokinetics.

  2. Development and validation of a physiology-based model for the prediction of pharmacokinetics/toxicokinetics in rabbits

    PubMed Central

    Hermes, Helen E.; Teutonico, Donato; Preuss, Thomas G.; Schneckener, Sebastian

    2018-01-01

    The environmental fates of pharmaceuticals and the effects of crop protection products on non-target species are subjects that are undergoing intense review. Since measuring the concentrations and effects of xenobiotics on all affected species under all conceivable scenarios is not feasible, standard laboratory animals such as rabbits are tested, and the observed adverse effects are translated to focal species for environmental risk assessments. In that respect, mathematical modelling is becoming increasingly important for evaluating the consequences of pesticides in untested scenarios. In particular, physiologically based pharmacokinetic/toxicokinetic (PBPK/TK) modelling is a well-established methodology used to predict tissue concentrations based on the absorption, distribution, metabolism and excretion of drugs and toxicants. In the present work, a rabbit PBPK/TK model is developed and evaluated with data available from the literature. The model predictions include scenarios of both intravenous (i.v.) and oral (p.o.) administration of small and large compounds. The presented rabbit PBPK/TK model predicts the pharmacokinetics (Cmax, AUC) of the tested compounds with an average 1.7-fold error. This result indicates a good predictive capacity of the model, which enables its use for risk assessment modelling and simulations. PMID:29561908

  3. Pharmacokinetic and Safety Analyses of Tenofovir and Tenofovir-Emtricitabine Vaginal Tablets in Pigtailed Macaques

    PubMed Central

    Pereira, Lara E.; Friend, David R.; Garber, David A.; McNicholl, Janet M.; Hendry, R. Michael; Doncel, Gustavo F.

    2014-01-01

    Vaginal rapidly disintegrating tablets (RDTs) containing tenofovir (TFV) or TFV and emtricitabine (FTC) were evaluated for safety and pharmacokinetics in pigtailed macaques. Two separate animal groups (n = 4) received TFV (10 mg) or TFV-FTC (10 mg each) RDTs, administered near the cervix. A third group (n = 4) received 1 ml TFV gel. Blood plasma, vaginal tissue biopsy specimens, and vaginal fluids were collected before and after product application at 0, 0.5, 1, 4, and 24 h. A disintegration time of <30 min following vaginal application of the RDTs was noted, with negligible effects on local inflammatory cytokines, vaginal pH, and microflora. TFV pharmacokinetics were generally similar for both RDTs and gel, with peak median concentrations in vaginal tissues and vaginal secretions being on the order of 104 to 105 ng/g (147 to 571 μM) and 106 ng/g (12 to 34 mM), respectively, at 1 to 4 h postdose. At 24 h, however, TFV vaginal tissue levels were more sustained after RDT dosing, with median TFV concentrations being approximately 1 log higher than those with gel dosing. FTC pharmacokinetics after combination RDT dosing were similar to those of TFV, with peak median vaginal tissue and fluid levels being on the order of 104 ng/g (374 μM) and 106 ng/g (32 mM), respectively, at 1 h postdose with levels in fluid remaining high at 24 h. RDTs are a promising alternative vaginal dosage form, delivering TFV and/or FTC at levels that would be considered inhibitory to simian-human immunodeficiency virus in the macaque vaginal microenvironment over a 24-h period. PMID:24566178

  4. Comparison of Dapivirine Vaginal Gel and Film Formulation Pharmacokinetics and Pharmacodynamics (FAME 02B)

    PubMed Central

    Marzinke, Mark A.; Bakshi, Rahul P.; Fuchs, Edward J.; Radebaugh, Christine L.; Aung, Wutyi; Spiegel, Hans M.L.; Coleman, Jenell S.; Rohan, Lisa C.; Hendrix, Craig W.

    2017-01-01

    Abstract While preexposure prophylaxis with oral tenofovir/emtricitabine reduces HIV acquisition rates, poor adherence to and acceptability of vaginal gels and the potential for evolving drug resistance have led to development of vaginal film formulations and other antiretroviral drugs, respectively, including the non-nucleoside reverse transcriptase inhibitor dapivirine. In this two-arm crossover study of a novel fast-dissolving dapivirine film and a previously studied semisolid dapivirine gel, 10 healthy women received a single 1.25 mg vaginal dose of each study product; one withdrew after the first dose. Clinical, pharmacokinetic, and antiviral pharmacodynamic assessments (ex vivo HIV-BaL challenge of tissue explants) were performed over 168 h postdose. Six of ten participants experienced mild to moderate adverse effects, similar between products, with no severe adverse events or adverse events attributed to study products. There were no statistically significant differences in plasma, cervicovaginal fluid (CVF), or cervical tissue dapivirine concentrations between the gel and film (all p > .05). CVF dapivirine concentrations were 1.5 and 6 log10 greater than tissue and plasma concentrations, respectively (p < .001). Both film and gel demonstrated reduced cervical tissue infectivity after ex vivo HIV challenge 5 h postdose, compared to baseline and 72-h postdose biopsies (p < .05 for gel, p = .06 for film). There was no difference in ex vivo explant HIV challenge between gel and film. The dapivirine film and gel performed similarly in terms of tolerability, pharmacokinetics, and antiviral effect. Dapivirine film may provide an alternative to pharmacokinetically comparable dapivirine gel formulations. Effectiveness remains to be tested. PMID:27809557

  5. Vandetanib-eluting Radiopaque Beads: In vivo Pharmacokinetics, Safety and Toxicity Evaluation following Swine Liver Embolization.

    PubMed

    Denys, Alban; Czuczman, Peter; Grey, David; Bascal, Zainab; Whomsley, Rhys; Kilpatrick, Hugh; Lewis, Andrew L

    2017-01-01

    To evaluate the plasma and tissue pharmacokinetics, safety and toxicity following intra-arterial hepatic artery administration of Vandetanib (VTB)-eluting Radiopaque Beads (VERB) in healthy swine. In a first phase, healthy swine were treated with hepatic intra-arterial administration of VERB at target dose loading strengths of 36 mg/mL (VERB36), 72 mg/mL (VERB72) and 120 mg/mL (VERB120). Blood and tissue samples were taken and analysed for VTB and metabolites to determine pharmacokinetic parameters for the different dose forms over 30 days. In a second phase, animals were treated with unloaded radiopaque beads or high dose VTB loaded beads (VERB100, 100 mg/mL). Tissue samples from embolized and non-embolized areas of the liver were evaluated at necropsy (30 and 90 days) for determination of VTB and metabolite levels and tissue pathology. Imaging was performed prior to sacrifice using multi-detector computed tomography (MDCT) and imaging findings correlated with pathological changes in the tissue and location of the radiopaque beads. The peak plasma levels of VTB (C max ) released from the various doses of VERB ranged between 6.19-17.3 ng/mL indicating a low systemic burst release. The plasma profile of VTB was consistent with a distribution phase up to 6 h after administration followed by elimination with a half-life of 20-23 h. The AUC of VTB and its major metabolite N-desmethyl vandetanib (NDM VTB) was approximately linear with the dose strength of VERB. VTB plasma levels were at or below limits of detection two weeks after administration. In liver samples, VTB and NDM VTB were present in treated sections at 30 days after administration at levels above the in vitro IC 50 for biological effectiveness. At 90 days both analytes were still present in treated liver but were near or below the limit of quantification in untreated liver sections, demonstrating sustained release from the VERB. Comparison of the reduction of the liver lobe size and associated tissue

  6. Pharmacokinetics of Rilpivirine in HIV-Infected Pregnant Women.

    PubMed

    Tran, Anna H; Best, Brookie M; Stek, Alice; Wang, Jiajia; Capparelli, Edmund V; Burchett, Sandra K; Kreitchmann, Regis; Rungruengthanakit, Kittipong; George, Kathleen; Cressey, Tim R; Chakhtoura, Nahida; Smith, Elizabeth; Shapiro, David E; Mirochnick, Mark

    2016-07-01

    Rilpivirine pharmacokinetics is defined by its absorption, distribution, metabolism, and excretion. Pregnancy can affect these factors by changes in cardiac output, protein binding, volume of distribution, and cytochrome P450 (CYP) 3A4 activity. Rilpivirine is metabolized by CYP3A4. The impact of pregnancy on rilpivirine pharmacokinetics is largely unknown. International Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is a multicenter, nonblinded, prospective study evaluating antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving rilpivirine 25 mg once daily as part of their combination antiretrovirals for clinical care. Thirty-two women were enrolled in this study. Intensive pharmacokinetic sampling was performed at steady state during the second trimester, the third trimester, and postpartum. Maternal and umbilical cord blood samples were obtained at delivery. Plasma rilpivirine concentration was measured using liquid chromatography-mass spectrometry; lower limit of quantitation was 10 ng/mL. Median (range) AUC0-24 were 1969 (867-4987, n = 15), 1669 (556-4312, n = 28), and 2387 (188-6736, n = 28) ng·h/mL in the second trimester, the third trimester, and postpartum, respectively (P < 0.05 for either trimester vs postpartum). Median (range) C24 were 63 (37-225, n = 17), 56 (<10-181, n = 30), and 81 (<10-299, n = 28) ng/mL (P < 0.05 for either trimester vs postpartum). High variability in pharmacokinetic parameters was observed between subjects. Median (range) cord blood/maternal concentration ratio was 0.55 (0.3-0.8, n = 21). Delivery HIV-1 RNA was ≤50 copies per milliliter in 70% and ≤400 copies per milliliter in 90% of women. Cmin were significantly lower at 15 visits with detectable HIV-1 RNA compared with 61 visits with undetectable HIV-1 RNA, 29 (<10-93) vs 63 (15-200) ng/mL (P = 0.0001). Cmin was below the protein binding-adjusted EC90 concentration (12.2 ng/mL) at 4 visits in 3 of 31 women (10

  7. Pharmacokinetics of topically applied pilocarpine in the albino rabbit eye.

    PubMed

    Makoid, M C; Robinson, J R

    1979-04-01

    The temporal and spatial pattern of [3H]-pilocarpine nitrate distribution in the albino rabbit eye following topical administration was determined. A four-compartment caternary chain model describing this disposition corresponds to the precorneal area, the cornea, the aqueous humor, and the lens and vitreous. Simultaneous computer fitting of data from tissue corresponding to some compartments in the model supported the proposed model. Additional support was provided by the excellent correlation between predicted and observed values in multiple-dosing studies. Several important aspects of ocular drug disposition are evident from the model. The extensive parallel elimination at the absorption site gives rise to an apparent absorption rate constant that is one to two orders of magnitude larger than the true absorption rate constant. In addition, aqueous flow accounts for most of the drug removal. Thus, major effects on absorption and elimination, independent of the drug structure, suggest the possibility of similar pharmacokinetics for vastly different drugs.

  8. Simultaneous pharmacogenetics-based population pharmacokinetic analysis of darunavir and ritonavir in HIV-infected patients.

    PubMed

    Moltó, José; Xinarianos, George; Miranda, Cristina; Pushpakom, Sudeep; Cedeño, Samandhy; Clotet, Bonaventura; Owen, Andrew; Valle, Marta

    2013-07-01

    with first-order absorption and elimination. The darunavir peripheral volume of distribution decreased as α1-acid glycoprotein concentrations increased. Darunavir clearance was 12 % lower in patients with SLCO3A1 rs8027174 GT/TT genotypes, while homozygosity for the rs4294800 A allele was associated with 2.5-fold higher central volume of distribution. Body weight influenced ritonavir clearance. Ritonavir inhibited darunavir clearance following a maximum-effect model. A population pharmacokinetic model to simultaneously describe the pharmacokinetics of darunavir and ritonavir was developed in HIV-infected patients. The model provides better understanding of the interaction between darunavir and ritonavir and suggests an association between SLCO3A1 polymorphisms and darunavir pharmacokinetics. Bayesian estimates of individual darunavir parameters and ritonavir may be useful to predict darunavir exposure.

  9. Population Pharmacokinetics and Therapeutic Efficacy of Febuxostat in Patients with Severe Renal Impairment.

    PubMed

    Hira, Daiki; Chisaki, Yugo; Noda, Satoshi; Araki, Hisazumi; Uzu, Takashi; Maegawa, Hiroshi; Yano, Yoshitaka; Morita, Shin-Ya; Terada, Tomohiro

    2015-01-01

    The aim of the present study was to determine the influence of severe renal dysfunction (estimated glomerular filtration rate <30 ml/min/1.73 m(2), including hemodialysis) on the pharmacokinetics and therapeutic effects of febuxostat using a population pharmacokinetic analysis. This study recruited patients with hyperuricemia who were initially treated with allopurinol, but were switched to febuxostat, and it consists of 2 sub-studies: a pharmacokinetic study (26 patients) and retrospective efficacy evaluation study (51 patients). The demographic and clinical data of patients were collected from electronic medical records. Plasma febuxostat concentrations were obtained at each hospital visit. Population pharmacokinetic modeling was performed with NONMEM version 7.2. A total of 128 plasma febuxostat concentrations from 26 patients were used in the population pharmacokinetic analysis. The data were best described by a 1-compartment model with first order absorption. Covariate analysis revealed that renal function did not influence the pharmacokinetics of febuxostat, whereas actual body weight significantly influenced apparent clearance and apparent volume of distribution. The retrospective efficacy analysis showed the favorable therapeutic response of febuxostat switched from allopurinol in patients with moderate to severe renal impairment. No serious adverse event associated with febuxostat was observed irrespective of renal function. The population pharmacokinetic analysis and therapeutic analysis of febuxostat revealed that severe renal dysfunction had no influence on the pharmacokinetic parameters of febuxostat. These results suggest that febuxostat is tolerated well by patients with severe renal impairment. © 2015 S. Karger AG, Basel.

  10. Murine pharmacokinetics and antitumor efficacy of the photodynamic sensitizer 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a.

    PubMed

    Bellnier, D A; Henderson, B W; Pandey, R K; Potter, W R; Dougherty, T J

    1993-09-01

    The combination of the new photodynamic sensitizer 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) and laser light of wavelength 665 nm showed antitumor activity against two s.c.-implanted murine tumors. HPPH also sensitized normal mouse foot tissue to light but photosensitivity decreased rapidly with time after HPPH administration. Mechanistic studies revealed that HPPH induced little direct tumor cell toxicity but was an effective mediator of vascular photodamage. Pharmacokinetic studies following intravenous injection of 1 mg [14C]HPPH per kilogram revealed a biexponential decay with time, with plasma alpha and beta half-lives of 0.69 and 21 h respectively. Fecal excretion was the primary route of elimination. The highest levels of [14C]HPPH were found in the liver, which also showed the greatest long-term retention. The sequence of decreasing uptake levels was the liver, adrenals, lung, spleen, kidney, urinary bladder, heart, eye, skin, pancreas, muscle, testes, fat and brain. This distribution correlated with the relative blood perfusion rates in the tissues.

  11. Tubocurarine and pancuronium: a pharmacokinetic view.

    PubMed

    Shanks, C A; Somogyi, A A; Ramzan, M I; Triggs, E J

    1980-02-01

    This review is an attempt to bring together the pharmacokinetic data on d-tubocurarine and pancuronium with clinical observations on relaxant dosage and effect. The modelling techniques used here represent an oversimplification of the relationships between relaxant plasma concentration and response as they do not predict either the time of onset of paralysis or its peak intensity. However, they do enable calculation of a bolus dose of relaxant required to achieve a particular intensity of paralysis for the average patient once pseudo-distribution equilibrium has been achieved. This has been further extended to predict the cumulation of the relaxants with subsequent dosage in average patients. Suggested regimens incorporating bolus and infusion doses of the relaxants to achieve continuous neuromuscular blockade have been calculated also. Averaged pharmacokinetic parameters derived from patients with renal or hepatic dysfunction have been used to predict the likely duration and intensities of paralysis for the relaxants.

  12. Pharmacokinetics of Budesonide Administered with Surfactant in Premature Lambs: Implications for Neonatal Clinical Trials

    PubMed Central

    Roberts, Jessica K.; Stockmann, Chris; Dahl, Mar Janna; Albertine, Kurt H.; Egan, Edmund; Lin, Zhenjian; Reilly, Christopher A.; Ballard, Philip L.; Ballard, Roberta A.; Ward, Robert M.

    2017-01-01

    Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature human infants, which may persist through adulthood. Airway inflammation has been firmly established in the pathogenesis of BPD. Previous studies to reduce airway inflammation with high-dose dexamethasone demonstrated adverse neurological outcomes, despite lower incidences of BPD. Instillation of budesonide and surfactant can facilitate early extubation and reduce the incidence of BPD and death among very low birth weight infants. However, the pharmacokinetics of budesonide and its distribution into the lung and brain are unknown. Therefore, 5 premature lambs were administered 0.25 mg/kg budesonide, with surfactant as the vehicle. Plasma and tissue samples were taken from the lambs for measurement of budesonide, 16α-hydroxy prednisolone, and budesonide palmitate using LC/MS/MS. Peak plasma budesonide concentrations were inversely correlated with the oxygenation index (correlation coefficient of −0.75). Plasma budesonide concentrations were extremely low (~10% of expected) for two lambs that had high oxygenation indices and were excluded from further analyses. For the remaining 5 premature lambs, a non-compartmental analysis demonstrated an AUCinf of 148.77 ± 28.16 h*μg/L, half-life of 4.76 ± 1.79 h, and Cmax of 46.17 ± 17.71 μg/L. Using population pharmacokinetic methods, a one-compartment model with exponential residual error and first-order absorption adequately described the data. The apparent clearance and apparent volume of distribution of budesonide were estimated at 6.29 L/h (1.99 L/h/kg) and 29.1 L (9.2 L/kg), respectively. Budesonide and budesonide palmitate, but not 16α-hydroxy prednisolone, were detected in lung tissue. In this study, budesonide and its metabolites were not detected in the brain, which suggests that intratracheal instillation suggests that after local pulmonary deposition, there is no evidence of budesonide accumulation in the central nervous system. Overall

  13. Pharmacokinetics of Budesonide Administered with Surfactant in Premature Lambs: Implications for Neonatal Clinical Trials.

    PubMed

    Roberts, Jessica K; Stockmann, Chris; Dahl, Mar Janna; Albertine, Kurt H; Egan, Edmund; Lin, Zhenjian; Reilly, Christopher A; Ballard, Philip L; Ballard, Roberta A; Ward, Robert M

    2016-01-01

    Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature human infants, which may persist through adulthood. Airway inflammation has been firmly established in the pathogenesis of BPD. Previous studies to reduce airway inflammation with high-dose dexamethasone demonstrated adverse neurological outcomes, despite lower incidences of BPD. Instillation of budesonide and surfactant can facilitate early extubation and reduce the incidence of BPD and death among very low birth weight infants. However, the pharmacokinetics of budesonide and its distribution into the lung and brain are unknown. Therefore, 5 premature lambs were administered 0.25 mg/kg budesonide, with surfactant as the vehicle. Plasma and tissue samples were taken from the lambs for measurement of budesonide, 16α- hydroxy prednisolone, and budesonide palmitate using LC/MS/MS. Peak plasma budesonide concentrations were inversely correlated with the oxygenation index (correlation coefficient of -0.75). plasma budesonide concentrations were extremely low (~10% of expected) for two lambs that had high oxygenation indices and were excluded from further analyses. For the remaining 5 premature lambs, a non-compartmental analysis demonstrated an AUCinf of 148.77 ± 28.16 h*μg/L, half-life of 4.76 ± 1.79 h, and Cmax of 46.17 ± 17.71 µg/L. Using population pharmacokinetic methods, a onecompartment model with exponential residual error and first-order absorption adequately described the data. The apparent clearance and apparent volume of distribution of budesonide were estimated at 6.29 L/h (1.99 L/h/kg) and 29.1 L (9.2 L/kg), respectively. Budesonide and budesonide palmitate, but not 16α-hydroxy prednisolone, were detected in lung tissue. In this study, budesonide and its metabolites were not detected in the brain, which suggests that intratracheal instillation suggests that after local pulmonary deposition, there is no evidence of budesonide accumulation in the central nervous system. Overall

  14. Preparation, pharmacokinetics and tumour-suppressive activity of berberine liposomes.

    PubMed

    Wang, Xinghui; Wang, Qiong; Liu, Zhihui; Zheng, Xiao

    2017-06-01

    Berberine (BBR) has shown promising antitumour effects in vitro. However, intravenous administration of BBR solution is complicated by lethal adverse cardiovascular effects. The aim of this study was to prepare common and polyethylene glycol (PEG)-modified long-circulating BBR liposomes and evaluate their efficacy and safety as potential antitumour agents. Physiochemical properties of common and long-circulating BBR liposomes were characterized including particle size, Zeta potential and thermal stability. Pharmacokinetic and tissue distribution study of liposomal BBR was performed in rats and tumour-bearing nude mice, respectively. Antitumour efficacy and safety were observed in SGC-7901 tumour-xenografted mice. Berberine liposomes showed homogenous morphology, storage stability and sustained-releasing behaviour in vitro. BBR liposomes led to significantly increased circulation retention of BBR in comparison with BBR solution. In tumour-bearing mice, BBR liposomes selectively increased BBR concentrations in the liver, spleen, lung and tumour, while conferred lower distribution to the heart and kidney. Importantly, chronic administration of BBR liposomes proved effective and safe in suppressing the tumour growth in nude mice, especially the PEG-modified long-circulating liposomes. Our study suggested that BBR liposomes may provide a safe form of intravenous drug therapy for strengthening the antitumour effects of BBR. © 2017 Royal Pharmaceutical Society.

  15. Population pharmacokinetics of oxycodone in patients with cancer-related pain.

    PubMed

    Komatsu, Toshiaki; Kokubun, Hideya; Suzuki, Ai; Takayanagi, Risa; Yamada, Yasuhiko; Matoba, Motohiro; Yago, Kazuo

    2012-09-01

    Oxycodone is an opioid widely prescribed to cancer patients for pain relief. However, the pharmacokinetics of oxycodone has not been sufficiently examined. Therefore the aim of this work was to study population pharmacokinetics of oxycodone in patients with cancer pain. The authors analyzed 108 serum oxycodone samples of 33 individuals with nonlinear mixed-effects model (NONMEM). Population pharmacokinetics was calculated using the one-compartment model of clearance, volume of distribution, bioavailability, absorption constant rate, and lag time. An exponential error model was used to determine interindividual variability and a relative error model was applied to assess residual variability. Population pharmacokinetics of oxycodone at the end point were as follows: CL(L/h) = 10.7 × [1 + (2 - Child-Pugh Classification)] (Class: A = 0, B = 1, C = 2); V(d) (L) = 193; k(a) (h(-1)) = 0.336; T(lag) (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, V(d): 44.6%, and F: 37.0%, and residual variability was 16.2%. As the total clearance in patients with liver dysfunction (Child-Pugh class B) was reduced to 33.3%, serum concentration of oxycodone increased by 1.5. Therefore, it became clear that dose adjustments are essential when treating patients with liver dysfunction. These findings suggest that population parameters are useful for evaluating pharmacokinetics of oxycodone in patients with cancer pain.

  16. Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children

    PubMed Central

    Kumpulainen, Elina; Välitalo, Pyry; Kokki, Merja; Lehtonen, Marko; Hooker, Andrew; Ranta, Veli-Pekka; Kokki, Hannu

    2010-01-01

    AIMS This study was designed to characterize paediatric pharmacokinetics and central nervous system exposure of flurbiprofen. METHODS The pharmacokinetics of flurbiprofen were studied in 64 healthy children aged 3 months to 13 years, undergoing surgery with spinal anaesthesia. Children were administered preoperatively a single dose of flurbiprofen intravenously as prodrug (n = 27) or by mouth as syrup (n = 37). A single cerebrospinal fluid (CSF) sample (n = 60) was collected at the induction of anaesthesia, and plasma samples (n = 304) before, during and after the operation (up to 20 h after administration). A population pharmacokinetic model was built using the NONMEM software package. RESULTS Flurbiprofen concentrations in plasma were well described by a three compartment model. The apparent bioavailability of oral flurbiprofen syrup was 81%. The estimated clearance (CL) was 0.96 l h−1 70 kg−1. Age did not affect the clearance after weight had been included as a covariate. The estimated volume of distribution at steady state (Vss) was 8.1 l 70 kg−1. Flurbiprofen permeated into the CSF, reaching concentrations that were seven-fold higher compared with unbound plasma concentrations. CONCLUSIONS Flurbiprofen pharmacokinetics can be described using only weight as a covariate in children above 6 months, while more research is needed in neonates and in younger infants. PMID:20840447

  17. Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy Greyhound dogs

    PubMed Central

    KuKanich, Butch; Allen, Philip

    2014-01-01

    The purpose of this study was to compare the pharmacokinetics of two highly protein bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy Greyhound dogs (3 males and 3 females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL/min/kg) was faster than buprenorphine (10.3 mL/min/kg). The terminal half-life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including: octanol:water partition coefficient and pKa the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95-98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs. PMID:24684621

  18. Population pharmacokinetics of ϵ-aminocaproic acid in adolescents undergoing posterior spinal fusion surgery

    PubMed Central

    Stricker, P. A.; Gastonguay, M. R.; Singh, D.; Fiadjoe, J. E.; Sussman, E. M.; Pruitt, E. Y.; Goebel, T. K.; Zuppa, A. F.

    2015-01-01

    Background Despite demonstrated efficacy of ϵ-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations. Methods Twenty children ages 12–17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics. Results Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min−1 70 kg−1 (6.32 ml min−1 kg−0.75), intercompartmental clearance of 200 ml min−1 70 kg−1 (8.26 ml min−1 kg−0.75), central volume of distribution of 8.78 litre 70 kg−1 (0.13 litre kg−1), and peripheral volume of distribution of 15.8 litre 70 kg−1 (0.23 litre kg−1). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics. Conclusions The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg−1 loading dose and 40 mg kg−1 h−1 infusion; weight ≤25 kg–<50 kg, 100 mg kg−1 loading dose and 35 mg kg−1 h−1 infusion; and weight ≥50 kg, 100 mg kg−1 loading dose and 30 mg kg−1 h−1 infusion. An efficacy trial employing this dosing strategy is warranted. Clinical trial registration NCT01408823. PMID:25586726

  19. Human pharmacokinetics of iohexol. A new nonionic contrast medium

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Olsson, B.; Aulie, A.; Sveen, K.

    1983-03-01

    The pharmacokinetics of iohexol, a new nonionic, water-soluble contrast medium, have been determined after intravenous injection in 20 healthy volunteers, at four different dose levels (125-500 mg I/kg). The apparent volume of distribution was 0.27 1/kg, indicating distribution in the extracellular water. The biologic half-life was 121 minutes, comparable with that of other intravascular contrast media. Iohexol was excreted completely unmetabolized in the urine, with a 100% recovery 24 hours after injection. A comparison of iohexol and chromium-51 (/sup 51/Cr)-EDTA clearances indicates that iohexol is mainly excreted by glomerular filtration. The /sup 51/Cr-EDTA clearance was the same when injected separatelymore » and concomitantly with iohexol, indicating that glomerular filtration rate is not affected by iohexol. No dose dependency was observed in the investigated parameters t1/2 alpha, t1/2 beta, Vd, ClT or ClR. Iohexol pharmacokinetics are in correspondence with previously reported data on intravascular contrast media.« less

  20. [Correlations of pharmacokinetics and pharmacodynamics of a combined preparation containing pyrrolidone and pyroglutamic acid].

    PubMed

    Sariev, A K; Lun'shina, E V; Zherdev, V P; Mirzoian, N R

    2006-01-01

    Experiments showed that a new drug composition containing pyrrolidone and pyroglutamic acid exhibits a significant cerebrovascular effect upon peroral administration in rats. The pharmacokinetics of pyrrolidone monitored upon its combined administration with pyroglutamic acid shows that this drug, as a component of the composition, is characterized by a high absolute bioavailability and permeability trough the blood-brain barrier. The presence of pyroglutamic acid slows down the absorption and elimination of pyrrolidone and enhances its distribution in the organs and tissues. There is a correlation between the concentration of pyrrolidone in the brain, on the one hand, and the levels of cerebral microcirculation and arterial pressure on the other hand. An increase in the concentration of pyrrolidone in the brain is accompanied by more intensive cerebral blood flow and by a decrease in the arterial pressure.

  1. A dynamic system with digital lock-in-photon-counting for pharmacokinetic diffuse fluorescence tomography

    NASA Astrophysics Data System (ADS)

    Yin, Guoyan; Zhang, Limin; Zhang, Yanqi; Liu, Han; Du, Wenwen; Ma, Wenjuan; Zhao, Huijuan; Gao, Feng

    2018-02-01

    Pharmacokinetic diffuse fluorescence tomography (DFT) can describe the metabolic processes of fluorescent agents in biomedical tissue and provide helpful information for tumor differentiation. In this paper, a dynamic DFT system was developed by employing digital lock-in-photon-counting with square wave modulation, which predominates in ultra-high sensitivity and measurement parallelism. In this system, 16 frequency-encoded laser diodes (LDs) driven by self-designed light source system were distributed evenly in the imaging plane and irradiated simultaneously. Meanwhile, 16 detection fibers collected emission light in parallel by the digital lock-in-photon-counting module. The fundamental performances of the proposed system were assessed with phantom experiments in terms of stability, linearity, anti-crosstalk as well as images reconstruction. The results validated the availability of the proposed dynamic DFT system.

  2. Development of a Physiologically Based Pharmacokinetic Model for Triadimefon and Triadimenol in Rats and Humans

    EPA Science Inventory

    A physiologically based pharmacokinetic (PBPK) model was developed for the conazole fungicide triadimefon and its primary metabolite, triadimenol. Rat tissue:blood partition coefficients and metabolic constants were measured in vitro for both compounds. Kinetic time course data...

  3. Tissue distribution of pretomanid in rat brain via mass spectrometry imaging.

    PubMed

    Shobo, Adeola; Bratkowska, Dominika; Baijnath, Sooraj; Naiker, Suhashni; Somboro, Anou M; Bester, Linda A; Singh, Sanil D; Naicker, Tricia; Kruger, Hendrik G; Govender, Thavendran

    2016-01-01

    1. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) combines the sensitivity and selectivity of mass spectrometry with spatial analysis to provide a new dimension for histological analyses of the distribution of drugs in tissue. Pretomanid is a pro-drug belonging to a class of antibiotics known as nitroimidizoles, which have been proven to be active under hypoxic conditions and to the best of our knowledge there have been no studies investigating the distribution and localisation of this class of compounds in the brain using MALDI MSI. 2. Herein, we report on the distribution of pretomanid in the healthy rat brain after intraperitoneal administration (20 mg/kg) using MALDI MSI. Our findings showed that the drug localises in specific compartments of the rat brain viz. the corpus callosum, a dense network of neurons connecting left and right cerebral hemispheres. 3. This study proves that MALDI MSI technique has great potential for mapping the pretomanid distribution in uninfected tissue samples, without the need for molecular labelling.

  4. The Effect of Nizatidine, a MATE2K Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Volunteers

    PubMed Central

    Morrissey, Kari M.; Stocker, Sophie L.; Chen, Eugene C.; Castro, Richard A.; Brett, Claire M.; Giacomini, Kathleen M.

    2015-01-01

    Background and Objectives In the proximal tubule, basic drugs are transported from the renal cells to the tubule lumen through the concerted action of the H+/organic cation antiporters, multidrug and toxin extrusion 1 (MATE1) and 2K (MATE2K). Dual inhibitors of the MATE transporters have been shown to have a clinically relevant effect on the pharmacokinetics of concomitantly administered basic drugs. However, the clinical impact of selective renal organic cation transport inhibition on the pharmacokinetics and pharmacodynamics of basic drugs, such as metformin, is unknown. This study sought to identify a selective MATE2K inhibitor in vitro and to determine its clinical impact on the pharmacokinetics and pharmacodynamics of metformin in healthy subjects. Methods A strategic cell-based screen of 71 U.S. Food and Drug Administration (FDA)-approved medications was conducted to identify selective inhibitors of renal organic cation transporters that are capable of inhibiting at clinically relevant concentrations. From this screen, nizatidine was identified and predicted to be a clinically potent and selective inhibitor of MATE2K-mediated transport. The effect of nizatidine on the pharmacokinetics and pharmacodynamics of metformin was evaluated in 12 healthy volunteers in an open-label, randomized, two-phase crossover drug-drug interaction (DDI) study. Results In healthy volunteers, the MATE2K-selective inhibitor, nizatidine, significantly increased the apparent volume of distribution, half-life and hypoglycemic activity of metformin. However, despite achieving unbound maximum concentrations greater than the in vitro inhibition potency (IC50) of MATE2K-mediated transport, nizatidine did not affect the renal clearance or net secretory clearance of metformin. Conclusion This study demonstrates that a selective inhibition of MATE2K by nizatidine, affected the apparent volume of distribution, tissue levels and peripheral effects of metformin. However, nizatidine did not alter

  5. Applications of physiologically based pharmacokinetic modeling for the optimization of anti-infective therapies.

    PubMed

    Moss, Darren Michael; Marzolini, Catia; Rajoli, Rajith K R; Siccardi, Marco

    2015-01-01

    The pharmacokinetic properties of anti-infective drugs are a determinant part of treatment success. Pathogen replication is inhibited if adequate drug levels are achieved in target sites, whereas excessive drug concentrations linked to toxicity are to be avoided. Anti-infective distribution can be predicted by integrating in vitro drug properties and mathematical descriptions of human anatomy in physiologically based pharmacokinetic models. This method reduces the need for animal and human studies and is used increasingly in drug development and simulation of clinical scenario such as, for instance, drug-drug interactions, dose optimization, novel formulations and pharmacokinetics in special populations. We have assessed the relevance of physiologically based pharmacokinetic modeling in the anti-infective research field, giving an overview of mechanisms involved in model design and have suggested strategies for future applications of physiologically based pharmacokinetic models. Physiologically based pharmacokinetic modeling provides a powerful tool in anti-infective optimization, and there is now no doubt that both industry and regulatory bodies have recognized the importance of this technology. It should be acknowledged, however, that major challenges remain to be addressed and that information detailing disease group physiology and anti-infective pharmacodynamics is required if a personalized medicine approach is to be achieved.

  6. A comprehensive physiologically based pharmacokinetic ...

    EPA Pesticide Factsheets

    Published physiologically based pharmacokinetic (PBPK) models from peer-reviewed articles are often well-parameterized, thoroughly-vetted, and can be utilized as excellent resources for the construction of models pertaining to related chemicals. Specifically, chemical-specific parameters and in vivo pharmacokinetic data used to calibrate these published models can act as valuable starting points for model development of new chemicals with similar molecular structures. A knowledgebase for published PBPK-related articles was compiled to support PBPK model construction for new chemicals based on their close analogues within the knowledgebase, and a web-based interface was developed to allow users to query those close analogues. A list of 689 unique chemicals and their corresponding 1751 articles was created after analysis of 2,245 PBPK-related articles. For each model, the PMID, chemical name, major metabolites, species, gender, life stages and tissue compartments were extracted from the published articles. PaDEL-Descriptor, a Chemistry Development Kit based software, was used to calculate molecular fingerprints. Tanimoto index was implemented in the user interface as measurement of structural similarity. The utility of the PBPK knowledgebase and web-based user interface was demonstrated using two case studies with ethylbenzene and gefitinib. Our PBPK knowledgebase is a novel tool for ranking chemicals based on similarities to other chemicals associated with existi

  7. Carbon-14 radiolabeling and tissue distribution evaluation of MMV390048.

    PubMed

    Sonopo, Molahlehi S; Pillay, Adushan; Chibale, Kelly; Marjanovic-Painter, Biljana; Donini, Cristina; Zeevaart, Jan R

    2016-12-01

    The antimalarial compound MMV390048 ([ 14 C]-11) was labeled with carbon-14 isotope via a 3-step synthesis. It was obtained in a 15.5% radiochemical overall yield from carbon-14 labeled methyl iodide with a radiochemical purity of >99%. After single oral administration of [ 14 C]-11 to albino and pigmented rats its tissue distribution profile was studied. Tissue distribution results showed high local exposure in the GI tract and excretory organs but low exposure of all other tissues. The radioactivity uptake was higher in the eyes of the pigmented rats than in the eyes of the albino rats at all-time points. The highest accumulation reached in the eyes of the pigmented rats was 0.46% at 6 hours. However, these levels are still very low as compared to the other organs studied. There was very little radioactivity from MMV390048 ([ 14 C]-11) present in the skin of both the albino and pigmented rats. The results obtained are supportive of further development of MMV390048 as a potential antimalarial compound. Copyright © 2016 John Wiley & Sons, Ltd.

  8. [Diagnostic value of quantitative pharmacokinetic parameters and relative quantitative pharmacokinetic parameters in breast lesions with dynamic contrast-enhanced MRI].

    PubMed

    Sun, T T; Liu, W H; Zhang, Y Q; Li, L H; Wang, R; Ye, Y Y

    2017-08-01

    Objective: To explore the differential between the value of dynamic contrast-enhanced MRI quantitative pharmacokinetic parameters and relative pharmacokinetic quantitative parameters in breast lesions. Methods: Retrospective analysis of 255 patients(262 breast lesions) who was obtained by clinical palpation , ultrasound or full-field digital mammography , and then all lessions were pathologically confirmed in Zhongda Hospital, Southeast University from May 2012 to May 2016. A 3.0 T MRI scanner was used to obtain the quantitative MR pharmacokinetic parameters: volume transfer constant (K(trans)), exchange rate constant (k(ep))and extravascular extracellular volume fraction (V(e)). And measured the quantitative pharmacokinetic parameters of normal glands tissues which on the same side of the same level of the lesions; and then calculated the value of relative pharmacokinetic parameters: rK(rans)、rk(ep) and rV(e).To explore the diagnostic value of two pharmacokinetic parameters in differential diagnosis of benign and malignant breast lesions using receiver operating curves and model of logistic regression. Results: (1)There were significant differences between benign lesions and malignant lesions in K(trans) and k(ep) ( t =15.489, 15.022, respectively, P <0.05), there were no significant differences between benign lesions and malignant lesions in V(e)( t =-2.346, P >0.05). The areas under the ROC curve(AUC)of K(trans), k(ep) and V(e) between malignant and benign lesions were 0.933, 0.948 and 0.387, the sensitivity of K(trans), k(ep) and V(e) were 77.1%, 85.0%, 51.0% , and the specificity of K(trans), k(ep) and V(e) were 96.3%, 93.6%, 60.8% for the differential diagnosis of breast lesions if taken the maximum Youden's index as cut-off. (2)There were significant differences between benign lesions and malignant lesions in rK(trans), rk(ep) and rV(e) ( t =14.177, 11.726, 2.477, respectively, P <0.05). The AUC of rK(trans), rk(ep) and rV(e) between malignant and benign

  9. A Physiologically Based Pharmacokinetic Model for Pregnant Women to Predict the Pharmacokinetics of Drugs Metabolized Via Several Enzymatic Pathways.

    PubMed

    Dallmann, André; Ince, Ibrahim; Coboeken, Katrin; Eissing, Thomas; Hempel, Georg

    2017-09-18

    Physiologically based pharmacokinetic modeling is considered a valuable tool for predicting pharmacokinetic changes in pregnancy to subsequently guide in-vivo pharmacokinetic trials in pregnant women. The objective of this study was to extend and verify a previously developed physiologically based pharmacokinetic model for pregnant women for the prediction of pharmacokinetics of drugs metabolized via several cytochrome P450 enzymes. Quantitative information on gestation-specific changes in enzyme activity available in the literature was incorporated in a pregnancy physiologically based pharmacokinetic model and the pharmacokinetics of eight drugs metabolized via one or multiple cytochrome P450 enzymes was predicted. The tested drugs were caffeine, midazolam, nifedipine, metoprolol, ondansetron, granisetron, diazepam, and metronidazole. Pharmacokinetic predictions were evaluated by comparison with in-vivo pharmacokinetic data obtained from the literature. The pregnancy physiologically based pharmacokinetic model successfully predicted the pharmacokinetics of all tested drugs. The observed pregnancy-induced pharmacokinetic changes were qualitatively and quantitatively reasonably well predicted for all drugs. Ninety-seven percent of the mean plasma concentrations predicted in pregnant women fell within a twofold error range and 63% within a 1.25-fold error range. For all drugs, the predicted area under the concentration-time curve was within a 1.25-fold error range. The presented pregnancy physiologically based pharmacokinetic model can quantitatively predict the pharmacokinetics of drugs that are metabolized via one or multiple cytochrome P450 enzymes by integrating prior knowledge of the pregnancy-related effect on these enzymes. This pregnancy physiologically based pharmacokinetic model may thus be used to identify potential exposure changes in pregnant women a priori and to eventually support informed decision making when clinical trials are designed in this

  10. Nitrate pharmacokinetics: Taking note of the difference.

    PubMed

    James, Philip E; Willis, Gareth R; Allen, Jason D; Winyard, Paul G; Jones, Andrew M

    2015-08-01

    It is now recognised that administration of oral nitrate (NO3(-)), in its various forms, increases the level of nitric oxide (NO) metabolites in the circulation of humans. Its application to modulate physiology and alleviate cardiovascular dysfunction in some patients is now recorded and shows particular promise in hypertension, in modifying platelet activation/aggregation, and in conditions where tissue ischaemia prevails. The potential of oral NO3(-) to modify exercise/performance via elevation of plasma nitrite concentration ([NO2(-)]) has been applied across a range of human test systems. Herein we discuss how the choice of NO3(-) source, route of administration and resulting pharmacokinetics might influence the outcome of physiological measures and potentially contribute to discrepancies in performance trials. There are but a few examples of detailed pharmacokinetic data on which the majority of researchers base their test protocols in different cohorts/settings. We compare and contrast the results of key publications with the aim of highlighting a consensus of our current understanding and critical considerations for those entering the field. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Predictive analysis of thermal distribution and damage in thermotherapy on biological tissue

    NASA Astrophysics Data System (ADS)

    Fanjul-Vélez, Félix; Arce-Diego, José Luis

    2007-05-01

    The use of optical techniques is increasing the possibilities and success of medical praxis in certain cases, either in tissue characterization or treatment. Photodynamic therapy (PDT) or low intensity laser treatment (LILT) are two examples of the latter. Another very interesting implementation is thermotherapy, which consists of controlling temperature increase in a pathological biological tissue. With this method it is possible to provoke an improvement on specific diseases, but a previous analysis of treatment is needed in order for the patient not to suffer any collateral damage, an essential point due to security margins in medical procedures. In this work, a predictive analysis of thermal distribution in a biological tissue irradiated by an optical source is presented. Optical propagation is based on a RTT (Radiation Transport Theory) model solved via a numerical Monte Carlo method, in a multi-layered tissue. Data obtained are included in a bio-heat equation that models heat transference, taking into account conduction, convection, radiation, blood perfusion and vaporization depending on the specific problem. Spatial-temporal differential bio-heat equation is solved via a numerical finite difference approach. Experimental temperature distributions on animal tissue irradiated by laser radiation are shown. From thermal distribution in tissue, thermal damage is studied, based on an Arrhenius analysis, as a way of predicting harmful effects. The complete model can be used for concrete treatment proposals, as a way of predicting treatment effects and consequently decide which optical source parameters are appropriate for the specific disease, mainly wavelength and optical power, with reasonable security margins in the process.

  12. Pharmacokinetic Profiling of Conjugated Therapeutic Oligonucleotides: A High-Throughput Method Based Upon Serial Blood Microsampling Coupled to Peptide Nucleic Acid Hybridization Assay.

    PubMed

    Godinho, Bruno M D C; Gilbert, James W; Haraszti, Reka A; Coles, Andrew H; Biscans, Annabelle; Roux, Loic; Nikan, Mehran; Echeverria, Dimas; Hassler, Matthew; Khvorova, Anastasia

    2017-12-01

    Therapeutic oligonucleotides, such as small interfering RNAs (siRNAs), hold great promise for the treatment of incurable genetically defined disorders by targeting cognate toxic gene products for degradation. To achieve meaningful tissue distribution and efficacy in vivo, siRNAs must be conjugated or formulated. Clear understanding of the pharmacokinetic (PK)/pharmacodynamic behavior of these compounds is necessary to optimize and characterize the performance of therapeutic oligonucleotides in vivo. In this study, we describe a simple and reproducible methodology for the evaluation of in vivo blood/plasma PK profiles and tissue distribution of oligonucleotides. The method is based on serial blood microsampling from the saphenous vein, coupled to peptide nucleic acid hybridization assay for quantification of guide strands. Performed with minimal number of animals, this method allowed unequivocal detection and sensitive quantification without the need for amplification, or further modification of the oligonucleotides. Using this methodology, we compared plasma clearances and tissue distribution profiles of two different hydrophobically modified siRNAs (hsiRNAs). Notably, cholesterol-hsiRNA presented slow plasma clearances and mainly accumulated in the liver, whereas, phosphocholine-docosahexaenoic acid-hsiRNA was rapidly cleared from the plasma and preferably accumulated in the kidney. These data suggest that the PK/biodistribution profiles of modified hsiRNAs are determined by the chemical nature of the conjugate. Importantly, the method described in this study constitutes a simple platform to conduct pilot assessments of the basic clearance and tissue distribution profiles, which can be broadly applied for evaluation of new chemical variants of siRNAs and micro-RNAs.

  13. Evaluation of the whole body physiologically based pharmacokinetic (WB-PBPK) modeling of drugs.

    PubMed

    Munir, Anum; Azam, Shumaila; Fazal, Sahar; Bhatti, A I

    2018-08-14

    The Physiologically based pharmacokinetic (PBPK) modeling is a supporting tool in drug discovery and improvement. Simulations produced by these models help to save time and aids in examining the effects of different variables on the pharmacokinetics of drugs. For this purpose, Sheila and Peters suggested a PBPK model capable of performing simulations to study a given drug absorption. There is a need to extend this model to the whole body entailing all another process like distribution, metabolism, and elimination, besides absorption. The aim of this scientific study is to hypothesize a WB-PBPK model through integrating absorption, distribution, metabolism, and elimination processes with the existing PBPK model.Absorption, distribution, metabolism, and elimination models are designed, integrated with PBPK model and validated. For validation purposes, clinical records of few drugs are collected from the literature. The developed WB-PBPK model is affirmed by comparing the simulations produced by the model against the searched clinical data. . It is proposed that the WB-PBPK model may be used in pharmaceutical industries to create of the pharmacokinetic profiles of drug candidates for better outcomes, as it is advance PBPK model and creates comprehensive PK profiles for drug ADME in concentration-time plots. Copyright © 2018 Elsevier Ltd. All rights reserved.

  14. Population Pharmacokinetics of Darbepoetin Alfa in Conjunction with Hypothermia for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy.

    PubMed

    Roberts, Jessica K; Stockmann, Chris; Ward, Robert M; Beachy, Joanna; Baserga, Mariana C; Spigarelli, Michael G; Sherwin, Catherine M T

    2015-12-01

    The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemic encephalopathy treated with hypothermia. Neonates ≥36 weeks gestation and <12 h postpartum with moderate to severe hypoxic-ischemic encephalopathy who were undergoing hypothermia treatment were recruited in this randomized, multicenter, investigational, new drug pharmacokinetic study. Two intravenous darbepoetin alfa treatment groups were evaluated: 2 and 10 µg/kg. Serum erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay. Monolix 4.3.1 was used to estimate darbepoetin alfa clearance and volume of distribution. Covariates tested included: birthweight, gestational age, postnatal age, postmenstrual age, sex, Sarnat score, and study site. Darbepoetin alfa pharmacokinetics were well described by a one-compartment model with exponential error. Clearance and the volume of distribution were scaled by birthweight (centered on the mean) a priori. Additionally, gestational age (also centered on the mean) significantly affected darbepoetin alfa clearance. Clearance and volume of distribution were estimated as 0.0465 L/h (95% confidence interval 0.0392-0.0537) and 1.58 L (95% confidence interval 1.29-1.87), respectively. A one-compartment model successfully described the pharmacokinetics of darbepoetin alfa among hypothermic neonates treated for hypoxic-ischemic encephalopathy. Clearance decreased with increasing gestational age.

  15. Biodistribution and pharmacokinetics of dapivirine-loaded nanoparticles after vaginal delivery in mice.

    PubMed

    das Neves, José; Araújo, Francisca; Andrade, Fernanda; Amiji, Mansoor; Bahia, Maria Fernanda; Sarmento, Bruno

    2014-07-01

    To assess the potential of polymeric nanoparticles (NPs) to affect the genital distribution and local and systemic pharmacokinetics (PK) of the anti-HIV microbicide drug candidate dapivirine after vaginal delivery. Dapivirine-loaded, poly(ethylene oxide)-coated poly(epsilon-caprolactone) (PEO-PCL) NPs were prepared by a nanoprecipitation method. Genital distribution of NPs and their ability to modify the PK of dapivirine up to 24 h was assessed after vaginal instillation in a female mouse model. Also, the safety of NPs upon daily administration for 14 days was assessed by histological analysis and chemokine/cytokine content in vaginal lavages. PEO-PCL NPs (180-200 nm) were rapidly eliminated after administration but able to distribute throughout the vagina and lower uterus, and capable of tackling mucus and penetrate the epithelial lining. Nanocarriers modified the PK of dapivirine, with higher drug levels being recovered from vaginal lavages and vaginal/lower uterine tissues as compared to a drug suspension. Systemic drug exposure was reduced when NPs were used. Also, NPs were shown safe upon administration for 14 days. Dapivirine-loaded PEO-PCL NPs were able to provide likely favorable genital drug levels, thus attesting the potential value of using this vaginal drug delivery nanosystem in the context of HIV prophylaxis.

  16. Pharmacokinetics, brain distribution and plasma protein binding of carbamazepine and nine derivatives: new set of data for predictive in silico ADME models.

    PubMed

    Fortuna, Ana; Alves, Gilberto; Soares-da-Silva, Patrício; Falcão, Amílcar

    2013-11-01

    In silico approaches to predict absorption, distribution, metabolism and excretion (ADME) of new drug candidates are gaining a relevant importance in drug discovery programmes. When considering particularly the pharmacokinetics during the development of oral antiepileptic drugs (AEDs), one of the most prominent goals is designing compounds with good bioavailability and brain penetration. Thus, it is expected that in silico models able to predict these features may be applied during the early stages of AEDs discovery. The present investigation was mainly carried out in order to generate in vivo pharmacokinetic data that can be utilized for development and validation of in silico models. For this purpose, a single dose of each compound (1.4mmol/kg) was orally administered to male CD-1 mice. After quantifying the parent compound and main metabolites in plasma and brain up to 12h post-dosing, a non-compartmental pharmacokinetic analysis was performed and the corresponding brain/plasma ratios were calculated. Moreover the plasma protein binding was estimated in vitro applying the ultrafiltration procedure. The present in vivo pharmacokinetic characterization of the test compounds and corresponding metabolites demonstrated that the metabolism extensively compromised the in vivo activity of CBZ derivatives and their toxicity. Furthermore, it was clearly evidenced that the time to reach maximum peak concentration, bioavailability (given by the area under the curve) and metabolic stability (given by the AUC0-12h ratio of the parent compound and total systemic drug) influenced the in vivo pharmacological activities and must be considered as primary parameters to be investigated. All the test compounds presented brain/plasma ratios lower than 1.0, suggesting that the blood-brain barrier restricts drug entry into the brain. In agreement with in vitro studies already performed within our research group, CBZ, CBZ-10,11-epoxide and oxcarbazepine exhibited the highest brain

  17. A tissue dose-based comparative exposure assessment of manganese using physiologically based pharmacokinetic modeling—The importance of homeostatic control for an essential metal

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gentry, P. Robinan, E-mail: rgentry@ramboll.com

    A physiologically-based pharmacokinetic (PBPK) model (Schroeter et al., 2011) was applied to simulate target tissue manganese (Mn) concentrations following occupational and environmental exposures. These estimates of target tissue Mn concentrations were compared to determine margins of safety (MOS) and to evaluate the biological relevance of applying safety factors to derive acceptable Mn air concentrations. Mn blood concentrations measured in occupational studies permitted verification of the human PBPK models, increasing confidence in the resulting estimates. Mn exposure was determined based on measured ambient air Mn concentrations and dietary data in Canada and the United States (US). Incorporating dietary and inhalation exposuresmore » into the models indicated that increases in target tissue concentrations above endogenous levels only begin to occur when humans are exposed to levels of Mn in ambient air (i.e. > 10 μg/m{sup 3}) that are far higher than those currently measured in Canada or the US. A MOS greater than three orders of magnitude was observed, indicating that current Mn air concentrations are far below concentrations that would be required to produce the target tissue Mn concentrations associated with subclinical neurological effects. This application of PBPK modeling for an essential element clearly demonstrates that the conventional application of default factors to “convert” an occupational exposure to an equivalent continuous environmental exposure, followed by the application of safety factors, is not appropriate in the case of Mn. PBPK modeling demonstrates that the relationship between ambient Mn exposures and dose-to-target tissue is not linear due to normal tissue background levels and homeostatic controls. - Highlights: • Manganese is an essential nutrient, adding complexity to its risk assessment. • Nonlinearities in biological processes are important for manganese risk assessment. • A PBPK model was used to estimate target

  18. Quantitative bioimaging of p-boronophenylalanine in thin liver tissue sections as a tool for treatment planning in boron neutron capture therapy.

    PubMed

    Reifschneider, Olga; Schütz, Christian L; Brochhausen, Christoph; Hampel, Gabriele; Ross, Tobias; Sperling, Michael; Karst, Uwe

    2015-03-01

    An analytical method using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was developed and applied to assess enrichment of 10B-containing p-boronophenylalanine-fructose (BPA-f) and its pharmacokinetic distribution in human tissues after application for boron neutron capture therapy (BNCT). High spatial resolution (50 μm) and limits of detection in the low parts-per-billion range were achieved using a Nd:YAG laser of 213 nm wavelength. External calibration by means of 10B-enriched standards based on whole blood proved to yield precise quantification results. Using this calibration method, quantification of 10B in cancerous and healthy tissue was carried out. Additionally, the distribution of 11B was investigated, providing 10B enrichment in the investigated tissues. Quantitative imaging of 10B by means of LA-ICP-MS was demonstrated as a new option to characterise the efficacy of boron compounds for BNCT.

  19. The pharmacokinetics of intraosseous atropine in hypovolemic swine.

    PubMed

    Yost, Jonathan; Baldwin, Phillip; Bellenger, Sarah; Bradshaw, Freida; Causapin, Edna; Demotica, Richelle; Livingston, Michael; Lee, Cynthia; Gegel, Brian; Burgert, James; Claessens, Adam; Johnson, Don; Loughren, Michael

    2015-01-01

    Compare the pharmacokinetics of atropine administered via the intravenous (IV), intramuscular (IM), and intraosseous (IO) routes in a normovolemic and hypovolemic swine model. Prospective, between subjects, experimental study. Vivarium. Yorkshire-cross swine (N = 36). Atropine was administered via IV, IM, or IO routes to normovolemic and hypovolemic swine. Blood samples were drawn at regular intervals after atropine administration and analyzed for plasma atropine concentration. Pharmacokinetic parameters were obtained from modeling the plasma concentrations. Pharmacokinetic parameters, maximum concentration (Cmax) and time to maximum concentration (Tmax). The IV and IO groups in both the normovolemic and hypovolemic models reached peak plasma concentration immediately and had a very rapid distribution phase with no apparent absorption phase for the IO groups. Peak plasma concentration and time to reach peak concentration were both significantly lower for the IM groups. There was a significant increase in absorption time with IM administration in the hypovolemic model compared to the normovolemic model. The IO route is an effective method of administering atropine and is comparable to the IV route even under conditions of significant hemorrhage. Therapeutic levels of atropine may be delayed and possibly difficult to obtain via IM injection in the presence of hypovolemic shock.

  20. Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis.

    PubMed

    Wring, Stephen A; Randolph, Ryan; Park, SeongHee; Abruzzo, George; Chen, Qing; Flattery, Amy; Garrett, Graig; Peel, Michael; Outcalt, Russell; Powell, Kendall; Trucksis, Michelle; Angulo, David; Borroto-Esoda, Katyna

    2017-04-01

    SCY-078 (MK-3118) is a novel, semisynthetic derivative of enfumafungin and represents the first compound of the triterpene class of antifungals. SCY-078 exhibits potent inhibition of β-(1,3)-d-glucan synthesis, an essential cell wall component of many pathogenic fungi, including Candida spp. and Aspergillus spp. SCY-078 is currently in phase 2 clinical development for the treatment of invasive fungal diseases. In vitro disposition studies to assess solubility, intestinal permeability, and metabolic stability were predictive of good oral bioavailability. Preclinical pharmacokinetic studies were consistent with once-daily administration to humans. After intravenous delivery, plasma clearance in rodents and dogs was low, representing <15% and <25% of hepatic blood flow, respectively. The terminal elimination-phase half-life was 5.5 to 8.7 h in rodents, and it was ∼9.3 h in dogs. The volume of distribution at steady-state was high (4.7 to 5.3 liters/kg), a finding suggestive of extensive tissue distribution. Exposure of SCY-078 in kidney tissue, a target organ for invasive fungal disease such as candidiasis, exceeded plasma by 20- to 25-fold for the area under the concentration-time curve from 0 h to infinity (AUC 0-∞ ) and C max SCY-078 achieved efficacy endpoints following oral delivery across multiple murine models of disseminated candidiasis. The pharmacokinetic/pharmacodynamic indices C max /MIC and AUC/MIC correlated with outcome. Target therapeutic exposure, expressed as the plasma AUC 0-24 , was comparable across models, with an upper value of 11.2 μg·h/ml (15.4 μM·h); the corresponding mean value for free drug AUC/MIC was ∼0.75. Overall, these results demonstrate that SCY-078 has the oral and intravenous (i.v.) pharmacokinetic properties and potency in murine infection models of disseminated candidiasis to support further investigation as a novel i.v. and oral treatment for invasive fungal diseases. Copyright © 2017 Wring et al.

  1. Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis

    PubMed Central

    Randolph, Ryan; Park, SeongHee; Abruzzo, George; Chen, Qing; Flattery, Amy; Garrett, Graig; Peel, Michael; Outcalt, Russell; Powell, Kendall; Trucksis, Michelle; Angulo, David; Borroto-Esoda, Katyna

    2017-01-01

    ABSTRACT SCY-078 (MK-3118) is a novel, semisynthetic derivative of enfumafungin and represents the first compound of the triterpene class of antifungals. SCY-078 exhibits potent inhibition of β-(1,3)-d-glucan synthesis, an essential cell wall component of many pathogenic fungi, including Candida spp. and Aspergillus spp. SCY-078 is currently in phase 2 clinical development for the treatment of invasive fungal diseases. In vitro disposition studies to assess solubility, intestinal permeability, and metabolic stability were predictive of good oral bioavailability. Preclinical pharmacokinetic studies were consistent with once-daily administration to humans. After intravenous delivery, plasma clearance in rodents and dogs was low, representing <15% and <25% of hepatic blood flow, respectively. The terminal elimination-phase half-life was 5.5 to 8.7 h in rodents, and it was ∼9.3 h in dogs. The volume of distribution at steady-state was high (4.7 to 5.3 liters/kg), a finding suggestive of extensive tissue distribution. Exposure of SCY-078 in kidney tissue, a target organ for invasive fungal disease such as candidiasis, exceeded plasma by 20- to 25-fold for the area under the concentration-time curve from 0 h to infinity (AUC0–∞) and Cmax. SCY-078 achieved efficacy endpoints following oral delivery across multiple murine models of disseminated candidiasis. The pharmacokinetic/pharmacodynamic indices Cmax/MIC and AUC/MIC correlated with outcome. Target therapeutic exposure, expressed as the plasma AUC0–24, was comparable across models, with an upper value of 11.2 μg·h/ml (15.4 μM·h); the corresponding mean value for free drug AUC/MIC was ∼0.75. Overall, these results demonstrate that SCY-078 has the oral and intravenous (i.v.) pharmacokinetic properties and potency in murine infection models of disseminated candidiasis to support further investigation as a novel i.v. and oral treatment for invasive fungal diseases. PMID:28137806

  2. Image Guided Biodistribution and Pharmacokinetic Studies of Theranostics

    PubMed Central

    Ding, Hong; Wu, Fang

    2012-01-01

    Image guided technique is playing an increasingly important role in the investigation of the biodistribution and pharmacokinetics of drugs or drug delivery systems in various diseases, especially cancers. Besides anatomical imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), molecular imaging strategy including optical imaging, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) will facilitate the localization and quantization of radioisotope or optical probe labeled nanoparticle delivery systems in the category of theranostics. The quantitative measurement of the bio-distribution and pharmacokinetics of theranostics in the fields of new drug/probe development, diagnosis and treatment process monitoring as well as tracking the brain-blood-barrier (BBB) breaking through by high sensitive imaging method, and the applications of the representative imaging modalities are summarized in this review. PMID:23227121

  3. The effect of respiratory disorders on clinical pharmacokinetic variables.

    PubMed

    Taburet, A M; Tollier, C; Richard, C

    1990-12-01

    Respiratory disorders induce several pathophysiological changes involving gas exchange and acid-base balance, regional haemodynamics, and alterations of the alveolocapillary membrane. The consequences for the absorption, distribution and elimination of drugs are evaluated. Drug absorption after inhalation is not significantly impaired in patients. With drugs administered by this route, an average of 10% of the dose reaches the lungs. It is not completely clear whether changes in pulmonary endothelium in respiratory failure enhance lung absorption. The effects of changes in blood pH on plasma protein binding and volume of distribution are discussed, but relevant data are not available to explain the distribution changes observed in acutely ill patients. Lung diffusion of some antimicrobial agents is enhanced in patients with pulmonary infections. Decreased cardiac output and hepatic blood flow in patients under mechanical ventilation cause an increase in the plasma concentration of drugs with a high hepatic extraction ratio, such as lidocaine (lignocaine). On a theoretical basis, hypoxia should lead to decreased biotransformation of drugs with a low hepatic extraction ratio, but in vivo data with phenazone (antipyrine) or theophylline are conflicting. The effects of disease on the lung clearance of drugs are discussed but clinically relevant data are lacking. The pharmacokinetics of drugs in patients with asthma or chronic obstructive pulmonary disease are reviewed. Stable asthma and chronic obstructive pulmonary disease do not appear to affect the disposition of theophylline or beta 2-agonists such as salbutamol (albuterol) or terbutaline. Important variations in theophylline pharmacokinetics have been reported in critically ill patients, the causes of which are more likely to be linked to the poor condition of the patients than to a direct effect of hypoxia or hypercapnia. Little is known regarding the pharmacokinetics of cromoglycate, ipratropium, corticoids or

  4. Widespread Non-Hematopoietic Tissue Distribution by Transplanted Human Progenitor Cells with High Aldehyde Dehydrogenase Activity

    PubMed Central

    Hess, David A.; Craft, Timothy P.; Wirthlin, Louisa; Hohm, Sarah; Zhou, Ping; Eades, William C.; Creer, Michael H.; Sands, Mark S.; Nolta, Jan A.

    2011-01-01

    Transplanted adult progenitor cells distribute to peripheral organs and can promote endogenous cellular repair in damaged tissues. However, development of cell-based regenerative therapies has been hindered by the lack of pre-clinical models to efficiently assess multiple organ distribution and difficulty defining human cells with regenerative function. After transplantation into beta-glucuronidase (GUSB)-deficient NOD/SCID/MPSVII mice, we characterized the distribution of lineage depleted human umbilical cord blood-derived cells purified by selection using high aldehyde dehydrogenase activity (ALDH) with CD133 co-expression. ALDHhi or ALDHhiCD133+ cells produced robust hematopoietic reconstitution, and variable levels of tissue distribution in multiple organs. GUSB+ donor cells that co-expressed human (HLA-A,B,C) and hematopoietic (CD45+) cell surface markers were the primary cell phenotype found adjacent to the vascular beds of several tissues, including islet and ductal regions of mouse pancreata. In contrast, variable phenotypes were detected in the chimeric liver, with HLA+/CD45+ cells demonstrating robust GUSB expression adjacent to blood vessels, and CD45−/HLA− cells with diluted GUSB expression predominant in the liver parenchyma. However, true non-hematopoietic human (HLA+/CD45−) cells were rarely detected in other peripheral tissues, suggesting that these GUSB+/HLA−/CD45− cells in the liver were a result of downregulated human surface marker expression in vivo, not widespread seeding of non-hematopoietic cells. However, relying solely on continued expression of cell surface markers, as employed in traditional xenotransplantation models, may underestimate true tissue distribution. ALDH-expressing progenitor cells demonstrated widespread and tissue-specific distribution of variable cellular phenotypes, indicating that these adult progenitor cells should be explored in transplantation models of tissue damage. PMID:18055447

  5. Effect of Sophora flavescens on the pharmacokinetics of carbamazepine in rats.

    PubMed

    Shi, Lei; Dang, Xue-Liang; Liu, Xin-You; Wei, Hua-Mei; Yang, Meng-Meng; Zhang, Yan

    2014-12-01

    Carbamazepine (CBZ), an antiepileptic with narrow therapeutic window, is a substrate of CYP 3A4 which metabolizes CBZ to carbamazepine-10,11-epoxide (CBZE). CBZE is an active and toxicity metabolite, and it is a substrate of MRP-2. Using CBZ for a long time can cause hepatic injury. Sophora flavescens (SF) is a medicinal herb used for the protected hepatic injury. This study investigated the acute and chronic effects of SF on the pharmacokinetics of CBZ in rats. The concentrations of CBZ and CBZE in plasma and tissues were determined by HPLC method. The results showed that SF which significantly decreased the AUC0-t of CBZ, increased CBZE conversely. Tissue analysis showed that the concentrations of CBZ and CBZE in brain and liver were decreased by SF. In addition, the distribution of CBZE in kidney was reduced significantly, which influenced the CBZE excretion and increased the drug toxic potentially. Results in the current study suggest that patients using CBZ might be cautioned in the use of SF extract or Sophora-derived products. Meanwhile, patients receiving drugs which are substrates of CYP 3A4 and/or MRP-2 should be advised of the potential herb-drug interaction to reduce the risk of therapeutic failure or increased toxicity of conventional drug therapy.

  6. Pharmacokinetics, Biodistribution, and Toxicity Evaluation of Anti-SEMA3A (F11) in In Vivo Models.

    PubMed

    Lee, Jaehyun; Kim, Donggeon; Son, Eunju; Yoo, Su-Ji; Sa, Jason K; Shin, Yong Jae; Yoon, Yeup; Nam, DO-Hyun

    2018-05-01

    The aim of our study was to investigate the pharmacokinetics (PK), tissue distribution and toxicity of F11 antibody to semaphorin 3A in mouse models and explore its anti-angiogenic and tumor-inhibitory effect. Patient-derived xenograft (PDX) models were established via subcutaneous implantation of glioblastoma multiforme (GBM) cells and treated with F11. F11 significantly attenuated tumor growth and angiogenesis in the GBM PDX model. Within the range of administered doses, the PK of F11 in serum demonstrated a linear fashion, consistent with general PK profiles of soluble antigen-targeting antibodies. Additionally, the clearance level was detected at between 4.63 and 7.12 ml/d/kg, while the biological half-life was measured at 6.9 and 9.4 days. Tissue distribution of F11 in kidney, liver and heart was consistent with previously reported antibody patterns. However, the presence of F11 in the brain was an interesting finding. Collectively, our results revealed angiogenic and tumor-inhibitory effect of F11 antibody and its potential therapeutic use within a clinical framework based on PK, biodistribution and toxicity evaluation in mouse models. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  7. Effect of small-molecule modification on single-cell pharmacokinetics of PARP inhibitors.

    PubMed

    Thurber, Greg M; Reiner, Thomas; Yang, Katherine S; Kohler, Rainer H; Weissleder, Ralph

    2014-04-01

    The heterogeneous delivery of drugs in tumors is an established process contributing to variability in treatment outcome. Despite the general acceptance of variable delivery, the study of the underlying causes is challenging, given the complex tumor microenvironment including intra- and intertumor heterogeneity. The difficulty in studying this distribution is even more significant for small-molecule drugs where radiolabeled compounds or mass spectrometry detection lack the spatial and temporal resolution required to quantify the kinetics of drug distribution in vivo. In this work, we take advantage of the synthesis of fluorescent drug conjugates that retain their target binding but are designed with different physiochemical and thus pharmacokinetic properties. Using these probes, we followed the drug distribution in cell culture and tumor xenografts with temporal resolution of seconds and subcellular spatial resolution. These measurements, including in vivo permeability of small-molecule drugs, can be used directly in predictive pharmacokinetic models for the design of therapeutics and companion imaging agents as demonstrated by a finite element model.

  8. Effect of Small Molecule Modification on Single Cell Pharmacokinetics of PARP Inhibitors

    PubMed Central

    Thurber, Greg M.; Reiner, Thomas; Yang, Katherine S; Kohler, Rainer; Weissleder, Ralph

    2014-01-01

    The heterogeneous delivery of drugs in tumors is an established process contributing to variability in treatment outcome. Despite the general acceptance of variable delivery, the study of the underlying causes is challenging given the complex tumor microenvironment including intra- and inter-tumor heterogeneity. The difficulty in studying this distribution is even more significant for small molecule drugs where radiolabeled compounds or mass spectrometry detection lack the spatial and temporal resolution required to quantify the kinetics of drug distribution in vivo. In this work, we take advantage of the synthesis of fluorescent drug conjugates that retain their target binding but are designed with different physiochemical and thus pharmacokinetic properties. Using these probes, we followed the drug distribution in cell culture and tumor xenografts with temporal resolution of seconds and subcellular spatial resolution. These measurements, including in vivo permeability of small molecule drugs, can be used directly in predictive pharmacokinetic models for the design of therapeutics and companion imaging agents as demonstrated by a finite element model. PMID:24552776

  9. Pharmacokinetics of fentanyl in patients undergoing abdominal aortic surgery.

    PubMed

    Hudson, R J; Thomson, I R; Cannon, J E; Friesen, R M; Meatherall, R C

    1986-03-01

    The authors determined the pharmacokinetics of fentanyl 100 micrograms X kg-1 iv in patients undergoing elective abdominal aortic surgery. The mean (+/- SD) age of the ten patients was 67.2 +/- 8.7 yr; their mean weight was 78.5 +/- 13.7 kg. Seven patients had aortic aneurysm repair, and the other three patients had aortobifemoral grafts. Serum fentanyl concentrations were determined from samples drawn at increasing intervals over a 24-h period. A three-compartment pharmacokinetic model was fit to the concentration versus time data. Total drug clearance was 9.8 +/- 1.8 ml X min-1 X kg-1. The volume of distribution at steady-state (Vdss) was 5.4 +/- 1.9 X 1 kg-1. Elimination half-time was 8.7 +/- 2.5 h. There were no significant correlations between these pharmacokinetic parameters and patient's age, duration of aortic cross-clamping, duration of surgery, intraoperative blood loss, or volume of iv fluids given intraoperatively. In healthy volunteers or patients undergoing general surgery, other investigators report mean elimination half-times for fentanyl ranging from 1.7 to 4.4 h. The prolonged elimination half-time in patients having abdominal aortic surgery has important clinical implications. In particular, recovery from large doses will take much longer than would have been anticipated from previously published fentanyl pharmacokinetic data.

  10. New method for generating breast models featuring glandular tissue spatial distribution

    NASA Astrophysics Data System (ADS)

    Paixão, L.; Oliveira, B. B.; Oliveira, M. A.; Teixeira, M. H. A.; Fonseca, T. C. F.; Nogueira, M. S.

    2016-02-01

    Mammography is the main radiographic technique used for breast imaging. A major concern with mammographic imaging is the risk of radiation-induced breast cancer due to the high sensitivity of breast tissue. The mean glandular dose (DG) is the dosimetric quantity widely accepted to characterize the risk of radiation induced cancer. Previous studies have concluded that DG depends not only on the breast glandular content but also on the spatial distribution of glandular tissue within the breast. In this work, a new method for generating computational breast models featuring skin composition and glandular tissue distribution from patients undergoing digital mammography is proposed. Such models allow a more accurate way of calculating individualized breast glandular doses taking into consideration the glandular tissue fraction. Sixteen breast models of four patients with different glandularity breasts were simulated and the results were compared with those obtained from recommended DG conversion factors. The results show that the internationally recommended conversion factors may be overestimating the mean glandular dose to less dense breasts and underestimating the mean glandular dose for denser breasts. The methodology described in this work constitutes a powerful tool for breast dosimetry, especially for risk studies.

  11. A lead isotope distribution study in swine tissue using ICP-MS

    USGS Publications Warehouse

    May, T.W.; Wiedmeyer, Ray H.; Brown, L.D.; Casteel, S.W.

    1999-01-01

    In the United States lead is an ubiquitous environmental pollutant that is a serious human health hazard, especially for women of childbearing age, developing fetuses, and young children. Information concerning the uptake and distribution of lead to maternal and fetal tissues during pregnancy is poorly documented. A study was designed using domestic swine and lead isotope enrichment methodology to focus on maternal absorption and distribution of lead into bone and soft tissues, including the fetal compartment, under varying conditions of oral lead exposure and during altered physiological states (pregnant vs unbred). Total lead levels and Pb207/Pb206 ratios in bone (femur and vertebra), blood, and soft tissues (liver, kidney, brain) were determined by ICP-MS. Lead in fetal tissues derived from maternal bone could be differentiated from that derived from exogenous dosing. Unbred swine absorbed much less lead than pregnant females receiving the same dose. The accuracy and precision of ICP-MS at the instrumental level and for the entire method (sample collection, digestion, and analysis) were evaluated for both Pb207/Pb206 ratios and total lead. Several changes were suggested in method design to improve both instrumental and total method precision.

  12. Pharmacokinetics of cefpirome during the posttraumatic systemic inflammatory response syndrome.

    PubMed

    Jacolot, A; Incagnoli, P; Edouard, A R; Tod, M; Petitjean, O; Samii, K; Mimoz, O

    1999-05-01

    To determine the pharmacokinetic parameters of cefpirome, a new so-called fourth-generation cephalosporin, in previously healthy trauma patients with posttraumatic systemic inflammatory response syndrome (SIRS) and to compare them to parameters obtained in matched, healthy volunteers. A prospective study. 12-bed surgical intensive care unit in a university hospital. 9 severe [Injury Severity Score, median (range) 29 (16-50)] trauma patients on mechanical ventilation with proven or suspected cefpirome-susceptible nosocomial infection, with no renal or hepatic failure, and healthy volunteers matched for age (+/- 5 years), sex, and body surface area (+/- 10%) were enrolled. All were men. Cefpirome (2 g twice daily) was continuously infused over a 0.5 h period alone or concomitantly with ciprofloxacin (400 mg over 1 h, twice daily). Antibiotic concentrations in plasma were measured by high-performance liquid chromatography; their pharmacokinetic parameters were evaluated at 12 time points after the first drug administration using a noncompartmental model. Cefpirome pharmacokinetic parameters for the two groups were similar despite a wider variation for trauma patients. Specifically, the median (range) time during which the cefpirome concentration in plasma remained over 4 mg/l (corresponding to the French lower cutoff determining cefpirome susceptibility) was 9.5 (7- > 12) and 9 (8-12) h for trauma patients and healthy volunteers, respectively. In the group of five patients receiving combined antibiotic therapy, the interindividual variability of pharmacokinetics was wider for ciprofloxacin than for cefpirome. No major pharmacokinetic modification was noted when cefpirome was given to trauma patients with posttraumatic SIRS without significant organ failure, indicating that no dosage adjustment seems required in this population. However, larger studies including determination of antibiotic levels in tissues are warranted to confirm these results.

  13. Clinical pharmacokinetics and effects of vincristine sulfate in dogs with transmissible venereal tumor (TVT).

    PubMed

    Hantrakul, Supannika; Klangkaew, Narumol; Kunakornsawat, Sunee; Tansatit, Tawewan; Poapolathep, Ammart; Kumagai, Susumu; Poapolathep, Saranya

    2014-12-01

    This study was conducted to evaluate the pharmacokinetic characteristics of vincristine and their correlation with its clinical effects in dogs with transmissible venereal tumor (TVT). Dogs with TVT were intravenously administered vincristine sulfate at a dose of 0.7 mg/m(2) of body surface area. Blood samples were collected starting from 5 min to 48 hr after drug administration. The plasma concentration of vincristine was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of vincristine were characterized using a two-compartmental pharmacokinetic model. The volume of distribution, distribution half-life, elimination half-life and plasma clearance were 0.660 ± 0.210 l/kg, 21.5 ± 6.90 min, 47.6 ± 14.2 min and 0.010 ± 0.001 l/min/kg, respectively. Tumor regression was determined at weekly interval by a physical examination and histopathological analysis. In our study, three to eight administrations of vincristine at a dose of 0.7 mg/m(2) were able to induce a complete tumor regression without any evidence of gross lesion of disease. Therefore, this investigation provides the pharmacokinetic characteristics of vincristine in dogs with TVT, which may be used as an integration tool to gain a better understanding of the disposition properties of the drug and the correlation of these properties with the drug's clinical effects. In addition, we validated the LC-MS/MS method and found that it is suitable for the pharmacokinetic study of vincristine in dog plasma.

  14. Clinical Pharmacokinetics and Effects of Vincristine Sulfate in Dogs with Transmissible Venereal Tumor (TVT)

    PubMed Central

    HANTRAKUL, Supannika; KLANGKAEW, Narumol; KUNAKORNSAWAT, Sunee; TANSATIT, Tawewan; POAPOLATHEP, Ammart; KUMAGAI, Susumu; POAPOLATHEP, Saranya

    2014-01-01

    This study was conducted to evaluate the pharmacokinetic characteristics of vincristine and their correlation with its clinical effects in dogs with transmissible venereal tumor (TVT). Dogs with TVT were intravenously administered vincristine sulfate at a dose of 0.7 mg/m2 of body surface area. Blood samples were collected starting from 5 min to 48 hr after drug administration. The plasma concentration of vincristine was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of vincristine were characterized using a two-compartmental pharmacokinetic model. The volume of distribution, distribution half-life, elimination half-life and plasma clearance were 0.660 ± 0.210 l/kg, 21.5 ± 6.90 min, 47.6 ± 14.2 min and 0.010 ± 0.001 l/min/kg, respectively. Tumor regression was determined at weekly interval by a physical examination and histopathological analysis. In our study, three to eight administrations of vincristine at a dose of 0.7 mg/m2 were able to induce a complete tumor regression without any evidence of gross lesion of disease. Therefore, this investigation provides the pharmacokinetic characteristics of vincristine in dogs with TVT, which may be used as an integration tool to gain a better understanding of the disposition properties of the drug and the correlation of these properties with the drug’s clinical effects. In addition, we validated the LC-MS/MS method and found that it is suitable for the pharmacokinetic study of vincristine in dog plasma. PMID:25649934

  15. LASER BIOLOGY: Visualisation of the distributions of melanin and indocyanine green in biological tissues

    NASA Astrophysics Data System (ADS)

    Genina, E. A.; Fedosov, I. V.; Bashkatov, A. N.; Zimnyakov, D. A.; Altshuler, G. B.; Tuchin, V. V.

    2008-03-01

    A double-wavelength laser scanning microphotometer with the high spectral and spatial resolutions is developed for studying the distribution of endogenic and exogenic dyes in biological tissues. Samples of hair and skin biopsy with hair follicles stained with indocyanine green are studied. The spatial distribution of indocyanine green and melanin in the biological tissue is determined from the measured optical transmittance.

  16. Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy greyhound dogs.

    PubMed

    KuKanich, B; Allen, P

    2014-12-01

    The purpose of this study was to compare the pharmacokinetics of two highly protein-bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy greyhound dogs (three males and three females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry, and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL·min/kg) was faster than buprenorphine (10.3 mL·min/kg). The terminal half-life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including octanol-water partition coefficient and pKa, the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95-98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs. © 2014 John Wiley & Sons Ltd.

  17. Population pharmacokinetic modeling of furosemide in patients with hypertension and fluid overload conditions.

    PubMed

    Kodati, Devender; Yellu, Narsimhareddy

    2017-06-01

    Furosemide is a loop diuretic drug frequently indicated in hypertension and fluid overload conditions such as congestive heart failure and hepatic cirrhosis. The purpose of the study was to establish a population pharmacokinetic model for furosemide in Indian hypertensive and fluid overload patients, and to evaluate effects of covariates on the volume of distribution (V/F) and oral clearance (CL/F) of furosemide. A total of 188 furosemide plasma sample concentrations from 63 patients with hypertension or fluid overload conditions were collected in this study. The population pharmacokinetic model for furosemide was built using Phoenix NLME 1.3 software. The covariates included age, sex, body surface area, bodyweight, height and creatinine clearance (CRCL). The pharmacokinetic data of furosemide was adequately explained by a two-compartment linear pharmacokinetic model with first-order absorption and an absorption lag-time. The mean values of CL/F and Vd/F of furosemide in the patients were 15.054Lh -1 and 4.419L, respectively. Analysis of covariates showed that CRCL was significantly influencing the clearance of furosemide. The final population pharmacokinetic model was demonstrated to be appropriate and effective and it can be used to assess the pharmacokinetic parameters of furosemide in Indian patients with hypertension and fluid overload conditions. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.

  18. Bioprinting of Micro-Organ Tissue Analog for Drug Metabolism Study

    NASA Astrophysics Data System (ADS)

    Sun, Wei

    An evolving application of tissue engineering is to develop in vitro 3D cell/tissue models for drug screening and pharmacological study. In order to test in space, these in vitro models are mostly manufactured through micro-fabrication techniques and incorporate living cells with MEMS or microfluidic devices. These cell-integrated microfluidic devices, or referred as microorgans, are effective in furnishing reliable and inexpensive drug metabolism and toxicity studies [1-3]. This paper will present an on-going research collaborated between Drexel University and NASA JSC Radiation Physics Laboratory for applying a direct cell printing technique to freeform fabrication of 3D liver tissue analog in drug metabolism study. The paper will discuss modeling, design, and solid freeform fabrication of micro-fluidic flow patterns and bioprinting of 3D micro-liver chamber that biomimics liver physiological microenvironment for enhanced drug metabolization. Technical details to address bioprinting of 3D liver tissue analog, integration with a microfluidic device, and basic drug metabolism study for NASA's interests will presented. 1. Holtorf H. Leslie J. Chang R, Nam J, Culbertson C, Sun W, Gonda S, "Development of a Three-Dimensional Tissue-on-a-Chip Micro-Organ Device for Pharmacokinetic Analysis", the 47th Annual Meeting of the American Society for Cell Biology, Washington, DC, December 1-5, 2007. 2. Chang, R., Nam, J., Culbertson C., Holtorf, H., Jeevarajan, A., Gonda, S. and Sun, W., "Bio-printing and Modeling of Flow Patterns for Cell Encapsulated 3D Liver Chambers For Pharmacokinetic Study", TERMIS North America 2007 Conference and Exposition, Westin Harbour Castle, Toronto, Canada, June 13-16, 2007. 3.Starly, B., Chang, R., Sun, W., Culbertson, C., Holtorf, H. and Gonda, S., "Bioprinted Tissue-on-chip Application for Pharmacokinetic Studies", Proceedings of World Congress on Tissue Engineering and Regenerative Medicine, Pittsburgh, PA, USA, April 24-27, 2006.

  19. Intravenous Exposure of Pregnant Mice to Silver Nanoparticles: Silver Tissue Distribution and Effects in Maternal and Extra-Embryonic Tissues and Embryos

    NASA Astrophysics Data System (ADS)

    Austin, Carlye Anne

    This research explores the tissue distribution of silver, as well as adverse effects in pregnant mice and embryos, following prenatal silver nanoparticle (AgNP) exposure. Chapter one of this dissertation is a survey of the published literature on the reproductive and/or developmental toxicity of AgNPs. The available data indicate that AgNPs adversely affect sperm count, viability, and/or motility both in vivo and in vitro, and cause apoptosis and necrosis in spermatogonial stem cells and testicular cells. Additionally, AgNP exposure results in mortality and morphological deformities in fish embryos, but produces no adverse effects in chicken embryos. The current published research on in vivo AgNP exposure to mammals during gestation consists of only three studies, one of which is described in chapter two of this dissertation. These studies report results that may suggest a potential for adverse effects on fetal development (e.g. , decreased viability and fetal and placental weights, increased incidence of developmentally young embryos), but additional research is needed. Chapter two of this dissertation investigates the distribution of silver in tissues of pregnant mice and gestation day (GD) 10 embryos following intravenous maternal exposure to 50 nm AgNPs during early organogenesis (GDs 7-9). Examinations of embryo morphology and histology were also performed. Results demonstrated the presence of silver in all organs and tissues examined. Silver concentrations were highest in liver, spleen, and visceral yolk sac, and lowest in embryos. Groups of mice were also treated with soluble silver nitrate, and the pattern of silver tissue distribution following silver nitrate exposure was similar to that which followed AgNP treatment. Transmission electron microscopy-energy dispersive x-ray spectroscopy (TEM-EDS) confirmed the presence of vesicle-bound nanoparticulate silver in visceral yolk sac endoderm, but not mesoderm. This finding, along with the high silver

  20. Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data.

    PubMed

    Del Amo, Eva M; Urtti, Arto

    2015-08-01

    Intravitreal administration is the method of choice in drug delivery to the retina and/or choroid. Rabbit is the most commonly used animal species in intravitreal pharmacokinetics, but it has been criticized as being a poor model of human eye. The critique is based on some anatomical differences, properties of the vitreous humor, and observed differences in drug concentrations in the anterior chamber after intravitreal injections. We have systematically analyzed all published information on intravitreal pharmacokinetics in the rabbit and human eye. The analysis revealed major problems in the design of the pharmacokinetic studies. In this review we provide advice for study design. Overall, the pharmacokinetic parameters (clearance, volume of distribution, half-life) in the human and rabbit eye have good correlation and comparable absolute values. Therefore, reliable rabbit-to-man translation of intravitreal pharmacokinetics should be feasible. The relevant anatomical and physiological parameters in rabbit and man show only small differences. Furthermore, the claimed discrepancy between drug concentrations in the human and rabbit aqueous humor is not supported by the data analysis. Based on the available and properly conducted pharmacokinetic studies, the differences in the vitreous structure in rabbits and human patients do not lead to significant pharmacokinetic differences. This review is the first step towards inter-species translation of intravitreal pharmacokinetics. More information is still needed to dissect the roles of drug delivery systems, disease states, age and ocular manipulation on the intravitreal pharmacokinetics in rabbit and man. Anyway, the published data and the derived pharmacokinetic parameters indicate that the rabbit is a useful animal model in intravitreal pharmacokinetics. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Tissue distribution of sup 3 H-nicotine in rats after bolus or constant injection

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chowdhury, P.; Pasley, J.N.; Rayford, P.L.

    1989-01-01

    Two groups of rats, (N = 7), were fasted for 24 hrs prior to the study. On the day of the experiment, the animals were anesthetized and infused with either 5 ml nicotine solution (200 {mu}g/L) in saline containing 5 {mu}c {sup 3}H-nicotine, (sp. activity 50-80 mCi/mol) for 90 minutes or injected as a bolus with 0.5 ml of the same nicotine (200 {mu}g/L) solution. The animals were sacrificed 60 minutes after the injection or after the infusion was stopped. Blood and tissue samples were counted by liquid scintillation counting. Percent distribution of {sup 3}H-nicotine per gm of tissue wasmore » calculated from the total radioactivity recovered in individual tissues over the total activity injected into the rat and the values were compared using student's t test. Results: Distribution of {sup 3}H-nicotine was found highest in kidney (45-49%) among all tissues examined and was not different between routes of administration. Significantly higher retention of {sup 3}H-nicotine was found with continuous infusion in esophagus, fundus, antrum, spleen, cecum, pancreas, testes, heart and muscle when {sup 3}H-nicotine retentions were compared with bolus injection. In contrast, the distribution of {sup 3}H-nicotine in adrenal gland, was significantly lower in continuous infusion group. Distribution in blood was 6 fold higher in continuous infusion (7.26%) compared to bolus (1.11%) injection. The distribution {sup 3}H-nicotine in other tissues were not different by either routes of injection.« less

  2. Bioaccumulation and tissue distribution of antibiotics in wild marine fish from Laizhou Bay, North China.

    PubMed

    Liu, Sisi; Bekele, Tadiyose-Girma; Zhao, Hongxia; Cai, Xiyun; Chen, Jingwen

    2018-08-01

    Information about bioaccumulation and tissue distribution of antibiotics in wild marine fish is still limited. In the present study, tissue levels, bioaccumulation and distribution patterns of 9 sulfonamide (SA), trimethoprim (TMP), 5 fluoroquinolone (FQ), and 4 macrolide (ML) antibiotics were investigated in gill, muscle, kidney, and liver tissues of seven wild fish species collected from Laizhou Bay, North China in 2016. All the 19 antibiotics were detected in these fish tissues with the total concentrations ranging from 22ng/g dry weight (dw) to 500ng/g dw. The mean values of logarithm bioaccumulation factors (BAFs) in the gills, muscles, kidneys, and livers ranged from 2.2 to 4.8, 1.9 to 4.0, 2.5 to 4.9, and 2.5 to 5.4, respectively. Log BAFs of antibiotics in these tissues significantly increased (r=0.61-0.77, p<0.001) with their logarithm values of liposome-water distribution coefficient (D lipw ) except in the muscles, suggesting that D lipw can well assess the bioaccumulation potentials of antibiotics in phospholipid-rich tissues. In general, the SAs, TMP, and FQs were primarily accumulated in the muscles and the MLs were primarily in the livers, which may be related to their toxicokinetic processes of these marine fish. The present study for the first time reported the tissue distribution patterns of antibiotics in wild marine fish. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Pharmacokinetics and biodistribution of the cyclin-dependent kinase inhibitor -CR8- in mice

    PubMed Central

    2013-01-01

    Background CR8 is a second generation inhibitor of cyclin-dependent kinases derived from roscovitine. CR8 was shown to be 50–100 fold more potent than roscovitine in inducing apoptosis in different tumor cell lines. In the present investigation, we have established an analytical method for the quantification of CR8 in biological samples and evaluated its bioavailability, biodistribution and pharmacokinetics in mice. Methods A liquid chromatography method utilizing UV-detection was used for the determination of CR8. CR8 was administered either orally (100 mg/kg) or i.v. (50 mg/kg) and the animals were sacrificed at different time points. Blood samples and organs were collected, after which the pharmacokinetic parameters were calculated for plasma and organs. Results CR8 was eluted at 5 minutes in the high performance liquid chromatography system used. The LLOQ detection was 0.10 μg/ml and linearity was observed within the 0.10-10 μg/ml range (r2 > 0.998). The accuracy and precision were >86%, while the recovery from plasma was >95%. CR8 was stable for 2 months at room temperature in both solution and plasma. CR8 pharmacokinetics was fitted to a two-compartment open model after oral administration and to a one compartment model after i.v. injection. The elimination half-life was about 3 hours. Organ exposure to CR8 (expressed as % AUC organ vs. AUC plasma) was highest in liver (205%), adipose tissue (188%) and kidney (150%) and low in bone marrow (30%) and brain (15%) as compared to plasma. The oral bioavailability of CR8 was found to be essentially 100%. Conclusions We have developed a rapid and simple method for the analysis of CR8. CR8 pharmacokinetics pattern showed 100% bioavailability, long half-life and limited distribution to brain and bone marrow, which may allow systemic exposure higher than the IC50 reported for cell death in tumor cell lines. CR8 displays favorable pharmacological properties and is therefore a good candidate for future

  4. Population pharmacokinetics of ϵ-aminocaproic acid in adolescents undergoing posterior spinal fusion surgery.

    PubMed

    Stricker, P A; Gastonguay, M R; Singh, D; Fiadjoe, J E; Sussman, E M; Pruitt, E Y; Goebel, T K; Zuppa, A F

    2015-04-01

    Despite demonstrated efficacy of ϵ-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations. Twenty children ages 12-17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics. Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min(-1) 70 kg(-1) (6.32 ml min(-1) kg(-0.75)), intercompartmental clearance of 200 ml min(-1) 70 kg(-1) (8.26 ml min(-1) kg(-0.75)), central volume of distribution of 8.78 litre 70 kg(-1) (0.13 litre kg(-1)), and peripheral volume of distribution of 15.8 litre 70 kg(-1) (0.23 litre kg(-1)). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics. The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg(-1) loading dose and 40 mg kg(-1) h(-1) infusion; weight ≤25 kg-<50 kg, 100 mg kg(-1) loading dose and 35 mg kg(-1) h(-1) infusion; and weight ≥50 kg, 100 mg kg(-1) loading dose and 30 mg kg(-1) h(-1) infusion. An efficacy trial employing this dosing strategy is warranted. NCT01408823. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. In silico evaluation of gadofosveset pharmacokinetics in different population groups using the Simcyp® simulator platform.

    PubMed

    Spanakis, Marios; Marias, Kostas

    2014-12-01

    Gadofosveset is a Gd-based contrast agent used for magnetic resonance imaging (MRI). Gadolinium kinetic distribution models are implemented in T1-weighted dynamic contrast-enhanced perfusion MRI for characterization of lesion sites in the body. Physiology changes in a disease state potentially can influence the pharmacokinetics of drugs and to this respect modify the distribution properties of contrast agents. This work focuses on the in silico modelling of pharmacokinetic properties of gadofosveset in different population groups through the application of physiologically-based pharmacokinetic models (PBPK) embedded in Simcyp® population pharmacokinetics platform. Physicochemical and pharmacokinetic properties of gadofosveset were introduced into Simcyp® simulator platform and a min-PBPK model was applied. In silico clinical trials were generated simulating the administration of the recommended dose for the contrast agent (i.v., 30 mg/kg) in population cohorts of healthy volunteers, obese, renal and liver impairment, and in a generated virtual oncology population. Results were evaluated regarding basic pharmacokinetic parameters of Cmax, AUC and systemic CL and differences were assessed through ANOVA and estimation of ratio of geometric mean between healthy volunteers and the other population groups. Simcyp® predicted a mean Cmax = 551.60 mg/l, a mean AUC = 4079.12 mg/L*h and a mean systemic CL = 0.56 L/h for the virtual population of healthy volunteers. Obese population showed a modulation in Cmax and CL, attributed to increased administered dose. In renal and liver impairment cohorts a significant modulation in Cmax, AUC and CL of gadofosveset is predicted. Oncology population exhibited statistical significant differences regarding AUC when compared with healthy volunteers. This work employed Simcyp® population pharmacokinetics platform in order to compute gadofosveset's pharmacokinetic profiles through PBPK models and in silico clinical

  6. A Method for Medical Diagnosis Based on Optical Fluence Rate Distribution at Tissue Surface

    PubMed Central

    Hamdy, Omnia; El-Azab, Jala; Al-Saeed, Tarek A.; Hassan, Mahmoud F.

    2017-01-01

    Optical differentiation is a promising tool in biomedical diagnosis mainly because of its safety. The optical parameters’ values of biological tissues differ according to the histopathology of the tissue and hence could be used for differentiation. The optical fluence rate distribution on tissue boundaries depends on the optical parameters. So, providing image displays of such distributions can provide a visual means of biomedical diagnosis. In this work, an experimental setup was implemented to measure the spatially-resolved steady state diffuse reflectance and transmittance of native and coagulated chicken liver and native and boiled breast chicken skin at 635 and 808 nm wavelengths laser irradiation. With the measured values, the optical parameters of the samples were calculated in vitro using a combination of modified Kubelka-Munk model and Bouguer-Beer-Lambert law. The estimated optical parameters values were substituted in the diffusion equation to simulate the fluence rate at the tissue surface using the finite element method. Results were verified with Monte-Carlo simulation. The results obtained showed that the diffuse reflectance curves and fluence rate distribution images can provide discrimination tools between different tissue types and hence can be used for biomedical diagnosis. PMID:28930158

  7. A Method for Medical Diagnosis Based on Optical Fluence Rate Distribution at Tissue Surface.

    PubMed

    Hamdy, Omnia; El-Azab, Jala; Al-Saeed, Tarek A; Hassan, Mahmoud F; Solouma, Nahed H

    2017-09-20

    Optical differentiation is a promising tool in biomedical diagnosis mainly because of its safety. The optical parameters' values of biological tissues differ according to the histopathology of the tissue and hence could be used for differentiation. The optical fluence rate distribution on tissue boundaries depends on the optical parameters. So, providing image displays of such distributions can provide a visual means of biomedical diagnosis. In this work, an experimental setup was implemented to measure the spatially-resolved steady state diffuse reflectance and transmittance of native and coagulated chicken liver and native and boiled breast chicken skin at 635 and 808 nm wavelengths laser irradiation. With the measured values, the optical parameters of the samples were calculated in vitro using a combination of modified Kubelka-Munk model and Bouguer-Beer-Lambert law. The estimated optical parameters values were substituted in the diffusion equation to simulate the fluence rate at the tissue surface using the finite element method. Results were verified with Monte-Carlo simulation. The results obtained showed that the diffuse reflectance curves and fluence rate distribution images can provide discrimination tools between different tissue types and hence can be used for biomedical diagnosis.

  8. Temperature distribution analysis of tissue water vaporization during microwave ablation: experiments and simulations.

    PubMed

    Ai, Haiming; Wu, Shuicai; Gao, Hongjian; Zhao, Lei; Yang, Chunlan; Zeng, Yi

    2012-01-01

    The temperature distribution in the region near a microwave antenna is a critical factor that affects the entire temperature field during microwave ablation of tissue. It is challenging to predict this distribution precisely, because the temperature in the near-antenna region varies greatly. The effects of water vaporisation and subsequent tissue carbonisation in an ex vivo porcine liver were therefore studied experimentally and in simulations. The enthalpy and high-temperature specific absorption rate (SAR) of liver tissues were calculated and incorporated into the simulation process. The accuracy of predictions for near-field temperatures in our simulations has reached the level where the average maximum error is less than 5°C. In addition, a modified thermal model that accounts for water vaporisation and the change in the SAR distribution pattern is proposed and validated with experiment. The results from this study may be useful in the clinical practice of microwave ablation and can be applied to predict the temperature field in surgical planning.

  9. Laser induced heat source distribution in bio-tissues

    NASA Astrophysics Data System (ADS)

    Li, Xiaoxia; Fan, Shifu; Zhao, Youquan

    2006-09-01

    During numerical simulation of laser and tissue thermal interaction, the light fluence rate distribution should be formularized and constituted to the source term in the heat transfer equation. Usually the solution of light irradiative transport equation is given in extreme conditions such as full absorption (Lambert-Beer Law), full scattering (Lubelka-Munk theory), most scattering (Diffusion Approximation) et al. But in specific conditions, these solutions will induce different errors. The usually used Monte Carlo simulation (MCS) is more universal and exact but has difficulty to deal with dynamic parameter and fast simulation. Its area partition pattern has limits when applying FEM (finite element method) to solve the bio-heat transfer partial differential coefficient equation. Laser heat source plots of above methods showed much difference with MCS. In order to solve this problem, through analyzing different optical actions such as reflection, scattering and absorption on the laser induced heat generation in bio-tissue, a new attempt was made out which combined the modified beam broaden model and the diffusion approximation model. First the scattering coefficient was replaced by reduced scattering coefficient in the beam broaden model, which is more reasonable when scattering was treated as anisotropic scattering. Secondly the attenuation coefficient was replaced by effective attenuation coefficient in scattering dominating turbid bio-tissue. The computation results of the modified method were compared with Monte Carlo simulation and showed the model provided reasonable predictions of heat source term distribution than past methods. Such a research is useful for explaining the physical characteristics of heat source in the heat transfer equation, establishing effective photo-thermal model, and providing theory contrast for related laser medicine experiments.

  10. Pharmacokinetics and pharmacodynamics of LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one], an orally available nonsteroidal-selective androgen receptor modulator.

    PubMed

    Vajda, Eric G; López, Francisco J; Rix, Peter; Hill, Robert; Chen, Yanling; Lee, Kyoung-Jin; O'Brien, Z; Chang, William Y; Meglasson, Martin D; Lee, Yong-Hee

    2009-02-01

    Selective androgen receptor modulators (SARMs) are a new class of molecules in development to treat a variety of diseases. SARMs maintain the beneficial effects of androgens, including increased muscle mass and bone density, while having reduced activity on unwanted side effects. The mechanisms responsible for the tissue-selective activity of SARMs are not fully understood, and the pharmacokinetic (PK)/pharmacodynamic (PD) relationships are poorly described. Tissue-specific compound distribution potentially could be a mechanism responsible for apparent tissue selectivity. We examined the PK/PD relationship of a novel SARM, LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[3,2-f]quinolin-7(6H)-one], in a castrated rat model of androgen deficiency. LGD-3303 has potent activity on levator ani muscle but is a partial agonist on the preputial gland and ventral prostate. LGD-3303 never stimulated ventral prostate above intact levels despite increasing plasma concentrations of compound. Tissue-selective activity was maintained when LGD-3303 was dosed orally or by continuous infusion, two routes of administration with markedly different time versus exposure profiles. Despite the greater muscle activity relative to prostate activity, local tissue concentrations of LGD-3303 were higher in the prostate than in the levator ani muscle. LGD-3303 has SARM properties that are independent of its pharmacokinetic profile, suggesting that the principle mechanism for tissue-selective activity is the result of altered molecular interactions at the level of the androgen receptor.

  11. [Rare earth elements contents and distribution characteristics in nasopharyngeal carcinoma tissue].

    PubMed

    Zhang, Xiangmin; Lan, Xiaolin; Zhang, Lingzhen; Xiao, Fufu; Zhong, Zhaoming; Ye, Guilin; Li, Zong; Li, Shaojin

    2016-03-01

    To investigate the rare earth elements(REEs) contents and distribution characteristics in nasopharyngeal carcinoma( NPC) tissue in Gannan region. Thirty patients of NPC in Gannan region were included in this study. The REEs contents were measured by tandem mass spectrometer inductively coupled plasma(ICP-MS/MS) in 30 patients, and the REEs contents and distribution were analyzed. The average standard deviation value of REEs in lung cancer and normal lung tissues was the minimum mostly. Light REEs content was higher than the medium REEs, and medium REEs content was higher than the heavy REEs content. REEs contents changes in nasopharyngeal carcinoma were variable obviously, the absolute value of Nd, Ce, Pr, Gd and other light rare earth elements were variable widely. The degree of changes on Yb, Tb, Ho and other heavy rare earth elements were variable widely, and there was presence of Eu, Ce negative anomaly(δEu=0. 385 5, δCe= 0. 523 4). The distribution characteristic of REEs contents in NPC patients is consistent with the parity distribution. With increasing atomic sequence, the content is decline wavy. Their distribution patterns were a lack of heavy REEs and enrichment of light REEs, and there was Eu , Ce negative anomaly.

  12. A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide-induced granulocytopaenia.

    PubMed

    Scholz, M; Ackermann, M; Engel, C; Emmrich, F; Loeffler, M; Kamprad, M

    2009-12-01

    Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used as treatment for granulocytopaenia during cytotoxic chemotherapy; however, optimal scheduling of this pharmaceutical is unknown. Biomathematical models can help to pre-select optimal application schedules but precise pharmacokinetic properties of the pharmaceuticals are required at first. In this study, we have aimed to construct a pharmacokinetic model of G-CSF derivatives filgrastim and pegfilgrastim in mice. Healthy CD-1 mice and those with cyclophosphamide-induced granulocytopaenia were studied after administration of filgrastim and pegfilgrastim in different dosing and timing schedules. Close meshed time series of granulocytes and G-CSF plasma concentrations were determined. An ordinary differential equations model of pharmacokinetics was constructed on the basis of known mechanisms of drug distribution and degradation. Predictions of the model fit well with all experimental data for both filgrastim and pegfilgrastim. We obtained a unique parameter setting for all experimental scenarios. Differences in pharmacokinetics between filgrastim and pegfilgrastim can be explained by different estimates of model parameters rather than by different model mechanisms. Parameter estimates with respect to distribution and clearance of the drug derivatives are in agreement with qualitative experimental results. Dynamics of filgrastim and pegfilgrastim plasma levels can be explained by the same pharmacokinetic model but different model parameters. Beause of a strong clearance mechanism mediated by granulocytes, granulocytotic and granulocytopaenic conditions must be studied simultaneously to construct a reliable model. The pharmacokinetic model will be extended to a murine model of granulopoiesis under chemotherapy and G-CSF application.

  13. A three-tiered approach for linking pharmacokinetic ...

    EPA Pesticide Factsheets

    The power of the adverse outcome pathway (AOP) framework arises from its utilization of pathway-based data to describe the initial interaction of a chemical with a molecular target (molecular initiating event; (MIE), followed by a progression through a series of key events that lead to an adverse outcome relevant for regulatory purposes. The AOP itself is not chemical specific, thus providing the biological context necessary for interpreting high throughput (HT) toxicity screening results. Application of the AOP framework and HT predictions in ecological and human health risk assessment, however, requires the consideration of chemical-specific properties that influence external exposure doses and target tissue doses. To address this requirement, a three-tiered approach was developed to provide a workflow for connecting biology-based AOPs to biochemical-based pharmacokinetic properties (absorption, distribution, metabolism, excretion; ADME), and then to chemical/human activity-based exposure pathways. This approach included: (1) The power of the adverse outcome pathway (AOP) framework arisesfrom its utilization of pathway-based data to describe the initial interaction of a chemical with a molecular target (molecular initiating event; (MIE), followed by a progression through a series of key events that lead to an adverse outcome relevant for regulatory purposes. The AOP itself is not chemical specific, thus providing the biological context necessary for interpreti

  14. Absorption, distribution, metabolism and excretion of peginesatide, a novel erythropoiesis-stimulating agent, in rats

    PubMed Central

    Woodburn, Kathryn W.; Holmes, Christopher P.; Wilson, Susan D.; Fong, Kei-Lai; Press, Randall J.; Moriya, Yuu; Tagawa, Yoshihiko

    2011-01-01

    The pharmacokinetics(PK) (absorption, distribution, metabolism, excretion) of peginesatide.a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent (ESA), was evaluated in rats. The PK profile was evaluated at 0.1-5 mg·kg−1 IV using unlabeled or [14C]-labeled peginesatide. Mass balance, tissue distribution and metabolism were evaluated following IV administration of 5 mg·kg−1 [14C]-peginesatide, with tissue distribution also evaluated by quantitative whole-body autoradiography (QWBA) following an IV dose of 17 mg·kg−1[14C]-peginesatide. Plasma clearance was slow and elimination was biphasic with unchanged peginesatide representing >90% of the total radioactivity of the total radioactive exposure. Slow uptake of the radiolabeled compound from the vascular compartment into the tissues was observed. Biodistribution to bone marrow and extramedullary hematopoietic sites, and to highly vascularized lymphatic and excretory tissues occurred. A predominant degradation event to occur in vivo was the loss of one PEG chain from the branched PEG moiety to generate mono-PEG. Renal excretion was the primary mechanism (41%) of elimination, with parent molecule (67%) the major moiety excreted. In conclusion, elimination of [14C]-peginesatide-derived radioactivity was extended, retention preferentially occurred at sites of erythropoiesis (bone marrow), and urinary excretion was the primary elimination route. PMID:22188389

  15. Pharmacokinetic parameters explain the therapeutic activity of antimicrobial agents in a silkworm infection model.

    PubMed

    Paudel, Atmika; Panthee, Suresh; Urai, Makoto; Hamamoto, Hiroshi; Ohwada, Tomohiko; Sekimizu, Kazuhisa

    2018-01-25

    Poor pharmacokinetic parameters are a major reason for the lack of therapeutic activity of some drug candidates. Determining the pharmacokinetic parameters of drug candidates at an early stage of development requires an inexpensive animal model with few associated ethical issues. In this study, we used the silkworm infection model to perform structure-activity relationship studies of an antimicrobial agent, GPI0039, a novel nitrofuran dichloro-benzyl ester, and successfully identified compound 5, a nitrothiophene dichloro-benzyl ester, as a potent antimicrobial agent with superior therapeutic activity in the silkworm infection model. Further, we compared the pharmacokinetic parameters of compound 5 with a nitrothiophene benzyl ester lacking chlorine, compound 7, that exerted similar antimicrobial activity but had less therapeutic activity in silkworms, and examined the metabolism of these antimicrobial agents in human liver fractions in vitro. Compound 5 had appropriate pharmacokinetic parameters, such as an adequate half-life, slow clearance, large area under the curve, low volume of distribution, and long mean residence time, compared with compound 7, and was slowly metabolized by human liver fractions. These findings suggest that the therapeutic effectiveness of an antimicrobial agent in the silkworms reflects appropriate pharmacokinetic properties.

  16. Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease.

    PubMed

    Rosario, M; Dirks, N L; Gastonguay, M R; Fasanmade, A A; Wyant, T; Parikh, A; Sandborn, W J; Feagan, B G; Reinisch, W; Fox, I

    2015-07-01

    Vedolizumab, an anti-α(4)β(7) integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing. To characterise vedolizumab pharmacokinetics in patients with UC and CD, to identify clinically relevant determinants of vedolizumab clearance, and to describe the pharmacokinetic-pharmacodynamic relationship using population modelling. Data from a phase 1 healthy volunteer study, a phase 2 UC study, and 3 phase 3 UC/CD studies were included. Population pharmacokinetic analysis for repeated measures was conducted using nonlinear mixed effects modelling. Results from the base model, developed using extensive phase 1 and 2 data, were used to develop the full covariate model, which was fit to sparse phase 3 data. Vedolizumab pharmacokinetics was described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half-life of vedolizumab was 25.5 days; linear clearance (CL(L)) was 0.159 L/day for UC and 0.155 L/day for CD; central compartment volume of distribution (V(c)) was 3.19 L; and peripheral compartment volume of distribution was 1.66 L. Interindividual variabilities (%CV) were 35% for CLL and 19% for V(c); residual variance was 24%. Only extreme albumin and body weight values were identified as potential clinically important predictors of CL(L). Population pharmacokinetic parameters were similar in patients with moderately to severely active UC and CD. This analysis supports use of vedolizumab fixed dosing in these patients. Clinicaltrials.gov Identifiers: NCT01177228; NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2); NCT01224171 (GEMINI 3). © 2015 Takeda Pharmaceuticals International Co published by John Wiley & Sons

  17. Deriving Therapies for Children with Primary CNS Tumors Using Pharmacokinetic Modeling and Simulation of Cerebral Microdialysis Data

    PubMed Central

    Jacus, M.O.; Throm, S.L.; Turner, D.C.; Patel, Y.T.; Freeman, B.B.; Morfouace, M.; Boulos, N.; Stewart, C. F.

    2014-01-01

    The treatment of children with primary central nervous system (CNS) tumors continues to be a challenge despite recent advances in technology and diagnostics. In this overview, we describe our approach for identifying and evaluating active anticancer drugs through a process that enables rational translation from the lab to the clinic. The preclinical approach we discuss uses tumor subgroup-specific models of pediatric CNS tumors, cerebral microdialysis sampling of tumor extracellular fluid (tECF), and pharmacokinetic modeling and simulation to overcome challenges that currently hinder researchers in this field. This approach involves performing extensive systemic (plasma) and target site (CNS tumor) pharmacokinetic studies. Pharmacokinetic modeling and simulation of the data derived from these studies are then used to inform future decisions regarding drug administration, including dosage and schedule. Here, we also present how our approach was used to examine two FDA approved drugs, simvastatin and pemetrexed, as candidates for new therapies for pediatric CNS tumors. We determined that due to unfavorable pharmacokinetic characteristics and insufficient concentrations in tumor tissue in a mouse model of ependymoma, simvastatin would not be efficacious in further preclinical trials. In contrast to simvastatin, pemetrexed was advanced to preclinical efficacy studies after our studies determined that plasma exposures were similar to those in humans treated at similar tolerable dosages and adequate unbound concentrations were found in tumor tissue of medulloblastoma-bearing mice. Generally speaking, the high clinical failure rates for CNS drug candidates can be partially explained by the fact that therapies are often moved into clinical trials without extensive and rational preclinical studies to optimize the transition. Our approach addresses this limitation by using pharmacokinetic and pharmacodynamic modeling of data generated from appropriate in vivo models to

  18. Effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds.

    PubMed

    Kukanich, Butch; Borum, Stacy L

    2008-05-01

    To assess pharmacokinetics and pharmacodynamics of morphine and the effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds. 6 healthy Greyhounds, 3 male and 3 female. Morphine sulfate (0.5 mg/kg. IV) was administered to Greyhounds prior to and after 5 days of ketoconazole (12.7 +/- 0.6 mg/kg, PO) treatment. Plasma samples were obtained from blood samples that were collected at predetermined time points for measurement of morphine and ketoconazole concentrations by mass spectrometry. Pharmacokinetics of morphine were estimated by use of computer software. Pharmacodynamic effects of morphine in Greyhounds were similar to those of other studies in dogs and were similar between treatment groups. Morphine was rapidly eliminated with a half-life of 1.28 hours and a plasma clearance of 32.55 mL/min/kg. The volume of distribution was 3.6 L/kg. No significant differences in the pharmacokinetics of morphine were found after treatment with ketoconazole. Plasma concentrations of ketoconazole were high and persisted longer than expected in Greyhounds. Ketoconazole had no significant effect on morphine pharmacokinetics, and the pharmacodynamics were similar between treatment groups. Plasma concentrations of ketoconazole were higher than expected and persisted longer than expected in Greyhounds.

  19. Pharmacokinetics of lysine clonixinate in children in postoperative care.

    PubMed

    González-Martin, G; Cattan, C; Zuñiga, S

    1996-09-01

    The pharmacokinetics of 2 doses of intravenous lysine clonixinate (4 and 6 mg x kg-1) were studied in 10 children (age 4-10 years) under postoperative care. A single dose of the drug was injected in a forearm vein. Blood samples were collected at regular intervals for 3 hours. Serum clonixin concentrations (expressed as clonixin) were analyzed using a high pressure liquid chromatography method. Pharmacokinetic values were estimated by a nonlinear computer program. The distribution volume was similar in both groups of children (1.288 +/- 0.829 1 and 1. 139 +/- 0.667 1, respectively). There were no differences between the values of total plasma clearance and the administered doses (0.026 +/- 0.017 ml x min-1 and 0.017 +/- 0.008 ml x min-1, t = 1.07, p = 0.76). The elimination half-life was longer in children who received 6 mg x kg-1 (44.26 +/- 6.34 min vs 38.63 +/- 10.93 min) but this difference was not statistically significant (t = 0.99, p < 0.34). The pharmacokinetic parameters calculated in these children were different from those found by other authors in adults and experimental animals.

  20. Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol.

    PubMed

    Franken, L G; de Winter, B C M; van Esch, H J; van Zuylen, L; Baar, F P M; Tibboel, D; Mathôt, R A A; van Gelder, T; Koch, B C P

    2016-06-01

    A variety of medications are used for symptom control in palliative care, such as morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these patients as a result of physiological changes that occur at the end stage of life. This review gives an overview of how the pharmacokinetics in terminally ill patients may differ from the average population and discusses the effect of terminal illness on each of the four pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considerations are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and haloperidol). The pharmacokinetics of drugs in terminally ill patients can be complex and limited evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosing guidelines. Until then knowledge of pharmacokinetics and the physiological changes that occur in the final days of life can provide a base for dosing adjustments that will improve the quality of life of terminally ill patients. As the interaction of drugs with the physiology of dying is complex, pharmacological treatment is probably best assessed in a multi-disciplinary setting and the advice of a pharmacist, or clinical pharmacologist, is highly recommended.

  1. Characteristics and clinical implications of the pharmacokinetic profile of ibuprofen in patients with knee osteoarthritis.

    PubMed

    Gallelli, L; Galasso, O; Urzino, A; Saccà, S; Falcone, D; Palleria, C; Longo, P; Corigliano, A; Terracciano, R; Savino, R; Gasparini, G; De Sarro, G; Southworth, S R

    2012-12-01

    Ibuprofen is a non-selective cyclo-oxygenase (COX)-1/COX-2 inhibitor used to treat pain conditions and inflammation. Limited data have been published concerning the pharmacokinetic profile and clinical effects of ibuprofen in patients with osteoarthritis (OA). In this paper we compared the pharmacokinetic and clinical profile of ibuprofen (at a dosage of from 800 mg/day to 1800 mg/day) administered in patients affected by severe knee OA. Ibuprofen was administered for 7 days to patients who were scheduled to undergo knee arthroplasty due to OA. After 7 days, the ibuprofen concentration in plasma and synovial fluid was measured through both high-performance liquid chromatography (HPLC)-UV and gas chromatography-mass spectroscopy (GC/MS), while clinical effects were evaluated through both visual analogue scale (VAS) and Western Ontario and McMaster Universities (WOMAC) scores. The Naranjo scale and the WHO causality assessment scale were used for estimating the probability of adverse drug reactions (ADRs). The severity of ADRs was assessed by the modified Hartwig and Siegel scale. Ibuprofen showed a dose-dependent diffusion in both plasma and synovial fluid, which was related to the reduction of pain intensity and improvement of health status, without the development of ADRs. Ibuprofen at higher dosages can be expected to provide better control of OA symptoms as a result of higher tissue distribution.

  2. Pharmacokinetics in Wistar Rats of 5-[(4-Carboxybutanoyl)Amino]-2-Hydroxybenzoic Acid: A Novel Synthetic Derivative of 5-Aminosalicylic Acid (5-ASA) with Possible Anti-Inflammatory Activity

    PubMed Central

    Correa-Basurto, José; Rosales Hernández, Martha Cecilia; Padilla Martínez, Itzia Irene; Mendieta-Wejebe, Jessica Elena

    2016-01-01

    5-[(4-carboxybutanoyl)amino]-2-hydroxybenzoic acid (C2) is a novel synthetic derivative of 5-aminosalicylic acid (5-ASA), which is currently being evaluated ex vivo as an anti-inflammatory agent and has shown satisfactory results. This study aimed to obtain the pharmacokinetic profiles, tissue distribution and plasma protein binding of C2 in Wistar Rats. Additionally, an HPLC method was developed and validated to quantify C2 in rat plasma. The pharmacokinetic profiles of intragastric, intravenous and intraperitoneal administration routes at singles doses of 100, 50, and 100 mg/kg, respectively, were studied in Wistar rats. The elimination half-life of intravenously administered C2 was approximately 33 min. The maximum plasma level of C2 was reached approximately 24 min after intragastric administration, with a Cmax value of 2.5 g/mL and an AUCtot value of 157 μg min-1/mL; the oral bioavailability was approximately 13%. Following a single intragastric or oral dose (100 mg/kg), C2 was distributed and detected in all examined tissues (including the brain and colon). The results showed that C2 accumulates over time. The plasma protein binding results indicated that the unbound fraction of C2 at concentrations of 1 to 20 μg/mL ranged from 89.8% to 92.5%, meaning that this fraction of C2 is available to cross tissues. Finally, the blood-plasma partitioning (BP ratio) of C2 in rat plasma was 0.71 and 0.6 at concentrations of 5 and 10 μg/mL, respectively, which indicates that C2 is free in the plasmatic phase and not inside blood cells. The results of this study suggest that a fraction of the administered C2 dose is absorbed in the stomach, and the fraction that is not absorbed reaches the small intestine and colon. This distribution constitutes the main advantage of C2 compared with 5-ASA for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). PMID:27454774

  3. Comparative pharmacokinetic study of mangiferin after oral administration of pure mangiferin and US patented polyherbal formulation to rats.

    PubMed

    Kammalla, Ananth Kumar; Ramasamy, Mohan Kumar; Inampudi, Jyothi; Dubey, Govind Prasad; Agrawal, Aruna; Kaliappan, Ilango

    2015-04-01

    The US patented polyherbal formulation for the prevention and management of type II diabetes and its vascular complications was used for the present study. The xanthone glycoside mangiferin is one of the major effector constituents in the Salacia species with potential anti-diabetic activity. The pharmacokinetic differences of mangiferin following oral administration of pure mangiferin and polyherbal formulation containing Salacia species were studied with approximately the same dose 30 mg/kg mangiferin and its distribution among the major tissue in Wistar rats. Plasma samples were collected at different time points (15, 30, 60, 120, 180, 240, 360, 480, 600, 1,440, 2,160, and 2880 min) and subsequently analyzed using a validated simple and rapid LC-MS method. Plasma concentration versus time profiles were explored by non-compartmental analysis. Mangiferin plasma exposure was significantly increased when administered from formulation compared to the standard mangiferin. Mangiferin resided significantly longer in the body (last mean residence time (MRTlast)) when given in the form of the formulation (3.65 h). Cmax values of formulation (44.16 μg/mL) administration were elevated when compared to equivalent dose of the pure mangiferin (15.23 μg/mL). Tissue distribution study of mangiferin from polyherbal formulation was also studied. In conclusion, the exposure of mangiferin is enhanced after formulation and administration and could result in superior efficacy of polyherbal formulation when compared to an equivalent dose of mangiferin. The results indicate that the reason which delays the elimination of mangiferin and enhances its bioavailability might the interactions of the some other constituents present in the polyherbal formulation. Distribution study results indicate that mangiferin was extensively bound to the various tissues like the small intestine, heart, kidney, spleen, and liver except brain tissue.

  4. Clinical Predictors of Venetoclax Pharmacokinetics in Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients: a Pooled Population Pharmacokinetic Analysis.

    PubMed

    Jones, Aksana K; Freise, Kevin J; Agarwal, Suresh K; Humerickhouse, Rod A; Wong, Shekman L; Salem, Ahmed Hamed

    2016-09-01

    Venetoclax (ABT-199/GDC-0199) is a selective, potent, first-in-class BCL-2 inhibitor that restores apoptosis in cancer cells and has demonstrated clinical efficacy in a variety of hematological malignancies. The objective of this analysis was to characterize the population pharmacokinetics of venetoclax and identify demographic, pathophysiologic, and treatment factors that influence its pharmacokinetics. Plasma concentration samples from 505 subjects enrolled in 8 clinical studies were analyzed using non-linear mixed-effects modeling. Venetoclax plasma concentrations were best described by a two-compartment PK model with first-order absorption and elimination. The terminal half-life in cancer subjects was estimated to be approximately 26 h. Moderate and strong CYP3A inhibitors decreased venetoclax apparent clearance by 19% and 84%, respectively, while weak CYP3A inhibitors and inducers did not affect clearance. Additionally, concomitant rituximab administration was estimated to increase venetoclax apparent clearance by 21%. Gastric acid-reducing agent co-administration had no impact on the rate or extent of venetoclax absorption. Females had 32% lower central volume of distribution when compared to males. Food increased the bioavailability by 2.99- to 4.25-fold when compared to the fasting state. Mild and moderate renal and hepatic impairment, body weight, age, race, weak CYP3A inhibitors and inducers as well as OATP1B1 transporter phenotype and P-gp, BCRP, and OATP1B1/OATP1B3 modulators had no impact on venetoclax pharmacokinetics. Venetoclax showed minimal accumulation with accumulation ratio of 1.30-1.44. In conclusion, the concomitant administration of moderate and strong CYP3A inhibitors and rituximab as well as food were the main factors impacting venetoclax pharmacokinetics, while patient characteristics had only minimal impact.

  5. Development of good modelling practice for phsiologically based pharmacokinetic models for use in risk assessment: The first steps

    EPA Science Inventory

    The increasing use of tissue dosimetry estimated using pharmacokinetic models in chemical risk assessments in multiple countries necessitates the need to develop internationally recognized good modelling practices. These practices would facilitate sharing of models and model eva...

  6. Tissue distribution and excretion kinetics of orally administered silica nanoparticles in rats

    PubMed Central

    Lee, Jeong-A; Kim, Mi-Kyung; Paek, Hee-Jeong; Kim, Yu-Ri; Kim, Meyoung-Kon; Lee, Jong-Kwon; Jeong, Jayoung; Choi, Soo-Jin

    2014-01-01

    Purpose The effects of particle size on the tissue distribution and excretion kinetics of silica nanoparticles and their biological fates were investigated following a single oral administration to male and female rats. Methods Silica nanoparticles of two different sizes (20 nm and 100 nm) were orally administered to male and female rats, respectively. Tissue distribution kinetics, excretion profiles, and fates in tissues were analyzed using elemental analysis and transmission electron microscopy. Results The differently sized silica nanoparticles mainly distributed to kidneys and liver for 3 days post-administration and, to some extent, to lungs and spleen for 2 days post-administration, regardless of particle size or sex. Transmission electron microscopy and energy dispersive spectroscopy studies in tissues demonstrated almost intact particles in liver, but partially decomposed particles with an irregular morphology were found in kidneys, especially in rats that had been administered 20 nm nanoparticles. Size-dependent excretion kinetics were apparent and the smaller 20 nm particles were found to be more rapidly eliminated than the larger 100 nm particles. Elimination profiles showed 7%–8% of silica nanoparticles were excreted via urine, but most nanoparticles were excreted via feces, regardless of particle size or sex. Conclusion The kidneys, liver, lungs, and spleen were found to be the target organs of orally-administered silica nanoparticles in rats, and this organ distribution was not affected by particle size or animal sex. In vivo, silica nanoparticles were found to retain their particulate form, although more decomposition was observed in kidneys, especially for 20 nm particles. Urinary and fecal excretion pathways were determined to play roles in the elimination of silica nanoparticles, but 20 nm particles were secreted more rapidly, presumably because they are more easily decomposed. These findings will be of interest to those seeking to predict

  7. Triprotic acid-base microequilibria and pharmacokinetic sequelae of cetirizine.

    PubMed

    Marosi, Attila; Kovács, Zsuzsanna; Béni, Szabolcs; Kökösi, József; Noszál, Béla

    2009-06-28

    (1)H NMR-pH titrations of cetirizine, the widely used antihistamine and four related compounds were carried out and the related 11 macroscopic protonation constants were determined. The interactivity parameter between the two piperazine amine groups was obtained from two symmetric piperazine derivatives. Combining these two types of datasets, all the 12 microconstants and derived tautomeric constants of cetirizine were calculated. Upon this basis, the conflicting literature data of cetirizine microspeciation were clarified, and the pharmacokinetic absorption-distribution properties could be interpreted. The pH-dependent distribution of the microspecies is provided.

  8. The pharmacokinetics of morphine and lidocaine in nine severe trauma patients.

    PubMed

    Berkenstadt, H; Mayan, H; Segal, E; Rotenberg, M; Almog, S; Perel, A; Ezra, D

    1999-12-01

    To study the pharmacokinetic parameters of morphine and lidocaine after a single intravenous (i.v.) bolus in severe trauma patients. Clinical case study. Department of Anesthesiology and Intensive Care of a university hospital. Nine patients, ages 24 to 91 years (mean 54.4 yrs), admitted to the hospital with severe trauma (Injury Severity Score > 20) were included in the study. After initial evaluation and stabilization, a single i.v. dose of morphine 0.025 mg/kg and lidocaine 1.5 mg/kg was given separately, and blood samples were drawn for each drug serum concentration. Morphine pharmacokinetics was studied in eight patients, lidocaine pharmacokinetics in seven patients, and both drugs were studied in six patients. Morphine clearance 2.5 to 10 ml/kg/min (6 +/- 2.6, mean +/- SD) and volume of distribution 0.28 to 3.30 L/kg (1.4 +/- 1.0) were found to be lower than values described previously for healthy volunteers (33.5 +/- 9 ml/kg/min and 5.16 +/- 1.40 L/kg, respectively), and are similar to those described in trauma patients (5 +/- 2.9 ml/kg/min and 0.9 +/- 0.2 L/kg, respectively). In contrast, lidocaine clearance 4.5 to 9.4 ml/kg/min (6.7 +/- 1.7) and volume of distribution 0.39 to 1.20 L/kg (0.72 +/- 0.28) were similar to the value described in healthy volunteers (10 ml/kg/min and 1.32 L/kg, respectively). Changes in pharmacokinetics of drugs eliminated by the liver may occur in patients with severe trauma. The preserved lidocaine clearance indicates an almost normal hepatic blood flow and suggests that other mechanisms may be involved in the lower morphine clearance. The findings may have applications for the treatment of severe trauma patients and suggest that drug monitoring might be needed in some instances so as to avoid toxicity.

  9. Compartmental Pharmacokinetics of the Antifungal Echinocandin Caspofungin (MK-0991) in Rabbits

    PubMed Central

    Groll, Andreas H.; Gullick, Bryan M.; Petraitiene, Ruta; Petraitis, Vidmantas; Candelario, Myrna; Piscitelli, Stephen C.; Walsh, Thomas J.

    2001-01-01

    The pharmacokinetics of the antifungal echinocandin-lipopeptide caspofungin (MK-0991) in plasma were studied in groups of three healthy rabbits after single and multiple daily intravenous administration of doses of 1, 3, and 6 mg/kg of body weight. Concentrations were measured by a validated high-performance liquid chromatography method and fitted into a three-compartment open pharmacokinetic model. Across the investigated dosage range, caspofungin displayed dose-independent pharmacokinetics. Following administration over 7 days, the mean peak concentration in plasma (Cmax) ± standard error of the mean increased from 16.01 ± 0.61 μg/ml at the 1-mg/kg dose to 105.52 ± 8.92 μg/ml at the 6-mg/kg dose; the mean area under the curve from 0 h to infinity rose from 13.15 ± 2.37 to 158.43 ± 15.58 μg · h/ml, respectively. The mean apparent volume of distribution at steady state (Vdss) was 0.299 ± 0.011 liter/kg at the 1-mg/kg dose and 0.351 ± 0.016 liter/kg at the 6-mg/kg dose (not significant [NS]). Clearance (CL) ranged from 0.086 ± 0.017 liter/kg/h at the 1-mg/kg dose to 0.043 ± 0.004 liter/kg/h at the 6-mg/kg dose (NS), and the mean terminal half-life was between 30 and 34 h (NS). Except for a trend towards an increased Vdss, there were no significant differences in pharmacokinetic parameters in comparison to those after single-dose administration. Caspofungin was well tolerated, displayed linear pharmacokinetics that fit into a three-compartment pharmacokinetic model, and achieved sustained concentrations in plasma that were multiple times in excess of reported MICs for susceptible opportunistic fungi. PMID:11158761

  10. [Postmortem distribution of tetrodotoxin in tissues and body fluids of guinea pigs].

    PubMed

    Liu, Wei; Da, Qing; Shen, Min

    2012-06-01

    To investigate the postmortem distribution of tetrodotoxin in tissues and body fluids of guinea pig, and to provide method and evidence for forensic identification and clinical diagnosis and treatment. Guinea pigs were intragastric administrated with 100, 50, 15 microg/kg tetrodotoxin, respectively. The poisoning symptoms were observed. The samples of heart, liver, spleen, lung, kidney, brain, stomach, intestines, bile, heart blood and urine were collected. The concentrations of tetrodotoxin in tissues and body fluids were measured with liquid chromatography-tandem mass spectrometry (LC-MS/MS). After administrated with tetrodotoxin, all guinea pigs came out poisoning signs including tachypnea, weary and dead finally. Tetrodotoxin concentrations in lung, stomach, intestines and urine were higher, followed by blood, heart and brain. The concentration in bile was the lowest. Postmortem distribution of tetrodotoxin in guinea pig is uneven. The concentration in the lung, stomach, intestines, urine and heart blood are higher, those tissues could be used for diagnosis of tetrodotoxin poisoning.

  11. The Constraints, Construction, and Verification of a Strain-Specific Physiologically Based Pharmacokinetic Rat Model.

    PubMed

    Musther, Helen; Harwood, Matthew D; Yang, Jiansong; Turner, David B; Rostami-Hodjegan, Amin; Jamei, Masoud

    2017-09-01

    The use of in vitro-in vivo extrapolation (IVIVE) techniques, mechanistically incorporated within physiologically based pharmacokinetic (PBPK) models, can harness in vitro drug data and enhance understanding of in vivo pharmacokinetics. This study's objective was to develop a user-friendly rat (250 g, male Sprague-Dawley) IVIVE-linked PBPK model. A 13-compartment PBPK model including mechanistic absorption models was developed, with required system data (anatomical, physiological, and relevant IVIVE scaling factors) collated from literature and analyzed. Overall, 178 system parameter values for the model are provided. This study also highlights gaps in available system data required for strain-specific rat PBPK model development. The model's functionality and performance were assessed using previous literature-sourced in vitro properties for diazepam, metoprolol, and midazolam. The results of simulations were compared against observed pharmacokinetic rat data. Predicted and observed concentration profiles in 10 tissues for diazepam after a single intravenous (i.v.) dose making use of either observed i.v. clearance (CL iv ) or in vitro hepatocyte intrinsic clearance (CL int ) for simulations generally led to good predictions in various tissue compartments. Overall, all i.v. plasma concentration profiles were successfully predicted. However, there were challenges in predicting oral plasma concentration profiles for metoprolol and midazolam, and the potential reasons and according solutions are discussed. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  12. Systematic considerations for a multicomponent pharmacokinetic study of Epimedii wushanensis herba: From method establishment to pharmacokinetic marker selection.

    PubMed

    Wang, Caihong; Wu, Caisheng; Zhang, Jinlan; Jin, Ying

    2015-04-15

    Prenylflavonoids are major active components of Epimedii wushanensis herba (EWH). The global pharmacokinetics of prenylflavonoids are unclear, as these compounds yield multiple, often unidentified metabolites. This study successfully elucidated the pharmacokinetic profiles of EWH extract and five EWH-derived prenylflavonoid monomers in rats. The study was a comprehensive analysis of metabolic pathways and pharmacokinetic markers. Major plasma compounds identified after oral administration of EWH-derived prototypes or extract included: (1) prenylflavonoid prototypes, (2) deglycosylated products, and (3) glucuronide conjugates. To select appropriate EWH-derived pharmacokinetic markers, a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was established to simultaneously monitor 14 major compounds in unhydrolyzed plasma and 10 potential pharmacokinetic markers in hydrolyzed plasma. The pharmacokinetic profiles indicated that the glucuronide conjugates of icaritin were the principle circulating metabolites and that total icaritin accounted for ∼99% of prenylflavonoid exposure after administration of EWH-derived materials to rats. To further investigate icaritin as a prospective pharmacokinetic marker, correlation analysis was performed between total icaritin and its glucuronide conjugates, and a strong correlation (r > 0.5) was found, indicating that total icaritin content accurately reflected changes in the exposure levels of the glucuronide conjugates over time. Therefore, icaritin is a sufficient pharmacokinetic marker for evaluating dynamic prenylflavonoid exposure levels. Next, a mathematical model was developed based on the prenylflavonoid content of EWH and the exposure levels in rats, using icaritin as the pharmacokinetic marker. This model accurately predicted exposure levels in vivo, with similar predicted vs. experimental area under the curve (AUC)(0-96 h) values for total icaritin (24.1 vs. 32.0 mg/L h). Icaritin in

  13. Population Pharmacokinetics of Vancomycin in Patients Undergoing Allogeneic Hematopoietic Stem-Cell Transplantation.

    PubMed

    Okada, Akira; Kariya, Misato; Irie, Kei; Okada, Yutaka; Hiramoto, Nobuhiro; Hashimoto, Hisako; Kajioka, Ryosuke; Maruyama, Chika; Kasai, Hidefumi; Hamori, Mami; Nishimura, Asako; Shibata, Nobuhito; Fukushima, Keizo; Sugioka, Nobuyuki

    2018-05-15

    Vancomycin is a commonly used antimicrobial agent for patients undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Vancomycin has large inter- and intraindividual pharmacokinetic variability, which is mainly described by renal function; various studies have indicated that vancomycin pharmacokinetics are altered in special populations. However, little is known regarding vancomycin pharmacokinetics in patients undergoing allo-HSCT. Therefore, we aimed to develop a population pharmacokinetic (PopPK) model of vancomycin in patients undergoing allo-HSCT for effective and safe antimicrobial therapy and to develop a vancomycin dosing nomogram for a vancomycin optimal-dosing strategy. In total, 285 observations from 95 patients undergoing allo-HSCT were available. The final PopPK parameter estimates were central volume of distribution (V1, L), 39.2; clearance (L/h), 4.25; peripheral volume of distribution (V2, L), 56.1; and intercompartmental clearance (L/h), 1.95. The developed vancomycin model revealed an increase in V1 and V2 compared with those in the general population that consisted of patients with methicillin-resistant Staphylococcus aureus. Moreover, serum creatinine was reduced because of an increase in the plasma fraction because of destruction of hematopoietic stem cells accompanying allo-HSCT pretreatment, suggesting that the Cockcroft-Gault equation-based creatinine clearance value was overestimated. To our knowledge, this is the first PopPK study to develop a dosing nomogram for vancomycin in patients undergoing allo-HSCT and was proven to be useful in optimizing the dosage and dosing interval of vancomycin in these patients. This strategy will provide more useful information for vancomycin therapy with an evidence-based dose adjustment. © 2018, The American College of Clinical Pharmacology.

  14. Pharmacokinetics of liposomal-encapsulated and un-encapsulated vincristine after injection of liposomal vincristine sulfate in beagle dogs.

    PubMed

    Zhong, Jie; Mao, Wenxue; Shi, Rong; Jiang, Peng; Wang, Qian; Zhu, Rong; Wang, Tianming; Ma, Yueming

    2014-03-01

    Vincristine sulfate (VCR) is a potent and widely used anti-tumor drug. Encapsulating VCR with liposomes improves its therapeutic index. However, there is little known about the pharmacokinetic features of un-encapsulated VCR (UE-VCR) and encapsulated VCR (E-VCR). Two groups of beagle dogs were intravenously administered a single 0.07 mg/kg dose of VCR liposomal injection (L-VCR) and VCR ordinary injection (I-VCR), respectively. The concentrations of UE-VCR, E-VCR and total VCR (T-VCR) were determined by separating UE-VCR and E-VCR, using solid-phase extraction and validated liquid chromatography-tandem mass spectrometry-based methods. Pharmacokinetic parameters were calculated, using the compartment model. The pharmacokinetic parameters of L-VCR and I-VCR were compared using a Student's t test. After intravenous injection of L-VCR, the pharmacokinetic parameters of E-VCR were similar to those of T-VCR. The concentrations of UE-VCR were very low, and its AUC (0-72h) was only 2.5 % that of T-VCR. Compared with I-VCR, plasma AUC of E-VCR increased, with significantly extended distribution t 1/2 and reduced distribution volume of the peripheral department. C2 min and AUC 0-1h of plasma UE-VCR decreased, with a similar elimination t 1/2. The increased therapeutic index of L-VCR is demonstrated by the pharmacokinetic features, higher exposure to E-VCR and lower peak concentration of UE-VCR, following intravenous injection.

  15. Fourier polarimetry of the birefringence distribution of myocardium tissue

    NASA Astrophysics Data System (ADS)

    Ushenko, O. G.; Dubolazov, O. V.; Ushenko, V. O.; Gorsky, M. P.; Soltys, I. V.; Olar, O. V.

    2015-11-01

    The results of optical modeling of biological tissues polycrystalline multilayer networks have been presented. Algorithms of reconstruction of parameter distributions were determined that describe the linear and circular birefringence. For the separation of the manifestations of these mechanisms we propose a method of space-frequency filtering. Criteria for differentiation of causes of death due to coronary heart disease (CHD) and acute coronary insufficiency (ACI) were found.

  16. Physiologically based Pharmacokinetic Modeling of 1,4-Dioxane in Rats, Mice, and Humans

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sweeney, Lisa M.; Thrall, Karla D.; Poet, Torka S.

    2008-01-01

    ABSTRACT 1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver and kidney damage at sufficiently high exposure levels. Two physiologically-based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed:partitionmore » coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassays. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.« less

  17. Relationship between inflammation and infliximab pharmacokinetics in rheumatoid arthritis

    PubMed Central

    Ternant, David; Ducourau, Emilie; Perdriger, Aleth; Corondan, Anca; Le Goff, Benoît; Devauchelle-Pensec, Valérie; Solau-Gervais, Elisabeth; Watier, Hervé; Goupille, Philippe; Paintaud, Gilles; Mulleman, Denis

    2014-01-01

    Aims Infliximab, an anti-tumour necrosis factor-α monoclonal antibody, is indicated in rheumatoid arthritis (RA). Our objective was to evaluate the influence of the sources of infliximab pharmacokinetic variability in RA. Methods Eighty-four patients treated with infliximab for RA were included in a prospective noncomparative study. They were analysed between two consecutive infliximab infusions. Infliximab concentrations were measured before the infusion, 2 h, 1 and 4 weeks after the infusion and immediately before the next infusion. Infliximab concentrations were described using a two-compartment population pharmacokinetic model. Results The mean (interindividual standard deviation) estimated central volume of distribution was 2.3 l (36%) and systemic clearance was 0.019 l h−1 (37%). The central volume of distribution increased with bodyweight; it was doubled between 50 and 90 kg. Systemic clearance increased with pre-infusion C-reactive protein concentration by 20%, varying from 3 to 14 mg l−1, and was decreased by 30% when methotrexate was coadministered. Conclusions The influence of methotrexate and inflammation on infliximab clearance suggests that individual adjustment of infliximab doses according to disease activity may be useful in RA. PMID:24354889

  18. Patient-Specific Pharmacokinetic Parameter Estimation on Dynamic Contrast-Enhanced MRI of Prostate: Preliminary Evaluation of a Novel AIF-Free Estimation Method

    PubMed Central

    Ginsburg, Shoshana B.; Taimen, Pekka; Merisaari, Harri; Vainio, Paula; Boström, Peter J.; Aronen, Hannu J.; Jambor, Ivan; Madabhushi, Anant

    2017-01-01

    Purpose To develop and evaluate a prostate-based method (PBM) for estimating pharmacokinetic parameters on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) by leveraging inherent differences in pharmacokinetic characteristics between the peripheral zone (PZ) and transition zone (TZ). Materials and Methods This retrospective study, approved by the Institutional Review Board, included 40 patients who underwent a multiparametric 3T MRI examination and subsequent radical prostatectomy. A two-step PBM for estimating pharmacokinetic parameters exploited the inherent differences in pharmacokinetic characteristics associated with the TZ and PZ. First, the reference region model was implemented to estimate ratios of Ktrans between normal TZ and PZ. Subsequently, the reference region model was leveraged again to estimate values for Ktrans and ve for every prostate voxel. The parameters of PBM were compared with those estimated using an arterial input function (AIF) derived from the femoral arteries. The ability of the parameters to differentiate prostate cancer (PCa) from benign tissue was evaluated on a voxel and lesion level. Additionally, the effect of temporal downsampling of the DCE MRI data was assessed. Results Significant differences (P < 0.05) in PBM Ktrans between PCa lesions and benign tissue were found in 26/27 patients with TZ lesions and in 33/38 patients with PZ lesions; significant differences in AIF-based Ktrans occurred in 26/27 and 30/38 patients, respectively. The 75th and 100th percentiles of Ktrans and ve estimated using PBM positively correlated with lesion size (P < 0.05). Conclusion Pharmacokinetic parameters estimated via PBM outperformed AIF-based parameters in PCa detection. PMID:27285161

  19. Metabolism and pharmacokinetics of selected halon replacement candidates.

    PubMed

    Dodd, D E; Brashear, W T; Vinegar, A

    1993-05-01

    Metabolism studies were conducted using Fischer 344 and Sprague-Dawley rats following inhalation exposure to 1.0% (v/v) air atmospheres of 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123), 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124), 1-chloro-1,1-difluoroethane (HCFC-142b), bromochlorodifluoromethane (Halon 1211), and perfluorohexane (PFH) for 2 h. There were no remarkable differences in results between the two strains of rats. Animals exposed to HCFC-123 or HCFC-124 excreted trifluoroacetic acid in their urine. Urinary fluoride concentrations were increased in rats exposed to HCFC-124, and urinary bromide levels were increased in rats exposed to Halon 1211. Small quantities of volatile metabolites 2-chloro-1,1,1-trifluoroethane (HCFC-133a) and 2-chloro-1,1-difluoroethylene were observed in the livers of rats exposed to HCFC-123. Rats exposed to HCFC-142b excreted chlorodifluoroacetic acid in their urine; no volatile metabolites were detected in tissue samples. For PFH studies, no metabolites were detected in the urine or tissues of exposed animals. These results are consistent with proposed oxidative and reductive pathways of metabolism for these chemicals. Pharmacokinetic studies were carried out in rats exposed by inhalation to 1.0%, 0.1%, or 0.01% of HCFC-123. Following exposure, blood concentrations of HCFC-123 fell sharply, whereas trifluoroacetic acid levels rose for approx. 5 h and then declined gradually. Using a physiologically based pharmacokinetic model, saturation of HCFC-123 metabolism was estimated to occur at approx. 0.2% (2000 ppm) HCFC-123.

  20. Obesity and skin and soft tissue infections: how to optimize antimicrobial usage for prevention and treatment?

    PubMed

    Grupper, Mordechai; Nicolau, David P

    2017-04-01

    Skin and soft tissue infections (SSTIs) are prevalent in the obese population, with rising trend expected. Although numerous antibiotics are available for the prevention and treatment of SSTIs, their characterization in obese patients is not a regulatory mandate. Consequently, information that carries importance for optimizing the dosing regimen in the obese population may not be readily available. This review focuses on the most recent pharmacokinetic and pharmacodynamic data on this topic with attention to cefazolin for surgical prophylaxis as well as antibiotics that are active against methicillin-resistant Staphylococcus aureus (MRSA). Moreover, the implications for optimizing SSTIs prevention and treatment in the obese population will also be discussed. On the basis of pharmacokinetic/pharmacodynamic considerations, most studies found a perioperative prophylactic cefazolin regimen of 2 g to be reasonable in the case of obese patients undergoing cesarean delivery or bariatric surgery. There is general paucity of data regarding the pharmacokinetic/pharmacodynamic characteristics of antimicrobials active against MRSA in obese patients, especially for the target tissue. Therapeutic drug monitoring has been correlated with pharmacokinetic/pharmacodynamic optimization for vancomycin and teicoplanin, and should be used in these cases. There is more supportive evidence for the use of oxazolidinones (linezolid and tedizolid), daptomycin and lipoglycopeptides (telavancin, dalbavancin and oritavancin) in the management of SSTIs in this population. The pharmacokinetic/pharmacodynamic approach, which can be used as a basis or supplement to clinical trials, provides valuable data and decision-making tools for optimizing regimens used for both prevention and treatment of SSTIs in the obese population. Important pharmacokinetic/pharmacodynamic characteristics of antibiotics, such as the penetration into the subcutaneous tissue and the probability of reaching the

  1. Photon beam dose distributions for patients with implanted temporary tissue expanders

    NASA Astrophysics Data System (ADS)

    Asena, A.; Kairn, T.; Crowe, S. B.; Trapp, J. V.

    2015-01-01

    This study examines the effects of temporary tissue expanders (TTEs) on the dose distributions of photon beams in breast cancer radiotherapy treatments. EBT2 radiochromic film and ion chamber measurements were taken to quantify the attenuation and backscatter effects of the inhomogeneity. Results illustrate that the internal magnetic port present in a tissue expander causes a dose reduction of approximately 25% in photon tangent fields immediately downstream of the implant. It was also shown that the silicone elastomer shell of the tissue expander reduced the dose to the target volume by as much as 8%. This work demonstrates the importance for an accurately modelled high-density implant in the treatment planning system for post-mastectomy breast cancer patients.

  2. Comparative experimental pharmacokinetics of benzimidazole derivatives.

    PubMed

    Sergeeva, S A; Gulyaeva, I L

    2008-12-01

    Comparative study of experimental kinetics of distribution of benzimidazole derivatives (bemithyl, etomerzole, and thietazole) in organs and tissues was carried out after single and course treatment. The drugs intensely passed into organs and tissues from the blood after treatment by all protocols. Specific features of drug distribution were detected; for example, splenic tissue selectively accumulated thietazole during course treatment.

  3. Innovations and Improvements in Pharmacokinetic Models Based on Physiology.

    PubMed

    Abbiati, Roberto Andrea; Manca, Davide

    2017-01-01

    Accompanied by significant improvements of modeling techniques and computational methods in medical sciences, the last thirty years saw the flourishing of pharmacokinetic models for applications in the pharmacometric field. In particular, physiologically based pharmacokinetic (PBPK) models, grounded on a mechanistic foundation, have been applied to explore a multiplicity of aspects with possible applications in patient care and new drugs development, as in the case of siRNA therapies. This article summarizes the features we recently introduced in PBPK modeling within a threeyear research project funded by Italian Research Ministry. Four major points are detailed: (i) the mathematical formulation of the model, which allows modulating its complexity as a function of the administration route and active principle; (ii) a dedicated parameter of the PBPK model quantifies the drugprotein binding, which affects the active principle distribution; (iii) the gall bladder compartment and the bile enterohepatic circulation process; (iv) the coupling of the pharmacokinetic and pharmacodynamic models to produce an overall understanding of the drug effects on mammalian body. The proposed model is applied to two separate endovenous (remifentanil) and oral (sorafenib) drug administrations. The resulting PBPK simulations are consistent with the literature experimental data. Blood concentration predictability is confirmed in multiple reference subjects. Furthermore, in case of sorafenib administration in mice, it is possible to evaluate the drug concentration in the liver and reproduce the effects of the enterohepatic circulation. Finally, a preliminary application of the coupling of the pharmacokinetic/pharmacodynamic models is presented and discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Pharmacokinetic Properties of Memantine after a Single Intraperitoneal Administration and Multiple Oral Doses in Euploid Mice and in the Ts65Dn Mouse Model of Down's Syndrome.

    PubMed

    Victorino, Daniella B; Bederman, Ilya R; Costa, Alberto C S

    2017-11-01

    Memantine is a drug approved for the treatment of moderate-to-severe Alzheimer's disease (AD), and there is ongoing research on the potential expansion of its clinical applicability. Published data on the pharmacokinetics of memantine in the mouse are still incomplete, particularly for chronic administration regimens and mouse models of specific genetic disorders. Down's syndrome (DS) is a genetic disorder known to affect multiple organs and systems, with the potential to alter significantly drug pharmacokinetics. Here, we describe a simple, efficient and sensitive GC/MS-based procedure for the determination of memantine concentrations in murine blood and tissue samples. We analysed pharmacokinetic properties of memantine, particularly its distribution in blood, brain and liver in the Ts65Dn mouse model of DS and euploid F1 hybrid mice after single intraperitoneal administrations of increasing doses of this drug. We also determined steady-state memantine concentrations in plasma, brain and liver after chronic oral administration of this drug in adult male Ts65Dn mice, euploid littermate controls and nursing or pregnant Ts65Dn mice. Our results revalidated the acute dose of memantine used in previously published work, determined the appropriate amount of memantine to be mixed into mouse chow to achieve steady and pharmacologically relevant plasma and tissue levels of this drug and demonstrated that memantine can be transferred from mother to offspring via maternal milk and placenta. Most of these findings are potentially applicable not only to the study of DS but also to other neurodevelopmental and neurodegenerative disorders. © 2017 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  5. SU-E-I-44: Some Preliminary Analysis of Angular Distribution of X-Ray Scattered On Soft Tissues

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ganezer, K; Krmar, M; Cvejic, Z

    2015-06-15

    Purpose: The angular distribution of x-radiation scattered at small angles (up to 16 degrees) from several different animal soft tissue (skin, fat, muscle, retina, etc) were measured using standard equipment devoted to study of crystal structure which provides excellent geometry conditions of measurements. showed measurable differences for different tissues. In the simplest possible case when measured samples do not differ in structure (different concentration solutions) it can be seen that intensity of scattered radiation is decreasing function of the concentration and the peak of the maximum of scattering distribution depends on the concentration as well. Methods: An x-ray scattering profilemore » usually consists of sharp diffraction peak; however some properties of the spatial profiles of scattered radiation as intensity, the peak position, height, area, FWHM, the ratio of peak heights, etc. Results: The data contained measurable differences for different tissues. In the simplest possible case when measured samples do not differ in structure (different concentration solutions) it can be seen that intensity of scattered radiation is decreasing function of the concentration and the peak of the maximum of scattering distribution depends on the concentration as well. Measurements of different samples in the very preliminary phase showed that simple biological material used in study showed slightly different scattering pattern, especially at higher angles (around 10degrees). Intensity of radiation scattered from same tissue type is very dependent on water content and several more parameters. Conclusion: This preliminary study using animal soft tissues on the angular distributions of scattered x-rays suggests that angular distributions of X-rays scattered off of soft tissues might be useful in distinguishing healthy tissue from malignant soft tissue.« less

  6. Modeling Human Exposure to Indoor Contaminants: External Source to Body Tissues.

    PubMed

    Webster, Eva M; Qian, Hua; Mackay, Donald; Christensen, Rebecca D; Tietjen, Britta; Zaleski, Rosemary

    2016-08-16

    Information on human indoor exposure is necessary to assess the potential risk to individuals from many chemicals of interest. Dynamic indoor and human physicologically based pharmacokinetic (PBPK) models of the distribution of nonionizing, organic chemical concentrations in indoor environments resulting in delivered tissue doses are developed, described and tested. The Indoor model successfully reproduced independently measured, reported time-dependent air concentrations of chloroform released during showering and of 2-butyoxyethanol following use of a volatile surface cleaner. The Indoor model predictions were also comparable to those from a higher tier consumer model (ConsExpo 4.1) for the surface cleaner scenario. The PBPK model successful reproduced observed chloroform exhaled air concentrations resulting from an inhalation exposure. Fugacity based modeling provided a seamless description of the partitioning, fluxes, accumulation and release of the chemical in indoor media and tissues of the exposed subject. This has the potential to assist in health risk assessments, provided that appropriate physical/chemical property, usage characteristics, and toxicological information are available.

  7. Relative sensitivities of DCE-MRI pharmacokinetic parameters to arterial input function (AIF) scaling

    NASA Astrophysics Data System (ADS)

    Li, Xin; Cai, Yu; Moloney, Brendan; Chen, Yiyi; Huang, Wei; Woods, Mark; Coakley, Fergus V.; Rooney, William D.; Garzotto, Mark G.; Springer, Charles S.

    2016-08-01

    Dynamic-Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) has been used widely for clinical applications. Pharmacokinetic modeling of DCE-MRI data that extracts quantitative contrast reagent/tissue-specific model parameters is the most investigated method. One of the primary challenges in pharmacokinetic analysis of DCE-MRI data is accurate and reliable measurement of the arterial input function (AIF), which is the driving force behind all pharmacokinetics. Because of effects such as inflow and partial volume averaging, AIF measured from individual arteries sometimes require amplitude scaling for better representation of the blood contrast reagent (CR) concentration time-courses. Empirical approaches like blinded AIF estimation or reference tissue AIF derivation can be useful and practical, especially when there is no clearly visible blood vessel within the imaging field-of-view (FOV). Similarly, these approaches generally also require magnitude scaling of the derived AIF time-courses. Since the AIF varies among individuals even with the same CR injection protocol and the perfect scaling factor for reconstructing the ground truth AIF often remains unknown, variations in estimated pharmacokinetic parameters due to varying AIF scaling factors are of special interest. In this work, using simulated and real prostate cancer DCE-MRI data, we examined parameter variations associated with AIF scaling. Our results show that, for both the fast-exchange-limit (FXL) Tofts model and the water exchange sensitized fast-exchange-regime (FXR) model, the commonly fitted CR transfer constant (Ktrans) and the extravascular, extracellular volume fraction (ve) scale nearly proportionally with the AIF, whereas the FXR-specific unidirectional cellular water efflux rate constant, kio, and the CR intravasation rate constant, kep, are both AIF scaling insensitive. This indicates that, for DCE-MRI of prostate cancer and possibly other cancers, kio and kep may be more suitable imaging

  8. Relative sensitivities of DCE-MRI pharmacokinetic parameters to arterial input function (AIF) scaling.

    PubMed

    Li, Xin; Cai, Yu; Moloney, Brendan; Chen, Yiyi; Huang, Wei; Woods, Mark; Coakley, Fergus V; Rooney, William D; Garzotto, Mark G; Springer, Charles S

    2016-08-01

    Dynamic-Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) has been used widely for clinical applications. Pharmacokinetic modeling of DCE-MRI data that extracts quantitative contrast reagent/tissue-specific model parameters is the most investigated method. One of the primary challenges in pharmacokinetic analysis of DCE-MRI data is accurate and reliable measurement of the arterial input function (AIF), which is the driving force behind all pharmacokinetics. Because of effects such as inflow and partial volume averaging, AIF measured from individual arteries sometimes require amplitude scaling for better representation of the blood contrast reagent (CR) concentration time-courses. Empirical approaches like blinded AIF estimation or reference tissue AIF derivation can be useful and practical, especially when there is no clearly visible blood vessel within the imaging field-of-view (FOV). Similarly, these approaches generally also require magnitude scaling of the derived AIF time-courses. Since the AIF varies among individuals even with the same CR injection protocol and the perfect scaling factor for reconstructing the ground truth AIF often remains unknown, variations in estimated pharmacokinetic parameters due to varying AIF scaling factors are of special interest. In this work, using simulated and real prostate cancer DCE-MRI data, we examined parameter variations associated with AIF scaling. Our results show that, for both the fast-exchange-limit (FXL) Tofts model and the water exchange sensitized fast-exchange-regime (FXR) model, the commonly fitted CR transfer constant (K(trans)) and the extravascular, extracellular volume fraction (ve) scale nearly proportionally with the AIF, whereas the FXR-specific unidirectional cellular water efflux rate constant, kio, and the CR intravasation rate constant, kep, are both AIF scaling insensitive. This indicates that, for DCE-MRI of prostate cancer and possibly other cancers, kio and kep may be more suitable imaging

  9. Pharmacokinetic study of darbepoetin alfa: absorption, distribution, and excretion after a single intravenous and subcutaneous administration to rats.

    PubMed

    Yoshioka, E; Kato, K; Shindo, H; Mitsuoka, C; Kitajima, S-I; Ogata, H; Misaizu, T

    2007-01-01

    KRN321 is a hyperglycosylated analogue of recombinant human erythropoietin (rHuEPO, epoetin alfa), and its absorption, distribution, and excretion have been studied after a single intravenous and subcutaneous administration of 125I-KRN321 at a dose of 0.5 microg kg-1 to male rats. The half-lives of immunoreactive radioactivity in the terminal phase after intravenous and subcutaneous administration were 14.05 and 14.36 h, respectively, and the bioavailability rate after subcutaneous administration was 47%. The total radioactivity in tissues was lower than that in the serum in all tissues excluding the thyroid gland and skin at the injection site (subcutaneous administration). The maximum concentrations were observed in the bone marrow or skin at the injection site followed by the thyroid gland, kidneys, adrenal glands, spleen, lungs, stomach and bladder. The radioactivity found in trichloroacetic acid-precipitated fractions suggested that a high-molecular weight compound, unchanged or mixed with endogenous protein, distributed to the tissues after administration. The whole-body autoradiographic findings in both groups were in agreement with the tissue distribution mentioned above. The blood cell uptake of KRN321 was low for both groups. The excretion ratios of radioactivity into urine and faeces up to 168 h were 71.4 and 14.1% after the intravenous administration and 74.9 and 12.0% after the subcutaneous administration. There was no difference in the excretion profile of radioactivity between the two groups.

  10. SUITABILITY OF USING IN VITRO AND COMPUTATIONALLY ESTIMATED PARAMETERS IN SIMPLIFIED PHARMACOKINETIC MODELS

    EPA Science Inventory

    A challenge in PBPK model development is estimating the parameters for absorption, distribution, metabolism, and excretion of the parent compound and metabolites of interest. One approach to reduce the number of parameters has been to simplify pharmacokinetic models by lumping p...

  11. Distribution and Metabolism of Lipocurc™ (Liposomal Curcumin) in Dog and Human Blood Cells: Species Selectivity and Pharmacokinetic Relevance.

    PubMed

    Bolger, Gordon T; Licollari, Albert; Tan, Aimin; Greil, Richard; Vcelar, Brigitta; Majeed, Muhammad; Helson, Lawrence

    2017-07-01

    The aim of this study was to investigate the distribution of curcumin (in the form of Lipocurc™) and its major metabolite tetrahydrocurcumin (THC) in Beagle dog and human red blood cells, peripheral blood mononuclear cells (PBMC) and hepatocytes. Lipocurc™ was used as the source of curcumin for the cell distribution assays. In vitro findings with red blood cells were also compared to in vivo pharmacokinetic data available from preclinical studies in dogs and phase I clinical studies in humans. High levels of curcumin were measured in PBMCs (625.5 ng/g w.w. cell pellet or 7,297 pg/10 6 cells in dog and 353.7 ng/g w.w. cell pellet or 6,809 pg/10 6 cells in human) and in hepatocytes (414.5 ng/g w.w. cell pellet or 14,005 pg/10 6 cells in dog and 813.5 ng/g w.w. cell pellet or 13,780 pg/10 6 cells in human). Lower curcumin levels were measured in red blood cells (dog: 78.4 ng/g w.w. cell pellet or 7.2 pg/10 6 cells, human: 201.5 ng/g w.w. cell pellet or 18.6 pg/10 6 cells). A decrease in the medium concentration of curcumin was observed in red blood cells and hepatocytes, but not in PBMCs. Red blood cell levels of THC were ~5-fold higher in dog compared to human and similar between dog and human for hepatocytes and PBMCs. The ratio of THC to curcumin found in the red blood cell medium following incubation was 6.3 for dog compared to 0.006 for human, while for PBMCs and hepatocytes the ratio of THC to curcumin in the medium did not display such marked species differences. There was an excellent correlation between the in vitro disposition of curcumin and THC following incubation with red blood cells and in vivo plasma levels of curcumin and THC in dog and human following intravenous infusion. The disposition of curcumin in blood cells is, therefore, species-dependent and of pharmacokinetic relevance. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  12. Pharmacokinetics of hederacoside C, an active ingredient in AG NPP709, in rats.

    PubMed

    Kim, Ju Myung; Yoon, Ji Na; Jung, Ji Won; Choi, Hye Duck; Shin, Young June; Han, Chang Kyun; Lee, Hye Suk; Kang, Hee Eun

    2013-11-01

    1. Hederacoside C (HDC) is one of the active ingredients in Hedera helix leaf extract (Ivy Ex.) and AG NPP709, a new botanical drug to treat acute respiratory infection and chronic inflammatory bronchitis. However, information regarding its pharmacokinetic properties remains limited. 2. Here, we report the pharmacokinetics of HDC in rats after intravenous administration of HDC (3, 12.5, and 25 mg/kg) and after oral administration of HDC, Ivy Ex., and AG NPP709 (equivalent to 12.5, 25, and 50 mg/kg HDC). 3. Linear pharmacokinetics of HDC were identified upon its intravenous administration at doses of 3-25 mg/kg. Intravenous administration of HDC results in relatively slow clearance (1.46-2.08 mL/min/kg) and a small volume of distribution at steady state (138-222 mL/kg), while oral administration results in a low absolute oral bioavailability (F) of 0.118-0.250%. The extremely low F of HDC may be due to poor absorption of HDC from the gastrointestinal (GI) tract and/or its decomposition therein. 4. The oral pharmacokinetics of HDC did not differ significantly among pure HDC, Ivy Ex., and AG NPP709.

  13. Pharmacokinetics of fluralaner in dogs following a single oral or intravenous administration.

    PubMed

    Kilp, Susanne; Ramirez, Diana; Allan, Mark J; Roepke, Rainer K A; Nuernberger, Martin C

    2014-03-07

    Fluralaner is a novel systemic insecticide and acaricide. The purpose of these studies was to investigate the pharmacokinetic properties of fluralaner in Beagle dogs following single oral or intravenous (i.v.) administration. Following the oral administration of 12.5, 25 or 50 mg fluralaner/kg body weight (BW), formulated as chewable tablets or i.v. administration of 12.5 mg fluralaner/kg BW, formulated as i.v. solution to 24 Beagles, plasma samples were collected until 112 days after treatment. Plasma concentrations of fluralaner were measured using HPLC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods. After oral administration, maximum plasma concentrations (C(max)) were reached within 1 day on average. Fluralaner was quantifiable in plasma for up to 112 days after single oral and i.v. treatment. The apparent half-life of fluralaner was 12-15 days and the mean residence time was 15-20 days. The apparent volume of distribution of fluralaner was 3.1 L/kg, and clearance was 0.14 L/kg/day. Fluralaner is readily absorbed after single-dose oral administration, and has a long elimination half-life, long mean residence time, relatively high apparent volume of distribution, and low clearance. These pharmacokinetic characteristics help to explain the prolonged activity of fluralaner against fleas and ticks on dogs after a single oral dose.

  14. Covariates of intravenous paracetamol pharmacokinetics in adults

    PubMed Central

    2014-01-01

    Background Pharmacokinetic estimates for intravenous paracetamol in individual adult cohorts are different to a certain extent, and understanding the covariates of these differences may guide dose individualization. In order to assess covariate effects of intravenous paracetamol disposition in adults, pharmacokinetic data on discrete studies were pooled. Methods This pooled analysis was based on 7 studies, resulting in 2755 time-concentration observations in 189 adults (mean age 46 SD 23 years; weight 73 SD 13 kg) given intravenous paracetamol. The effects of size, age, pregnancy and other clinical settings (intensive care, high dependency, orthopaedic or abdominal surgery) on clearance and volume of distribution were explored using non-linear mixed effects models. Results Paracetamol disposition was best described using normal fat mass (NFM) with allometric scaling as a size descriptor. A three-compartment linear disposition model revealed that the population parameter estimates (between subject variability,%) were central volume (V1) 24.6 (55.5%) L/70 kg with peripheral volumes of distribution V2 23.1 (49.6%) L/70 kg and V3 30.6 (78.9%) L/70 kg. Clearance (CL) was 16.7 (24.6%) L/h/70 kg and inter-compartment clearances were Q2 67.3 (25.7%) L/h/70 kg and Q3 2.04 (71.3%) L/h/70 kg. Clearance and V2 decreased only slightly with age. Sex differences in clearance were minor and of no significance. Clearance, relative to median values, was increased during pregnancy (FPREG = 1.14) and decreased during abdominal surgery (FABDCL = 0.715). Patients undergoing orthopaedic surgery had a reduced V2 (FORTHOV = 0.649), while those in intensive care had increased V2 (FICV = 1.51). Conclusions Size and age are important covariates for paracetamol pharmacokinetics explaining approximately 40% of clearance and V2 variability. Dose individualization in adult subpopulations would achieve little benefit in the scenarios explored. PMID:25342929

  15. Physiologically based pharmacokinetic modeling of a homologous series of barbiturates in the rat: a sensitivity analysis.

    PubMed

    Nestorov, I A; Aarons, L J; Rowland, M

    1997-08-01

    Sensitivity analysis studies the effects of the inherent variability and uncertainty in model parameters on the model outputs and may be a useful tool at all stages of the pharmacokinetic modeling process. The present study examined the sensitivity of a whole-body physiologically based pharmacokinetic (PBPK) model for the distribution kinetics of nine 5-n-alkyl-5-ethyl barbituric acids in arterial blood and 14 tissues (lung, liver, kidney, stomach, pancreas, spleen, gut, muscle, adipose, skin, bone, heart, brain, testes) after i.v. bolus administration to rats. The aims were to obtain new insights into the model used, to rank the model parameters involved according to their impact on the model outputs and to study the changes in the sensitivity induced by the increase in the lipophilicity of the homologues on ascending the series. Two approaches for sensitivity analysis have been implemented. The first, based on the Matrix Perturbation Theory, uses a sensitivity index defined as the normalized sensitivity of the 2-norm of the model compartmental matrix to perturbations in its entries. The second approach uses the traditional definition of the normalized sensitivity function as the relative change in a model state (a tissue concentration) corresponding to a relative change in a model parameter. Autosensitivity has been defined as sensitivity of a state to any of its parameters; cross-sensitivity as the sensitivity of a state to any other states' parameters. Using the two approaches, the sensitivity of representative tissue concentrations (lung, liver, kidney, stomach, gut, adipose, heart, and brain) to the following model parameters: tissue-to-unbound plasma partition coefficients, tissue blood flows, unbound renal and intrinsic hepatic clearance, permeability surface area product of the brain, have been analyzed. Both the tissues and the parameters were ranked according to their sensitivity and impact. The following general conclusions were drawn: (i) the overall

  16. Investigation of the cytotoxicity, apoptosis and pharmacokinetics of Raddeanin A.

    PubMed

    Gu, Guiying; Qi, Huanhuan; Jiang, Tianyue; Ma, Bo; Fang, Zheng; Xu, Hong; Zhang, Qi

    2017-03-01

    Raddeanin A, one of the triterpenoid saponins extracted from Anemone raddeana rhizome of the Ranunculaceae family, has demonstrated the ability to inhibit the growth of human hepatic and gastric cancer cells. However, the effects of Raddeanin A on human colon cancer cells have not been investigated extensively. The present study aimed to examine the antiproliferative and apoptosis-inducing effects of Raddeanin A on the HCT-116 human colon cancer cell line in vitro , and evaluate the pharmacokinetic and biodistribution properties of Raddeanin A in mice following a single oral administration. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to assess the in vitro cytotoxicity of Raddeanin A against HCT-116 cells. 4',6-Diamidino-2-phenylindole, dihydrochloride staining and flow cytometry were performed to further examine the apoptosis-inducing capability of Raddeanin A. The concentrations of Raddeanin A in the plasma and tissues were analyzed using liquid chromatography-tandem mass spectrometry. Raddeanin A showed a dose-dependent antiproliferative effect towards the HCT-116 cells, with a half maximal inhibitory concentration of ~1.4 µM. Treatment with Raddeanin A resulted in a significant induction of apoptosis, observed as apparent morphological changes of the nuclei, with a total apoptotic ratio of 41.8% at a concentration of 3 µM. Low concentrations of Raddeanin A were detected in the heart, liver, spleen, lung, kidney and plasma of the mice following oral administration, however, the majority of the Raddeanin A was distributed in the intestinal tract, particularly in the colon and caecum. These present study confirmed the growth-inhibitory and apoptosis-inducing effects of Raddeanin A on HCT-116 cells and performed preliminary examinations of its pharmacokinetic properties, which provide a foundation for further investigating the inhibitory mechanism on the colon cancer cells in vivo .

  17. Evaluation of Aztreonam Dosing Regimens in Patients With Normal and Impaired Renal Function: A Population Pharmacokinetic Modeling and Monte Carlo Simulation Analysis.

    PubMed

    Xu, Hongmei; Zhou, Wangda; Zhou, Diansong; Li, Jianguo; Al-Huniti, Nidal

    2017-03-01

    Aztreonam is a monocyclic β-lactam antibiotic often used to treat infections caused by Enterobacteriaceae or Pseudomonas aeruginosa. Despite the long history of clinical use, population pharmacokinetic modeling of aztreonam in renally impaired patients is not yet available. The aims of this study were to assess the impact of renal impairment on aztreonam exposure and to evaluate dosing regimens for patients with renal impairment. A population model describing aztreonam pharmacokinetics following intravenous administration was developed using plasma concentrations from 42 healthy volunteers and renally impaired patients from 2 clinical studies. The final pharmacokinetic model was used to predict aztreonam plasma concentrations and evaluate the probability of pharmacodynamic target attainment (PTA) in patients with different levels of renal function. A 2-compartment model with first-order elimination adequately described aztreonam pharmacokinetics. The population mean estimates of aztreonam clearance, intercompartmental clearance, volume of distribution of the central compartment, and volume of distribution of the peripheral compartment were 4.93 L/h, 9.26 L/h, 7.43 L, and 6.44 L, respectively. Creatinine clearance and body weight were the most significant variables to explain patient variability in aztreonam clearance and volume of distribution, respectively. Simulations using the final pharmacokinetic model resulted in a clinical susceptibility break point of 4 and 8 mg/L, respectively, based on the clinical use of 1- and 2-g loading doses with the same or reduced maintenance dose every 8 hours for various renal deficiency patients. The population pharmacokinetic modeling and PTA estimation support adequate PTAs (>90% PTA) from the aztreonam label for dose adjustment of aztreonam in patients with moderate and severe renal impairment. © 2016, The American College of Clinical Pharmacology.

  18. Ketorolac pharmacokinetics in experimental cirrhosis by bile duct ligation in the rat.

    PubMed

    Rivera-Espinosa, Liliana; Muriel, Pablo; Ordaz Gallo, Mónica; Pérez-Urizar, José; Palma-Aguirre, Antonio; Castañeda-Hernández, Gilberto

    2003-01-01

    The purpose of the present work was to study the pharmacokinetics of ketorolac, a poorly metabolized drug, in experimental cirrhosis. Cirrhosis was induced by bile duct ligation (BDL) for four weeks in male Wistar rats. Ketorolac was given intravenously (1 mg/kg ) or orally (3.2 mg/kg) to control (sham-operated) and BDL-rats. Determination of ketorolac in plasma was carried out by HPLC and estimation of pharmacokinetic parameters was performed by non-compartmental analysis. Indicators of liver damage and liver fibrosis were significantly increased (p < 0.05) in BDL compared to control rats. Experimental cirrhosis did not induce any significant alteration in intravenous ketorolac pharmacokinetics. Volume of distribution, clearance, AUC and t1/2 were similar in BDL and control animals. Notwithstanding, oral ketorolac bioavailability was significantly altered in BDL rats. AUC and Cmax were reduced, while tmax was prolonged, suggesting that both, the extent and the rate of ketorolac absorption were decreased. Results show that liver cirrhosis may result in significant pharmacokinetic alterations, even for poorly bio-transformed drugs, but that alterations may vary with the route of administration. In conclusion, uncritical generalizations on the effect of liver damage on drug kinetics should be avoided and systematic studies for every drug and every route of administration are thus recommended.

  19. Population pharmacokinetics of intravenous busulfan in patients undergoing hematopoietic stem cell transplantation.

    PubMed

    Takama, H; Tanaka, H; Nakashima, D; Ueda, R; Takaue, Y

    2006-02-01

    A population pharmacokinetic analysis was performed in 30 patients who received an intravenous busulfan and cyclophosphamide regimen before hematopoietic stem cell transplantation. Each patient received 0.8 mg/kg as a 2 h infusion every 6 h for 16 doses. A total of 690 concentration measurements were analyzed using the nonlinear mixed effect model (NONMEM) program. A one-compartment model with an additive error model as an intraindividual variability including an interoccasion variability (IOV) in clearance (CL) was sufficient to describe the concentration-time profile of busulfan. Actual body weight (ABW) was found to be the determinant for CL and the volume of distribution (V) according to NONMEM analysis. In this limited study, the age (range 7-53 years old; median, 30 years old) had no significant effect on busulfan pharmacokinetics. For a patient weighting 60 kg, the typical CL and V were estimated to be 8.87 l/h and 33.8 l, respectively. The interindividual variability of CL and V were 13.6 and 6.3%, respectively. The IOV (6.6%) in CL was estimated to be less than the intraindividual variability. These results indicate high interpatient and intrapatient consistency of busulfan pharmacokinetics after intravenous administration, which may eliminate the requirement for pharmacokinetic monitoring.

  20. Pharmacokinetics of ranitidine in preterm and term neonates with gastroesophageal reflux.

    PubMed

    Asseff, Ismael Lares; Gaucin, Graciela Benitez; Olguín, Hugo Juárez; Nájera, Jose Antonio Godinez; López, Alejandra Toledo; Guillé, Gabriela Pérez; Torres, Fausto Zamura

    2016-07-13

    The aim of this study was to determine the effect of gestational age on pharmacokinetics of ranitidine in newborns with gastroesophageal reflux. A prospective, descriptive and pharmacokinetic study was carried out in 30 pre-term and 20 full-term babies. 3 mg/kg of ranitidine was administered intravenously to all the babies and at 0.25, 0.5, 1, 2, 4, and 8 h following the administration, samples of blood were drawn to assess ranitidine levels using high performance liquid chromatographic technique. Pharmacokinetics of ranitidine had a bi-exponential behavior with a half-life elimination of (t1/2el) 2.79 h, area under curve (AUC) of 1688 ng/mL, volume of distribution (Vd) of 1.44 L/kg, and clearance (Cl) of 5.9 L/kg/h. The median plasmatic concentration in pre-terms was 1113 ng/mL and 280 ng/mL in full-terms. Vd, t1/2 and Cl presented high values in preterm although the correlation of Cl with glomerular filtration in term newborns was better. Plasma levels of ranitidine depend on the gestational age of the newborns. However, the possible relationship between after-birth age and pharmacokinetics of the neonates as their internal organs get matured without minding their gestational background.

  1. Formulation, pharmacokinetics and pharmacodynamics of topical microbicides

    PubMed Central

    Adams, Jessica L.; Kashuba, Angela D.M.

    2013-01-01

    The development of safe topical microbicides that effectively prevent human immunodeficiency virus (HIV) infection is a major goal in curbing the human immunodeficiency virus pandemic. A number of past failures resulting from mucosal toxicity or lack of efficacy have informed the field. Products that caused toxicity to the female genital tract mucosa, and thereby increased the likelihood of HIV acquisition, included nonoxynol 9, cellulose sulfate, and C31 G vaginal gel Savvy®. Topical products that were ineffective in preventing HIV infection include BufferGel®, Carraguard®, and PRO 2000®. Antiretroviral drugs such as tenofovir and dapivirine formulated into microbicide products have shown promise, but there is much to learn about ideal product formulation and acceptability, and drug distribution and disposition (pharmacokinetics). Current formulations for water-soluble molecules include vaginally or rectally applied gels, vaginal rings, films and tablets. Dosing strategies (e.g. coitally dependent or independent) will be based on the pharmacokinetics of the active ingredient and the tolerance for less than perfect adherence. PMID:22306523

  2. Population pharmacokinetics of tafenoquine during malaria prophylaxis in healthy subjects.

    PubMed

    Charles, Bruce G; Miller, Ann K; Nasveld, Peter E; Reid, Mark G; Harris, Ivor E; Edstein, Michael D

    2007-08-01

    The population pharmacokinetics of tafenoquine were studied in Australian soldiers taking tafenoquine for malarial prophylaxis. The subjects (476 males and 14 females) received a loading dose of 200 mg tafenoquine base daily for 3 days, followed by a weekly dose of 200 mg tafenoquine for 6 months. Blood samples were collected from each subject after the last loading dose and then at weeks 4, 8, and 16. Plasma tafenoquine concentrations were determined by liquid chromatography-tandem mass spectrometry. Population modeling was performed with NONMEM, using a one-compartment model. Typical values of the first-order absorption rate constant (K(a)), clearance (CL/F), and volume of distribution (V/F) were 0.243 h(-1), 0.056 liters/h/kg, and 23.7 liters/kg, respectively. The intersubject variability (coefficient of variation) in CL/F and V/F was 18% and 22%, respectively. The interoccasion variability in CL/F was 18%, and the mean elimination half-life was 12.7 days. A positive linear association between weight and both CL/F and V/F was found, but this had insufficient impact to warrant dosage adjustments. Model robustness was assessed by a nonparametric bootstrap (200 samples). A degenerate visual predictive check indicated that the raw data mirrored the postdose concentration-time profiles simulated (n = 1,000) from the final model. Individual pharmacokinetic estimates for tafenoquine did not predict the prophylactic outcome with the drug for four subjects who relapsed with Plasmodium vivax malaria, as they had similar pharmacokinetics to those who were free of malaria infection. No obvious pattern existed between the plasma tafenoquine concentration and the pharmacokinetic parameter values for subjects with and without drug-associated moderate or severe adverse events. This validated population pharmacokinetic model satisfactorily describes the disposition and variability of tafenoquine used for long-term malaria prophylaxis in a large cohort of soldiers on military

  3. Population Pharmacokinetics of Tafenoquine during Malaria Prophylaxis in Healthy Subjects▿

    PubMed Central

    Charles, Bruce G.; Miller, Ann K.; Nasveld, Peter E.; Reid, Mark G.; Harris, Ivor E.; Edstein, Michael D.

    2007-01-01

    The population pharmacokinetics of tafenoquine were studied in Australian soldiers taking tafenoquine for malarial prophylaxis. The subjects (476 males and 14 females) received a loading dose of 200 mg tafenoquine base daily for 3 days, followed by a weekly dose of 200 mg tafenoquine for 6 months. Blood samples were collected from each subject after the last loading dose and then at weeks 4, 8, and 16. Plasma tafenoquine concentrations were determined by liquid chromatography-tandem mass spectrometry. Population modeling was performed with NONMEM, using a one-compartment model. Typical values of the first-order absorption rate constant (Ka), clearance (CL/F), and volume of distribution (V/F) were 0.243 h−1, 0.056 liters/h/kg, and 23.7 liters/kg, respectively. The intersubject variability (coefficient of variation) in CL/F and V/F was 18% and 22%, respectively. The interoccasion variability in CL/F was 18%, and the mean elimination half-life was 12.7 days. A positive linear association between weight and both CL/F and V/F was found, but this had insufficient impact to warrant dosage adjustments. Model robustness was assessed by a nonparametric bootstrap (200 samples). A degenerate visual predictive check indicated that the raw data mirrored the postdose concentration-time profiles simulated (n = 1,000) from the final model. Individual pharmacokinetic estimates for tafenoquine did not predict the prophylactic outcome with the drug for four subjects who relapsed with Plasmodium vivax malaria, as they had similar pharmacokinetics to those who were free of malaria infection. No obvious pattern existed between the plasma tafenoquine concentration and the pharmacokinetic parameter values for subjects with and without drug-associated moderate or severe adverse events. This validated population pharmacokinetic model satisfactorily describes the disposition and variability of tafenoquine used for long-term malaria prophylaxis in a large cohort of soldiers on military

  4. Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV-infected infants and toddlers

    PubMed Central

    Zhao, Wei; Cella, Massimo; Della Pasqua, Oscar; Burger, David; Jacqz-Aigrain, Evelyne

    2012-01-01

    AIMS To develop a population pharmacokinetic model for abacavir in HIV-infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration–time curve (AUC) targeted dosage and individualize therapy. METHODS The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with first-order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross-validation and simulation–estimation method. RESULTS The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 l h−1 (RSE 6.3%), apparent central volume of distribution 4.94 l (RSE 28.7%), apparent peripheral volume of distribution 8.12 l (RSE14.2%), apparent intercompartment clearance 1.25 l h−1 (RSE 16.9%) and absorption rate constant 0.758 h−1 (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC0–t. CONCLUSIONS The population pharmacokinetic model developed for abacavir in HIV-infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC0–t was developed from the final model and can be used routinely to optimize individual dosing. PMID:21988586

  5. Comparison of amikacin pharmacokinetics in a killer whale (Orcinus orca) and a beluga whale (Delphinapterus leucas).

    PubMed

    KuKanich, Butch; Papich, Mark; Huff, David; Stoskopf, Michael

    2004-06-01

    Amikacin, an aminoglycoside antimicrobial, was administered to a killer whale (Orcinus orca) and a beluga whale (Delphinapterus leucas) for the treatment of clinical signs consistent with gram-negative aerobic bacterial infections. Dosage regimens were designed to target a maximal plasma concentration 8-10 times the minimum inhibitory concentrations of the pathogen and to reduce the risk of aminoglycoside toxicity. Allometric analysis of published pharmacokinetic parameters in mature animals yielded a relationship for amikacin's volume of distribution, in milliliters, given by the equation Vd = 151.058(BW)1.043. An initial dose for amikacin was estimated by calculating the volume of distribution and targeted maximal concentration. With this information, dosage regimens for i.m. administration were designed for a killer whale and a beluga whale. Therapeutic drug monitoring was performed on each whale to assess the individual pharmacokinetic parameters. The elimination half-life (5.99 hr), volume of distribution per bioavailability (319 ml/kg). and clearance per bioavailability (0.61 ml/min/kg) were calculated for the killer whale. The elimination half-life (5.03 hr), volume of distribution per bioavailability (229 ml/kg). and clearance per bioavailability (0.53 ml/min/kg) were calculated for the beluga whale. The volume of distribution predicted from the allometric equation for both whales was similar to the calculated pharmacokinetic parameter. Both whales exhibited a prolonged elimination half-life and decreased clearance when compared with other animal species despite normal renal parameters on biochemistry panels. Allometric principles and therapeutic drug monitoring were used to accurately determine the doses in these cases and to avoid toxicity.

  6. A validated UPLC-MS/MS method for the analysis of linezolid and a novel oxazolidinone derivative (PH027) in plasma and its application to tissue distribution study in rabbits.

    PubMed

    Hedaya, Mohsen A; Thomas, Vidhya; Abdel-Hamid, Mohamed E; Kehinde, Elijah O; Phillips, Oludotun A

    2017-01-01

    Linezolid is the first approved oxazolidinone antibacterial agent, whereas PH027 is a novel compound of the same class that exhibits good in vitro antibacterial activity. The objective of this study was to develop an UPLC-MS/MS assay for the analysis of linezolid and PH027 in plasma and to apply the method for comparative pharmacokinetic and tissue distribution studies of both compounds. Plasma samples and calibrators were extracted with diethyl ether after addition of the internal standard solution. After evaporation of the ether layer, the residue was reconstituted in mobile phase and injected into UPLC-MS/MS. The mobile phase consisted of 2mM ammonium acetate buffer solution and acetonitrile (70:30) at a flow rate of 0.2ml/min. Separation was achieved using UPLC BEH C 18 column, and quantitative determination of the analytes was performed using multiple-reaction monitoring (MRM) scanning mode. The method was validated by analyzing quality control tissue homogenate samples, and was applied to analyze tissue homogenate samples obtained following IV injections of linezolid and PH027 in rabbits. The developed UPLC-MS/MS method was linear in the concentration range of 50-5000ng/ml. Validation of the method proved that the method's precision, selectivity and stability were all within the acceptable limits. Linezolid and PH027 concentrations were accurately determined in the quality control tissue homogenate samples, and analysis of samples obtained following IV administration of the two compounds showed that the tissue to plasma concentration ratio of PH027 was higher than that of linezolid probably due to its higher lipophilicity. The developed UPLC-MS/MS method for the analysis of linezolid and PH027 in rabbit's plasma can accurately determine the concentrations of these compounds in different tissues. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Efficacy, pharmacokinetics, and biodistribution of thermosensitive chitosan/β-glycerophosphate hydrogel loaded with docetaxel.

    PubMed

    Li, Cuiyun; Ren, Shuangxia; Dai, Yu; Tian, Fengjie; Wang, Xin; Zhou, Sufeng; Deng, Shuhua; Liu, Qi; Zhao, Jie; Chen, Xijing

    2014-04-01

    Docetaxel (DTX) is a widely used anticancer drug for various solid tumors. However, its poor solubility in water and lack of specification are two limitations for clinical use. The aim of the study was to develop a thermosensitive chitosan/β-glycerophosphate (C/GP) hydrogel loaded with DTX for intratumoral delivery. The in vitro release profiles, in vivo antitumor efficacy, pharmacokinetics, and biodistribution of DTX-loaded C/GP hydrogel (DTX-C/GP) were evaluated. The results of in vitro release study demonstrated that DTX-C/GP had the property of controlled delivery for a reasonable time span of 3 weeks and the release period was substantially affected by initial DTX strength. The antitumor efficacy of DTX-C/GP was observed at 20 mg/kg in H22 tumor-bearing mice. It was found that the tumor volume was definitely minimized by intratumoral injection of DTX-C/GP. Compared with saline group, the tumor inhibition rate of blank gel, intravenous DTX solution, intratumoral DTX solution, and DTX-C/GP was 2.3%, 29.8%, 41.9%, and 58.1%, respectively. Further, the in vivo pharmacokinetic characteristics of DTX-C/GP correlated well with the in vitro release. DTX-C/GP significantly prolonged the DTX retention and maintained a high DTX concentration in tumor. The amount of DTX distributed to the normal tissues was minimized so that the toxicity was effectively reduced. In conclusion, DTX-C/GP demonstrated controlled release and significant efficacy and exhibited potential for further clinical development.

  8. Population Pharmacokinetics of Fentanyl in the Critically Ill

    PubMed Central

    Choi, Leena; Ferrell, Benjamin A; Vasilevskis, Eduard E; Pandharipande, Pratik P; Heltsley, Rebecca; Ely, E Wesley; Stein, C Michael; Girard, Timothy D

    2016-01-01

    Objective To characterize fentanyl population pharmacokinetics in patients with critical illness and identify patient characteristics associated with altered fentanyl concentrations. Design Prospective cohort study. Setting Medical and surgical ICUs in a large tertiary care hospital in the United States. Patients Patients with acute respiratory failure and/or shock who received fentanyl during the first five days of their ICU stay. Measurements and Main Results We collected clinical and hourly drug administration data and measured fentanyl concentrations in plasma collected once daily for up to five days after enrollment. Among 337 patients, the mean duration of infusion was 58 hours at a median rate of 100 µg/hr. Using a nonlinear mixed-effects model implemented by NONMEM, we found fentanyl pharmacokinetics were best described by a two-compartment model in which weight, severe liver disease, and congestive heart failure most affected fentanyl concentrations. For a patient population with a mean weight of 92 kg and no history of severe liver disease or congestive heart failure, the final model, which performed well in repeated 10-fold cross-validation, estimated total clearance (CL), intercompartmental clearance (Q), and volumes of distribution for the central (V1) and peripheral compartments (V2) to be 35 (95% confidence interval: 32 to 39) L/hr, 55 (42 to 68) L/hr, 203 (140 to 266) L, and 523 (428 to 618) L, respectively. Severity of illness was marginally associated with fentanyl pharmacokinetics but did not improve the model fit after liver and heart disease were included. Conclusions In this study, fentanyl pharmacokinetics during critical illness were strongly influenced by severe liver disease, congestive heart failure, and weight, factors that should be considered when dosing fentanyl in the ICU. Future studies are needed to determine if data-driven fentanyl dosing algorithms can improve outcomes for ICU patients. PMID:26491862

  9. Bioavailability and Pharmacokinetics of Oral Cocaine in Humans.

    PubMed

    Coe, Marion A; Jufer Phipps, Rebecca A; Cone, Edward J; Walsh, Sharon L

    2018-06-01

    The pharmacokinetic profile of oral cocaine has not been fully characterized and prospective data on oral bioavailability are limited. A within-subject study was performed to characterize the bioavailability and pharmacokinetics of oral cocaine. Fourteen healthy inpatient participants (six males) with current histories of cocaine use were administered two oral doses (100 and 200 mg) and one intravenous (IV) dose (40 mg) of cocaine during three separate dosing sessions. Plasma samples were collected for up to 24 h after dosing and analyzed for cocaine and metabolites by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis, and a two-factor model was used to assess for dose and sex differences. The mean ± SEM oral cocaine bioavailability was 0.32 ± 0.04 after 100 and 0.45 ± 0.06 after 200 mg oral cocaine. Volume of distribution (Vd) and clearance (CL) were both greatest after 100 mg oral (Vd = 4.2 L/kg; CL = 116.2 mL/[min kg]) compared to 200 mg oral (Vd = 2.9 L/kg; CL = 87.5 mL/[min kg]) and 40 mg IV (Vd = 1.3 L/kg; CL = 32.7 mL/[min kg]). Oral cocaine area-under-thecurve (AUC) and peak concentration increased in a dose-related manner. AUC metabolite-to-parent ratios of benzoylecgonine and ecgonine methyl ester were significantly higher after oral compared to IV administration and highest after the lower oral dose. In addition, minor metabolites were detected in higher concentrations after oral compared to IV cocaine. Oral cocaine produced a pharmacokinetic profile different from IV cocaine, which appears as a rightward and downward shift in the concentration-time profile. Cocaine bioavailability values were similar to previous estimates. Oral cocaine also produced a unique metabolic profile, with greater concentrations of major and minor metabolites.

  10. Distribution, composition and functions of gelatinous tissues in deep-sea fishes.

    PubMed

    Gerringer, Mackenzie E; Drazen, Jeffrey C; Linley, Thomas D; Summers, Adam P; Jamieson, Alan J; Yancey, Paul H

    2017-12-01

    Many deep-sea fishes have a gelatinous layer, or subdermal extracellular matrix, below the skin or around the spine. We document the distribution of gelatinous tissues across fish families (approx. 200 species in ten orders), then review and investigate their composition and function. Gelatinous tissues from nine species were analysed for water content (96.53 ± 1.78% s.d.), ionic composition, osmolality, protein (0.39 ± 0.23%), lipid (0.69 ± 0.56%) and carbohydrate (0.61 ± 0.28%). Results suggest that gelatinous tissues are mostly extracellular fluid, which may allow animals to grow inexpensively. Further, almost all gelatinous tissues floated in cold seawater, thus their lower density than seawater may contribute to buoyancy in some species. We also propose a new hypothesis: gelatinous tissues, which are inexpensive to grow, may sometimes be a method to increase swimming efficiency by fairing the transition from trunk to tail. Such a layer is particularly prominent in hadal snailfishes (Liparidae); therefore, a robotic snailfish model was designed and constructed to analyse the influence of gelatinous tissues on locomotory performance. The model swam faster with a watery layer, representing gelatinous tissue, around the tail than without. Results suggest that the tissues may, in addition to providing buoyancy and low-cost growth, aid deep-sea fish locomotion.

  11. Distribution, composition and functions of gelatinous tissues in deep-sea fishes

    PubMed Central

    Drazen, Jeffrey C.; Linley, Thomas D.; Summers, Adam P.; Jamieson, Alan J.; Yancey, Paul H.

    2017-01-01

    Many deep-sea fishes have a gelatinous layer, or subdermal extracellular matrix, below the skin or around the spine. We document the distribution of gelatinous tissues across fish families (approx. 200 species in ten orders), then review and investigate their composition and function. Gelatinous tissues from nine species were analysed for water content (96.53 ± 1.78% s.d.), ionic composition, osmolality, protein (0.39 ± 0.23%), lipid (0.69 ± 0.56%) and carbohydrate (0.61 ± 0.28%). Results suggest that gelatinous tissues are mostly extracellular fluid, which may allow animals to grow inexpensively. Further, almost all gelatinous tissues floated in cold seawater, thus their lower density than seawater may contribute to buoyancy in some species. We also propose a new hypothesis: gelatinous tissues, which are inexpensive to grow, may sometimes be a method to increase swimming efficiency by fairing the transition from trunk to tail. Such a layer is particularly prominent in hadal snailfishes (Liparidae); therefore, a robotic snailfish model was designed and constructed to analyse the influence of gelatinous tissues on locomotory performance. The model swam faster with a watery layer, representing gelatinous tissue, around the tail than without. Results suggest that the tissues may, in addition to providing buoyancy and low-cost growth, aid deep-sea fish locomotion. PMID:29308245

  12. Pharmacokinetic Study of 7 Compounds Following Oral Administration of Fructus Aurantii to Depressive Rats

    PubMed Central

    Zhang, Xianhua; Han, Linran; Liu, Jin; Xu, Qiuyue; Guo, Yuxin; Zheng, Wan; Wang, Jian; Huang, Xi; Ren, Ping

    2018-01-01

    In the present study, the pharmacokinetics of multi-components (naringenin, nobiletin, meranzin hydrate, narirutin, naringin, hesperidin, and neohesperidin) were investigated in acute depressive rats following oral administration of Fructus Aurantii (Zhi-Qiao, ZQ) extract (20 g/kg). A rapid and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established to quantitatively or qualitatively analyze the 7 absorbed ingredients in the plasma, hippocampus and cortex of acute depressive rats. Biological samples were separated on a 300SB-C18 column, and the 7 compounds were detected with sequential positive and negative ionization modes. Our results confirmed that ZQ has antidepressant effects by decreasing the immobility time. In addition, this validated method showed good linearity (r ≥ 0.9987), and the lower limits of quantification were 2.73–16.38 ng/mL for the 7 analytes. This method successfully determined the pharmacokinetics of the 7 compounds and separated two pairs of isomers in plasma of acute depressive rats following oral administration of ZQ extracts. The 7 active ingredients were also identified as marked compounds in target tissues and should be further examined in pharmacokinetic studies with acute depressive rats. So, pharmacokinetic compounds were precisely linked with the antidepressant effect of ZQ in our study. This relationship is well-understood and contributes to the application of Traditional Chinese Medicine (TCM). PMID:29556193

  13. Patient-specific pharmacokinetic parameter estimation on dynamic contrast-enhanced MRI of prostate: Preliminary evaluation of a novel AIF-free estimation method.

    PubMed

    Ginsburg, Shoshana B; Taimen, Pekka; Merisaari, Harri; Vainio, Paula; Boström, Peter J; Aronen, Hannu J; Jambor, Ivan; Madabhushi, Anant

    2016-12-01

    To develop and evaluate a prostate-based method (PBM) for estimating pharmacokinetic parameters on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) by leveraging inherent differences in pharmacokinetic characteristics between the peripheral zone (PZ) and transition zone (TZ). This retrospective study, approved by the Institutional Review Board, included 40 patients who underwent a multiparametric 3T MRI examination and subsequent radical prostatectomy. A two-step PBM for estimating pharmacokinetic parameters exploited the inherent differences in pharmacokinetic characteristics associated with the TZ and PZ. First, the reference region model was implemented to estimate ratios of K trans between normal TZ and PZ. Subsequently, the reference region model was leveraged again to estimate values for K trans and v e for every prostate voxel. The parameters of PBM were compared with those estimated using an arterial input function (AIF) derived from the femoral arteries. The ability of the parameters to differentiate prostate cancer (PCa) from benign tissue was evaluated on a voxel and lesion level. Additionally, the effect of temporal downsampling of the DCE MRI data was assessed. Significant differences (P < 0.05) in PBM K trans between PCa lesions and benign tissue were found in 26/27 patients with TZ lesions and in 33/38 patients with PZ lesions; significant differences in AIF-based K trans occurred in 26/27 and 30/38 patients, respectively. The 75 th and 100 th percentiles of K trans and v e estimated using PBM positively correlated with lesion size (P < 0.05). Pharmacokinetic parameters estimated via PBM outperformed AIF-based parameters in PCa detection. J. Magn. Reson. Imaging 2016;44:1405-1414. © 2016 International Society for Magnetic Resonance in Medicine.

  14. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2

    PubMed Central

    Boswell, C Andrew; Mundo, Eduardo E; Firestein, Ron; Zhang, Crystal; Mao, Weiguang; Gill, Herman; Young, Cynthia; Ljumanovic, Nina; Stainton, Shannon; Ulufatu, Sheila; Fourie, Aimee; Kozak, Katherine R; Fuji, Reina; Polakis, Paul; Khawli, Leslie A; Lin, Kedan

    2013-01-01

    Background and Purpose The success of antibody-drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen-independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance. Experimental Approach A series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by non-invasive single photon emission computed tomography – X-ray computed tomography imaging and immunohistochemistry. Key Results The intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target-mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As a proof of concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade. Conclusions and Implications Our findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues. PMID:22889168

  15. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2.

    PubMed

    Boswell, C Andrew; Mundo, Eduardo E; Firestein, Ron; Zhang, Crystal; Mao, Weiguang; Gill, Herman; Young, Cynthia; Ljumanovic, Nina; Stainton, Shannon; Ulufatu, Sheila; Fourie, Aimee; Kozak, Katherine R; Fuji, Reina; Polakis, Paul; Khawli, Leslie A; Lin, Kedan

    2013-01-01

    The success of antibody-drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen-independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance. A series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by non-invasive single photon emission computed tomography - X-ray computed tomography imaging and immunohistochemistry. The intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target-mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As a proof of concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade. Our findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues. © 2012 Genentech, Inc.. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  16. Population pharmacokinetics of oseltamivir and oseltamivir carboxylate in obese and non‐obese volunteers

    PubMed Central

    Chairat, Kalayanee; Jittamala, Podjanee; Hanpithakpong, Warunee; Day, Nicholas P. J.; White, Nicholas J.; Pukrittayakamee, Sasithon

    2016-01-01

    Aims The aims of the present study were to compare the pharmacokinetics of oseltamivir and its active antiviral metabolite oseltamivir carboxylate in obese and non‐obese individuals and to determine the effect of obesity on the pharmacokinetic properties of oseltamivir and oseltamivir carboxylate. Methods The population pharmacokinetic properties of oseltamivir and oseltamivir carboxylate were evaluated in 12 obese [body mass index (BMI) ≥30 kg m−2) and 12 non‐obese (BMI <30 kg m−2) Thai adult volunteers receiving a standard dose of 75 mg and a double dose of 150 mg in a randomized sequence. Concentration–time data were collected and analysed using nonlinear mixed‐effects modelling. Results The pharmacokinetics of oseltamivir and oseltamivir carboxylate were described simultaneously by first‐order absorption, with a one‐compartment disposition model for oseltamivir, followed by a metabolism compartment and a one‐compartment disposition model for oseltamivir carboxylate. Creatinine clearance was a significant predictor of oseltamivir carboxylate clearance {3.84% increase for each 10 ml min−1 increase in creatinine clearance [95% confidence interval (CI) 0.178%, 8.02%]}. Obese individuals had an approximately 25% (95% CI 24%, 28%) higher oseltamivir clearance, 20% higher oseltamivir volume of distribution (95% CI 19%, 23%) and 10% higher oseltamivir carboxylate clearance (95% CI 9%, 11%) compared with non‐obese individuals. However, these altered pharmacokinetic properties were small and did not change the overall exposure to oseltamivir carboxylate. Conclusions The results confirmed that a dose adjustment for oseltamivir in obese individuals is not necessary on the basis of its pharmacokinetics. PMID:26810861

  17. Disposition pathways and pharmacokinetics of herbal medicines in humans.

    PubMed

    He, S-M; Li, C G; Liu, J-P; Chan, E; Duan, W; Zhou, S-F

    2010-01-01

    Pharmacokinetic studies have become an integral part of modern drug development, but these studies are not regulatory needs for herbal remedies. This paper updates our current knowledge on the disposition pathways and pharmacokinetic properties of commonly used herbal medicines in humans. To retrieve relevant data, the authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to May 2010). Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are determining factors for the in vivo bioavailability, disposition and distribution of herbal remedies. There are increasing pharmacokinetic studies of herbal remedies, but these studies are mainly focused on a small number of herbal remedies including St John's wort, milk thistle, sculcap, curcumin, echinacea, ginseng, ginkgo, and ginger. The pharmacokinetic data of a small number of purified herbal ingredients, including anthocyanins, berberine, catechins, curcumin, lutein and quercetin, are available. For the majority of herbal remedies used in folk medicines, data on their disposition and biological fate in humans are lacking or in paucity. For a herbal medicine, the pharmacological effect is achieved when the bioactive agents or the metabolites reach and sustain proper levels at their sites of action. Both the dose levels and fates of active components in the body govern their target-site concentrations after administration of an herbal remedy. In this regard, a safe and optimal use of herbal medicines requires a

  18. Pharmacokinetic Study of Piracetam in Focal Cerebral Ischemic Rats.

    PubMed

    Paliwal, Pankaj; Dash, Debabrata; Krishnamurthy, Sairam

    2018-04-01

    Cerebral ischemia affects hepatic enzymes and brain permeability extensively. Piracetam was investigated up to phase III of clinical trials and there is lack of data on brain penetration in cerebral ischemic condition. Thus, knowledge of the pharmacokinetics and brain penetration of piracetam during ischemic condition would aid to improve pharmacotherapeutics in ischemic stroke. Focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h in male Wistar rats followed by reperfusion. After 24 h of middle cerebral artery occlusion or 22 h of reperfusion, piracetam was administered for pharmacokinetic, brain penetration, and pharmacological experiments. In pharmacokinetic study, blood samples were collected at different time points after 200-mg/kg (oral) and 75-mg/kg (intravenous) administration of piracetam through right external jugular vein cannulation. In brain penetration study, the cerebrospinal fluid, systemic blood, portal blood, and brain samples were collected at pre-designated time points after 200-mg/kg oral administration of piracetam. In a separate experiment, the pharmacological effect of the single oral dose of piracetam in middle cerebral artery occlusion was assessed at a dose of 200 mg/kg. All the pharmacokinetic parameters of piracetam including area under curve (AUC 0-24 ), maximum plasma concentration (C max ), time to reach the maximum plasma concentration (t max ), elimination half-life (t 1/2 ), volume of distribution (V z ), total body clearance, mean residence time, and bioavailability were found to be similar in ischemic stroke condition except for brain penetration. Piracetam exposure (AUC 0-2 ) in brain and CSF were found to be 2.4- and 3.1-fold higher, respectively, in ischemic stroke compared to control rats. Piracetam significantly reduced infarct volume by 35.77% caused by middle cerebral artery occlusion. There was no change in the pharmacokinetic parameters of piracetam in the ischemic stroke model except for

  19. Population pharmacokinetic modeling of epoetin delta in pediatric patients with chronic kidney disease.

    PubMed

    Knebel, William; Palmen, Mary; Dowell, James A; Gastonguay, Marc

    2008-07-01

    This analysis quantifies the population pharmacokinetics of subcutaneous and intravenous epoetin delta, an epoetin produced in a human cell line, in pediatric patients with chronic kidney disease and estimates the effects of covariate factors on epoetin delta and epoetin alfa pharmacokinetic parameters. Erythropoietin serum concentration data, taken from a phase III study conducted in 60 patients aged 1 to 17 years, were best described by a 1-compartment model with first-order absorption and elimination. The typical point estimates were clearance (0.268 L/h), central volume of distribution (1.03 L), absorption rate constant (0.0554 h(-1)), and bioavailability (0.708) for a 35-kg male < or = 10 years who was predialysis and on subcutaneous epoetin delta treatment. Erythropoietin pharmacokinetic parameters were similar in pediatric patients as compared with adults when scaled by weight. The subcutaneous administration of epoetin alfa exhibited lower systemic bioavailability than subcutaneous administration of epoetin delta.

  20. Pharmacodynamic and pharmacokinetic studies of agmatine after spinal administration in the mouse.

    PubMed

    Roberts, John C; Grocholski, Brent M; Kitto, Kelley F; Fairbanks, Carolyn A

    2005-09-01

    Agmatine is an endogenous decarboxylation product of arginine that has been previously shown to antagonize the N-methyl-d-aspartate (NMDA) receptor and inhibit nitric-oxide synthase. Many neuropharmacological studies have shown that exogenous administration of agmatine prevents or reverses biological phenomena dependent on central nervous system glutamatergic systems, including opioid-induced tolerance, opioid self-administration, and chronic pain. However, the central nervous system (CNS) pharmacokinetic profile of agmatine remains minimally defined. The present study determined the spinal cord pharmacokinetics and acute pharmacodynamics of intrathecally administered agmatine in mice. After a single bolus intrathecal injection, agmatine concentrations in spinal cord (cervical, thoracic, and lumbosacral) tissue and serum were quantified by an isocratic high-performance liquid chromatography fluorescence detection system. Agmatine persisted at near maximum concentrations in all levels of the spinal cord for several hours with a half-life of approximately 12 h. Initial agmatine concentrations in serum were 10% those in CNS. However, the serum half-life was less than 10 min after intrathecal injection of agmatine, consistent with previous preliminary pharmacokinetic reports of systemically administered agmatine. The pharmacodynamic response to agmatine in the NMDA-nociceptive behavior and thermal hyperalgesia tests was assessed. Whereas MK-801 (dizocilpine maleate) inhibits these two responses with equal potency, agmatine inhibits the thermal hyperalgesia with significantly increased potency compared with the nociceptive behavior, suggesting two sites of action. In contrast to the pharmacokinetic results, the agmatine inhibition of both behaviors had a duration of only 10 to 30 min. Collectively, these results suggest the existence of a currently undefined agmatinergic extracellular clearance process in spinal cord.

  1. Effect of co-medication on the pharmacokinetic parameters of phenobarbital in asphyxiated newborns.

    PubMed

    Šíma, M; Pokorná, P; Hronová, K; Slanař, O

    2015-01-01

    Phenobarbital is an anticonvulsive drug widely used in newborns with hypoxic-ischemic encephalopathy. The objective of our study was to describe possible effect of frequently co-administered medications (dopamine, dobutamine, norepinephrine, furosemide, phenytoin, and analgesics) on the phenobarbital pharmacokinetics in full term newborns with hypoxic-ischemic encephalopathy. Phenobarbital pharmacokinetic parameters (standardized intravenous loading dose was 10-20 mg/kg, maintenance dose 2-6 mg/kg/day) were computed using non-compartmental analysis. Co-medication was evaluated throughout the whole treatment period up to 5 days. Volume of distribution, clearance, and half-life median values (95 % CI) for phenobarbital in the whole study population (n=37) were 0.48 (0.41-0.56) l/kg, 0.0034 (0.0028-0.0040) l/h/kg, and 93.7 (88.1-99.2) h, respectively. Phenobarbital pharmacokinetic parameters were not significantly affected by vasoactive drugs (dopamine, dobutamine, and norepinephrine), furosemide, phenytoin, or analgesics. Furthermore, no dose-dependent alteration of phenobarbital pharmacokinetic parameters was noted for vasoactive medication at doses equivalent to cumulative vasoactive-inotropic score (area under the curve in a plot of vasoactive-inotropic score against time) 143.2-8473.6, furosemide at cumulative doses of 0.2-42.9 mg/kg, or phenytoin at cumulative doses of 10.3-46.2 mg/kg. Phenobarbital pharmacokinetics was not affected by investigated co-administered drugs used in newborns with hypoxic-ischemic encephalopathy in real clinical settings.

  2. Distribution of Tocopherols and Tocotrienols in Guinea Pig Tissues Following Parenteral Lipid Emulsion Infusion.

    PubMed

    Xu, Zhidong; Harvey, Kevin A; Pavlina, Thomas M; Zaloga, Gary P; Siddiqui, Rafat A

    2016-07-01

    Tocopherols and tocotrienols possess vitamin E activity and function as the major lipid-soluble antioxidants in the human body. Commercial lipid emulsions are composed of different oils and supply different amounts of vitamin E. The objective of this study was to measure all 8 vitamin E homologs within 4 different commercial lipid emulsions and evaluate their distribution in guinea pig tissues. The distribution of vitamin E homologs within plasma and guinea pig tissues was determined using a high-performance liquid chromatography (HPLC) system. Lipid hydroperoxides in lipid emulsions were determined using a commercial kit (Cayman Chemical Company, Ann Arbor, MI), and malondialdehyde tissue levels were determined using an HPLC system. The lipid emulsions contained variable amounts of tocopherols, which were significantly different between emulsions. Tocotrienols were present at very low concentrations (≤0.3%). We found no correlation between the amount of vitamin E present in the lipid emulsions and lipid peroxidation. Hydroperoxides were the lowest with an olive oil-based emulsion and highest with a fish oil emulsion. The predominant vitamin E homolog in guinea pig tissues was α-tocopherol. No tissues had detectable levels of tocotrienols. Vitamin E levels (primarily α-tocopherol and γ-tocopherol) were highly variable among organ tissues. Plasma levels were a poor reflection of most tissue levels. Vitamin E levels within different lipid emulsions and plasma/tissues are highly variable, and no one tissue or plasma sample serves as a good proxy for levels in other tissues. All study emulsions were well tolerated and did not significantly increase systemic lipid peroxidation. © 2014 American Society for Parenteral and Enteral Nutrition.

  3. The tissue distribution and excretion study of paeoniflorin-6'-O-benzene sulfonate (CP-25) in rats.

    PubMed

    Zhao, Mingyi; Zhou, Peng; Yu, Jun; James, Asenso; Xiao, Feng; Wang, Chun; Wei, Wei

    2018-03-09

    Paeoniflorin-6'-O-benzene sulfonate (code: CP-25) is a novel ester derivative of paeoniflorin (Pae). Compared to Pae, CP-25 has higher lipid solubility, bioavailability and better bioactivity. However, the tissue distribution and excretion of CP-25 still remain unknown. The LC-MS method was applied to investigate the tissue distribution and excretion of CP-25 in rats. As such, 50 mg/kg of CP-25 and Pae were administered to rats in multiple doses via an oral route. CP-25 and Pae were distributed widely and rapidly in all the tested tissues. Compared with Pae, the concentrations of CP-25 were almost increased evidently in most tissues. The highest CP-25 level was found in the liver (1476.33 ± 535.20 ng/g, male; 1970.38 ± 177.21 ng/g, female) at 3 h, and a high concentration of CP-25 was detected in male and female intestine, synovium, muscle, lung, and brain. Following a single oral dose of 50 mg/kg of CP-25 in rats, the total excretion of CP-25 was merely 21.8% (18.40, 3.19 and 0.22% for feces, bile and urine, respectively) in males; and was approximately 21.3% (14.04, 7.16 and 0.14% for feces, bile and urine, respectively) in females. The results indicated that the CP-25 concentration was higher in major tissues than Pae; CP-25 was primarily excreted through the feces; and there were gender-related differences in the tissue distribution and excretion.

  4. Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients.

    PubMed

    Sime, Fekade B; Stuart, Janine; Butler, Jenie; Starr, Therese; Wallis, Steven C; Pandey, Saurabh; Lipman, Jeffrey; Roberts, Jason A

    2018-06-01

    To date, there is no information on the intravenous (i.v.) posaconazole pharmacokinetics for intensive care unit (ICU) patients. This prospective observational study aimed to describe the pharmacokinetics of a single dose of i.v. posaconazole in critically ill patients. Patients with no history of allergy to triazole antifungals and requiring systemic antifungal therapy were enrolled if they were aged ≥18 years, central venous access was available, they were not pregnant, and they had not received prior posaconazole or drugs interacting with posaconazole. A single dose of 300 mg posaconazole was administered over 90 min. Total plasma concentrations were measured from serial plasma samples collected over 48 h, using a validated chromatographic method. The pharmacokinetic data set was analyzed by noncompartmental methods. Eight patients (7 male) were enrolled with the following characteristics: median age, 46 years (interquartile range [IQR], 40 to 51 years); median weight, 68 kg (IQR, 65 to 82 kg); and median albumin concentration, 20 g/liter (IQR, 18 to 24 g/liter). Median (IQR) pharmacokinetic parameter estimates were as follows: observed maximum concentration during sampling period ( C max ), 1,702 ng/ml (1,352 to 2,141 ng/ml); area under the concentration-time curve from zero to infinity (AUC 0-∞ ), 17,932 ng · h/ml (13,823 to 27,905 ng · h/ml); clearance (CL), 16.8 liters/h (11.1 to 21.7 liters/h); and volume of distribution ( V ), 529.1 liters (352.2 to 720.6 liters). The V and CL were greater than 2-fold and the AUC 0-∞ was 39% of the values reported for heathy volunteers. The AUC 0-∞ was only 52% of the steady-state AUC 0-24 reported for hematology patients. The median of estimated average steady-state concentrations was 747 ng/ml (IQR, 576 to 1,163 ng/ml), which is within but close to the lower end of the previously recommended therapeutic range of 500 to 2,500 ng/ml. In conclusion, we observed different pharmacokinetics of i.v. posaconazole in

  5. Pharmacokinetic Assessment of Efflux Transport in Sunitinib Distribution to the Brain

    PubMed Central

    Oberoi, Rajneet K.; Mittapalli, Rajendar K.

    2013-01-01

    This study quantitatively assessed transport mechanisms that limit the brain distribution of sunitinib and investigated adjuvant strategies to improve its brain delivery for the treatment of glioblastoma multiforme (GBM). Sunitinib has not shown significant activity in GBM clinical trials, despite positive results seen in preclinical xenograft studies. We performed in vivo studies in transgenic Friend leukemia virus strain B mice: wild-type, Mdr1a/b(−/−), Bcrp1(−/−), and Mdr1a/b(−/−)Bcrp1(−/−) genotypes were examined. The brain-to-plasma area under the curve ratio after an oral dose (20 mg/kg) was similar to the steady-state tissue distribution coefficient, indicating linear distribution kinetics in mice over this concentration range. Furthermore, the distribution of sunitinib to the brain increased after administration of selective P-glycoprotein (P-gp) or breast cancer resistance protein (Bcrp) pharmacological inhibitors and a dual inhibitor, elacridar, comparable to that of the corresponding transgenic genotype. The brain-to-plasma ratio after coadministration of elacridar in wild-type mice was ∼12 compared with ∼17.3 in Mdr1a/b(−/−)Bcrp1(−/−) mice. Overall, these findings indicate that there is a cooperation at the blood-brain barrier (BBB) in restricting the brain penetration of sunitinib, and brain delivery can be enhanced by administration of a dual inhibitor. These data indicate that the presence of cooperative efflux transporters, P-gp and Bcrp, in an intact BBB can protect invasive glioma cells from chemotherapy. Thus, one may consider the use of transporter inhibition as a powerful adjuvant in the design of future clinical trials for the targeted delivery of sunitinib in GBM. PMID:24113148

  6. Pharmacokinetics of intravenous ketorolac in cats undergoing gonadectomy.

    PubMed

    Villa, R; Ravasio, G; Ferraresi, C; Zonca, A; Carli, S; Borghi, L; Cagnardi, P

    2015-05-01

    To determine the pharmacokinetics of ketorolac tromethamine (0.5 mg/kg) when administered I/V to cats undergoing gonadectomy. Ketorolac was administered to nine female and three male shorthair domestic cats as an I/V bolus of 0.5 mg/kg after intubation, and 20 minutes prior to ovariectomy or orchiectomy. Intra-operative cardiorespiratory variables were monitored and blood samples were collected over 24 hours. Concentrations of ketorolac in serum were determined by high-performance liquid chromatography to establish pharmacokinetic parameters. During surgery, mean end tidal isoflurane concentration was 1.63 (SD 0.24)% and normocapnia and spontaneous ventilation were maintained in all animals. The kinetics of ketorolac was described by a two-compartment model. The distribution and elimination half-lives were 0.09 (SD 0.06) and 4.14 (SD 1.18) hours, respectively. The body clearance was 56.8 (SD 33.1) mL/h/kg. The volume of distribution at steady-state and the mean residence time were 323.9 (SD 115.7) mL/kg and 6.47 (SD 2.86) hours, respectively. On the basis of the results, concentrations of ketorolac in serum in cats were above the human effective concentrations for 5-6 hours postoperatively. However, other studies including a control group are advocated to further investigate the ketorolac kinetics and the analgesic efficacy in this species.

  7. Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents.

    PubMed

    Cheng, Hao; Xie, Zhiliang; Jones, William P; Wei, Xiaohui Tracey; Liu, Zhongfa; Wang, Dasheng; Kulp, Samuel K; Wang, Jiang; Coss, Christopher C; Chen, Ching-Shih; Marcucci, Guido; Garzon, Ramiro; Covey, Joseph M; Phelps, Mitch A; Chan, Kenneth K

    2016-05-01

    AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats. Oral bioavailability was estimated to be 26 and 100% in mice and rats, respectively. R-AR-42 was also evaluated intravenously in rats and was shown to display different pharmacokinetics with a much shorter terminal half-life compared to that of S-AR-42. Renal clearance was a minor elimination pathway for parental S-AR-42. Oral administration of S-AR-42 to tumor-bearing mice demonstrated high uptake and exposure of the parent drug in the lymphoid tissues, spleen, and bone marrow. This is the first report of the pharmacokinetics of this novel agent, which is now in early phase clinical trials.

  8. Disclosure of pharmacokinetic drug results to understand nonadherence.

    PubMed

    van der Straten, Ariane; Montgomery, Elizabeth T; Musara, Petina; Etima, Juliane; Naidoo, Sarita; Laborde, Nicole; Hartmann, Miriam; Levy, Lisa; Bennie, Thola; Cheng, Helen; Piper, Jeanna; Grossman, Cynthia I; Marrazzo, Jeanne; Mensch, Barbara

    2015-10-23

    In VOICE, a phase IIB trial of daily oral and vaginal tenofovir for HIV prevention, at least 50% of women receiving active products had undetectable tenofovir in all plasma samples tested. MTN-003D, an ancillary study using in-depth interviews (IDIs) and focus group discussions (FGDs), together with retrospective disclosure of plasma tenofovir pharmacokinetic results, explored adherence challenges during VOICE. We systematically recruited participants with pharmacokinetic data (median six plasma samples), categorized as low (0%, N = 79), inconsistent (1-74%, N = 28) or high (≥75%; N = 20) on the basis of frequency of tenofovir detection. Following disclosure of pharmacokinetic results, reactions were captured and adherence challenges systematically elicited; IDIs and FGDs were audio-recorded, transcribed, coded and thematically analysed. We interviewed 127 participants from South Africa, Uganda and Zimbabwe. The most common reactions to pharmacokinetic results included surprise (41%; low pharmacokinetic), acceptance (39%; inconsistent pharmacokinetic) and happiness (65%; high pharmacokinetic). On the basis of participants' explanations, we developed a typology of adherence patterns: noninitiation, discontinuation, misimplementation (resulting from visit-driven use, variable taking, modified dosing or regimen) and adherence. Fear of product side effects/harm was a frequent concern, fuelled by stories shared among participants. Although women with high pharmacokinetic levels reported similar concerns, several described strategies to overcome challenges. Women at all pharmacokinetic levels suggested real-time drug monitoring and feedback to improve adherence and reporting. Retrospective provision of pharmacokinetic results seemingly promoted candid discussions around nonadherence and study participation. The effect of real-time drug monitoring and feedback on adherence and accuracy of reporting should be evaluated in trials.

  9. Measuring the Pharmacokinetic Properties of Drugs with a Novel Surgical Rat Model.

    PubMed

    Christakis, Ioannis; Scott, Rebecca; Minnion, James; Cuenco, Joyceline; Tan, Tricia; Palazzo, Fausto; Bloom, Stephen

    2017-06-01

    Purpose/aim of the study: The pharmacokinetic (PK) parameters in animal models can help optimize novel candidate drugs prior to human trials. However, due to the complexity of pharmacokinetic experiments, their use is limited in academia. We present a novel surgical rat model for investigation of pharmacokinetic parameters and its use in an anti-obesity drug development program. The model uses anesthetized male Wistar rats, a jugular, a femoral catheter, and an insulin pump for peptide infusion. The following pharmacokinetic parameters were measured: metabolic clearance rate (MCR), half-life, and volume of distribution (Vd). Glucagon-like peptide 1 (GLP-1), glucagon (GCG), and exendin-4 (Ex-4) were used to validate the model. The pharmacokinetic parameters of anti-obesity drug candidates X1, X2, and X3 were measured. GLP-1 had a significantly higher MCR (83.9 ± 14.1 mL/min/kg) compared to GCG (40.7 ± 14.3 mL/min/kg) and Ex-4 (10.1 ± 2.5 mL/min/kg) (p < .01 and p < .001 respectively). Ex-4 had a statistically significant longer half-life (35.1 ± 7.4 min) compared to both GCG (3.2 ± 1.7 min) and GLP-1 (1.2 ± 0.4 min) (p < .01 for both GCG and GLP-1). Ex-4 had a statistically significant higher volume of distribution (429.7 ± 164.9 mL/kg) compared to both GCG (146.8 ± 49.6 mL/kg) and GLP-1 (149.7 ± 53.5 mL/kg) (p < .01 for both GCG and GLP-1). Peptide X3 had a statistically significant longer half-life (21.3 ± 3.5 min) compared to both X1 (3.9 ± 0.4 min) and X2 (16.1 ± 2.8 min) (p < .001 for both X1 and X2). We present an affordable and easily accessible platform for the measurement of PK parameters of peptides. This novel surgical rat model produces consistent and reproducible results while minimizing animal use.

  10. Validation and use of three complementary analytical methods (LC-FLS, LC-MS/MS and ICP-MS) to evaluate the pharmacokinetics, biodistribution and stability of motexafin gadolinium in plasma and tissues.

    PubMed

    Miles, Dale R; Mesfin, Mimi; Mody, Tarak D; Stiles, Mark; Lee, Jean; Fiene, John; Denis, Bernie; Boswell, Garry W

    2006-05-01

    Liquid chromatography-fluorescence (LC-FLS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma-mass spectrometry (ICP-MS) methods were developed and validated for the evaluation of motexafin gadolinium (MGd, Xcytrin) pharmacokinetics and biodistribution in plasma and tissues. The LC-FLS method exhibited the greatest sensitivity (0.0057 microg mL(-1)), and was used for pharmacokinetic, biodistribution, and protein binding studies with small sample sizes or low MGd concentrations. The LC-MS/MS method, which exhibited a short run time and excellent selectivity, was used for routine clinical plasma sample analysis. The ICP-MS method, which measured total Gd, was used in conjunction with LC methods to assess MGd stability in plasma. All three methods were validated using human plasma. The LC-FLS method was also validated using plasma, liver and kidneys from mice and rats. All three methods were shown to be accurate, precise and robust for each matrix validated. For three mice, the mean (standard deviation) concentration of MGd in plasma/tissues taken 5 hr after dosing with 23 mg kg(-1) MGd was determined by LC-FLS as follows: plasma (0.025+/-0.002 microg mL(-1)), liver (2.89+/-0.45 microg g(-1)), and kidney (6.09+/-1.05 microg g(-1)). Plasma samples from a subset of patients with brain metastases from extracranial tumors were analyzed using both LC-MS/MS and ICP-MS methods. For a representative patient, > or = 90% of the total Gd in plasma was accounted for as MGd over the first hour post dosing. By 24 hr post dosing, 63% of total Gd was accounted for as MGd, indicating some metabolism of MGd.

  11. DEVELOPMENT OF A HUMAN PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL FOR INORGANIC ARSENIC AND ITS MONO- AND DI-METHYLATED METABOLITES

    EPA Science Inventory

    A physiologically-based pharmacokinetic (PBPK) model was developed to estimate levels of arsenic and its metabolites in human tissues and urine after oral exposure to either arsenate (AsV) or arsnite (AsIII). The model consists of interconnected individual ...

  12. Distribution of PLGA-modified nanoparticles in 3D cell culture models of hypo-vascularized tumor tissue.

    PubMed

    Sims, Lee B; Huss, Maya K; Frieboes, Hermann B; Steinbach-Rankins, Jill M

    2017-10-05

    Advanced stage cancer treatments are often invasive and painful-typically comprised of surgery, chemotherapy, and/or radiation treatment. Low transport efficiency during systemic chemotherapy may require high chemotherapeutic doses to effectively target cancerous tissue, resulting in systemic toxicity. Nanotherapeutic platforms have been proposed as an alternative to more safely and effectively deliver therapeutic agents directly to tumor sites. However, cellular internalization and tumor penetration are often diametrically opposed, with limited access to tumor regions distal from vasculature, due to irregular tissue morphologies. To address these transport challenges, nanoparticles (NPs) are often surface-modified with ligands to enhance transport and longevity after localized or systemic administration. Here, we evaluate stealth polyethylene-glycol (PEG), cell-penetrating (MPG), and CPP-stealth (MPG/PEG) poly(lactic-co-glycolic-acid) (PLGA) NP co-treatment strategies in 3D cell culture representing hypo-vascularized tissue. Smaller, more regularly-shaped avascular tissue was generated using the hanging drop (HD) method, while more irregularly-shaped masses were formed with the liquid overlay (LO) technique. To compare NP distribution differences within the same type of tissue as a function of different cancer types, we selected HeLa, cervical epithelial adenocarcinoma cells; CaSki, cervical epidermoid carcinoma cells; and SiHa, grade II cervical squamous cell carcinoma cells. In HD tumors, enhanced distribution relative to unmodified NPs was measured for MPG and PEG NPs in HeLa, and for all modified NPs in SiHa spheroids. In LO tumors, the greatest distribution was observed for MPG and MPG/PEG NPs in HeLa, and for PEG and MPG/PEG NPs in SiHa spheroids. Pre-clinical evaluation of PLGA-modified NP distribution into hypo-vascularized tumor tissue may benefit from considering tissue morphology in addition to cancer type.

  13. Gender differences in cocaine pharmacokinetics in CF-1 mice.

    PubMed

    Visalli, Thomas; Turkall, Rita; Abdel-Rahman, Mohamed S

    2005-01-15

    Hepatocellular damage is thought to occur as a result of cytochrome P450-mediated oxidation of cocaine to norcocaine (NC), a precursor of the hepatotoxic nitrosonium ion. However, this damage occurs only in male mice, with females exhibiting minimal biochemical and histological signs of hepatocellular stress. The objective of this study was to determine the plasma time course and tissue disposition of cocaine and its metabolites to further investigate the role that metabolism may play in the gender difference observed. Male and female CF-1 mice were orally administered 20mg/kg cocaine hydrochloride once daily for 7 days. Blood samples were withdrawn at various time points post-injection and analyzed for cocaine and its metabolites benzoylecgonine (BE), norcocaine, ecgonine methyl ester (EME), and ecgonine (E). In addition, tissue concentrations of cocaine and its metabolites were determined in liver, heart, brain, and kidney tissue. The results demonstrated that the plasma elimination half-life of cocaine is nearly three times longer in males versus females. Non-hepatotoxic hydrolysis metabolites BE, EME, and E were higher in female tissues while norcocaine was detected in tissues of male animals only. This study revealed that differences in cocaine pharmacokinetics and the resultant differences in the biodisposition of cocaine and its metabolites in tissues contribute to the mechanism of gender difference seen in cocaine hepatotoxicity.

  14. Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition.

    PubMed

    Yu, Guo; Li, Guo-Fu; Markowitz, John S

    2016-05-01

    Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children (≥6 years of age), adolescents, and adults. Its metabolism and disposition are fairly complex, and primarily governed by cytochrome P450 (CYP) 2D6 (CYP2D6), whose protein expression varies substantially from person to person, and by race and ethnicity because of genetic polymorphism. These differences can be substantial, resulting in 8-10-fold differences in atomoxetine exposure between CYP2D6 poor metabolizers and extensive metabolizers. In this review, we have attempted to revisit and analyze all published clinical pharmacokinetic data on atomoxetine inclusive of public access documents from the new drug application submitted to the United States Food and Drug Administration (FDA). The present review focuses on atomoxetine metabolism, disposition, and genetic polymorphisms of CYP2D6 as they specifically relate to atomoxetine, and provides an in-depth discussion of the fundamental pharmacokinetics of the drug including its absorption, distribution, metabolism, and excretion in pediatric and adult populations. Further, a summary of relationships between genetic variants of CYP2D6 and to some degree, CYP2C19, are provided with respect to atomoxetine plasma concentrations, central nervous system (CNS) pharmacokinetics, and associated clinical implications for pharmacotherapy. Lastly, dosage adjustments based on pharmacokinetic principles are discussed.

  15. Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

    PubMed Central

    Yu, Guo; Li, Guo-Fu

    2016-01-01

    Abstract Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children (≥6 years of age), adolescents, and adults. Its metabolism and disposition are fairly complex, and primarily governed by cytochrome P450 (CYP) 2D6 (CYP2D6), whose protein expression varies substantially from person to person, and by race and ethnicity because of genetic polymorphism. These differences can be substantial, resulting in 8–10-fold differences in atomoxetine exposure between CYP2D6 poor metabolizers and extensive metabolizers. In this review, we have attempted to revisit and analyze all published clinical pharmacokinetic data on atomoxetine inclusive of public access documents from the new drug application submitted to the United States Food and Drug Administration (FDA). The present review focuses on atomoxetine metabolism, disposition, and genetic polymorphisms of CYP2D6 as they specifically relate to atomoxetine, and provides an in-depth discussion of the fundamental pharmacokinetics of the drug including its absorption, distribution, metabolism, and excretion in pediatric and adult populations. Further, a summary of relationships between genetic variants of CYP2D6 and to some degree, CYP2C19, are provided with respect to atomoxetine plasma concentrations, central nervous system (CNS) pharmacokinetics, and associated clinical implications for pharmacotherapy. Lastly, dosage adjustments based on pharmacokinetic principles are discussed. PMID:26859445

  16. Pharmacokinetics of Hydroxymethylnitrofurazone, a Promising New Prodrug for Chagas' Disease Treatment

    PubMed Central

    Serafim, Eliana Ometto Pavan; Silva, Antonio Távora de Albuquerque e; Moreno, Andréia de Haro; Vizioli, Ednir de Oliveira; Ferreira, Elizabeth Igne; Ribeiro, Maria Lucia

    2013-01-01

    Hydroxymethylnitrofurazone (NFOH) is a trypanocidal prodrug of nitrofurazone (NF), devoid of mutagenic toxicity. The purpose of this work was to study the chemical conversion of NFOH into NF in sodium acetate buffer (pH 1.2 and 7.4) and in human plasma and to determine preclinical pharmacokinetic parameters in rats. At pH 1.2, the NFOH was totally transformed into NF, the parent drug, after 48 h, while at pH 7.4, after the same period, the hydrolysis rate was 20%. In human plasma, 50% of NFOH was hydrolyzed after 24 h. In the investigation of kinetic disposition, the concentration of drug in serum versus time curve was used to calculate the pharmacokinetic parameters after a single-dose regimen. NFOH showed a time to maximum concentration of drug in serum (Tmax) as 1 h, suggesting faster absorption than NF (4 h). The most important results observed were the volume of distribution (V) of NFOH through the tissues, which showed a rate that is 20-fold higher (337.5 liters/kg of body weight) than that of NF (17.64 liters/kg), and the concentration of NF obtained by in vivo metabolism of NFOH, which was about four times lower (maximum concentration of drug in serum [Cmax] = 0.83 μg/ml; area under the concentration-time curve from 0 to 12 h [AUC0–12] = 5.683 μg/ml · h) than observed for administered NF (Cmax = 2.78 μg/ml; AUC0–12 = 54.49 μg/ml · h). These findings can explain the superior activity and lower toxicity of the prodrug NFOH in relation to its parent drug and confirm NFOH as a promising anti-Chagas' disease drug candidate. PMID:24080661

  17. Pharmacokinetics, Distribution, Metabolism, and Excretion of Omadacycline following a Single Intravenous or Oral Dose of 14C-Omadacycline in Rats

    PubMed Central

    Lin, Wen; Flarakos, Jimmy; Du, Yancy; Hu, Wenyu; He, Handan; Mangold, James; Tanaka, S. Ken

    2016-01-01

    ABSTRACT The absorption, distribution, metabolism, and excretion (ADME) of omadacycline, a first-in-class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive, Gram-negative, anaerobic, and atypical bacteria, were evaluated in rats. Tissue distribution was investigated by quantitative whole-body autoradiography in male Long-Evans Hooded (LEH) rats. Following an intravenous (i.v.) dose of 5 mg/kg of body weight, radioactivity widely and rapidly distributed into most tissues. The highest tissue-to-blood concentration ratios (t/b) were observed in bone mineral, thyroid gland, and Harderian gland at 24 h post-i.v. dose. There was no evidence of stable accumulation in uveal tract tissue, suggesting the absence of a stable binding interaction with melanin. Following a 90 mg/kg oral dose in LEH rats, the highest t/b were observed in bone mineral, Harderian gland, liver, spleen, and salivary gland. The plasma protein binding levels were 26% in the rat and 15% to 21% in other species. Omadacycline plasma clearance was 1.2 liters/h/kg, and its half-life was 4.6 h; the steady-state volume of distribution (Vss) was 6.89 liters/kg. Major circulating components in plasma were intact omadacycline and its epimer. Consistent with observations in human, approximately 80% of the dose was excreted into the feces as unchanged omadacycline after i.v. administration. Fecal excretion was primarily the result of biliary excretion (∼40%) and direct gastrointestinal secretion (∼30%). However, urinary excretion (∼30%) was equally prominent after i.v. dosing. PMID:27821446

  18. Pharmacokinetics of enrofloxacin and marbofloxacin in Japanese quails and common pheasants.

    PubMed

    Lashev, L D; Dimitrova, D J; Milanova, A; Moutafchieva, R G

    2015-04-01

    The pharmacokinetics of enrofloxacin and marbofloxacin was studied in Japanese quails and common pheasants. Healthy mature birds from both species and both genders were treated intravenously and orally with enrofloxacin (10 mg/kg) and marbofloxacin (5 mg/kg). After intravenous administration enrofloxacin was extensively metabolised to ciprofloxacin. Metabolites of marbofloxacin were not detected. Values of volume of distribution were respectively 4.63 l/kg and 3.67 l/kg for enrofloxacin and 1.56 l/kg and 1.43 l/kg for marbofloxacin. In quails, total body clearance values were higher than those in pheasants and other avian species. After oral application enrofloxacin was rapidly absorbed in quails, more rapidly than marbofloxacin. Pheasants absorbed both antimicrobials at a lower rate. Higher bioavailability was observed for marbofloxacin (118%). Relatively low bioavailability was established in quails for enrofloxacin (26.4%), accompanied by extensive conversion to ciprofloxacin. Generally, quails absorbed and eliminated both fluoroquinolones more rapidly than pheasants; the latter showed pharmacokinetics similar to poultry. Because of favourable pharmacokinetic properties, marbofloxacin should be preferred for oral administration in Japanese quails and pheasants for treatment of infections caused by equally susceptible pathogens.

  19. Pharmacokinetic Analysis of Dynamic 18F-Fluoromisonidazole PET Data in Non-Small Cell Lung Cancer.

    PubMed

    Schwartz, Jazmin; Grkovski, Milan; Rimner, Andreas; Schöder, Heiko; Zanzonico, Pat B; Carlin, Sean D; Staton, Kevin D; Humm, John L; Nehmeh, Sadek A

    2017-06-01

    Hypoxic tumors exhibit increased resistance to radiation, chemical, and immune therapies. 18 F-fluoromisonidazole ( 18 F-FMISO) PET is a noninvasive, quantitative imaging technique used to evaluate the magnitude and spatial distribution of tumor hypoxia. In this study, pharmacokinetic analysis (PKA) of 18 F-FMISO dynamic PET extended to 3 h after injection is reported for the first time, to our knowledge, in stage III-IV non-small cell lung cancer (NSCLC) patients. Methods: Sixteen patients diagnosed with NSCLC underwent 2 PET/CT scans (1-3 d apart) before radiation therapy: a 3-min static 18 F-FDG and a dynamic 18 F-FMISO scan lasting 168 ± 15 min. The latter data were acquired in 3 serial PET/CT dynamic imaging sessions, registered with each other and analyzed using pharmacokinetic modeling software. PKA was performed using a 2-tissue, 3-compartment irreversible model, and kinetic parameters were estimated for the volumes of interest determined using coregistered 18 F-FDG images for both the volume of interest-averaged and the voxelwise time-activity curves for each patient's lesions, normal lung, and muscle. Results: We derived average values of 18 F-FMISO kinetic parameters for NSCLC lesions as well as for normal lung and muscle. We also investigated the correlation between the trapping rate ( k 3 ) and delivery rate ( K 1 ), influx rate ( K i ) constants, and tissue-to-blood activity concentration ratios (TBRs) for all tissues. Lesions had trapping rates 1.6 times larger, on average, than those of normal lung and 4.4 times larger than those in muscle. Additionally, for almost all cases, k 3 and K i had a significant strong correlation for all tissue types. The TBR- k 3 correlation was less straightforward, showing a moderate to strong correlation for only 41% of lesions. Finally, K 1 - k 3 voxelwise correlations for tumors were varied, but negative for 76% of lesions, globally exhibiting a weak inverse relationship (average R = -0.23 ± 0.39). However, both

  20. Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies.

    PubMed

    van den Broek, Marcel P H; Groenendaal, Floris; Egberts, Antoine C G; Rademaker, Carin M A

    2010-05-01

    Examples of clinical applications of therapeutic hypothermia in modern clinical medicine include traumatic cardiac arrest, ischaemic stroke and, more recently, acute perinatal asphyxia in neonates. The exact mechanism of (neuro)protection by hypothermia is unknown. Since most enzymatic processes exhibit temperature dependency, it can be expected that therapeutic hypothermia may cause alterations in both pharmacokinetic and pharmacodynamic parameters, which could result in an increased risk of drug toxicity or therapy failure. Generalizable knowledge about the effect of therapeutic hypothermia on pharmacokinetics and pharmacodynamics could lead to more appropriate dosing and thereby prediction of clinical effects. This article reviews the evidence on the influence of therapeutic hypothermia on individual pharmacokinetic and pharmacodynamic parameters. A literature search was conducted within the PubMed, Embase and Cochrane databases from January 1965 to September 2008, comparing pharmacokinetic and/or pharmacodynamic parameters in hypothermia and normothermia regarding preclinical (animal) and clinical (human) studies. During hypothermia, pharmacokinetic parameters alter, resulting in drug and metabolite accumulation in the plasma for the majority of drugs. Impaired clearance is the most striking effect. Based on impaired clearance, dosages should be decreased considerably, especially for drugs with a low therapeutic index. Hypothetically, high-clearance compounds are affected more than low-clearance compounds because of the additional effect of impaired hepatic blood flow. The volume of distribution also changes, which may lead to therapy failure when it increases and could lead to toxicity when it decreases. The pH-partitioning hypothesis could contribute to the changes in the volumes of distribution for weak bases and acids, depending on their acid dissociation constants and acid-base status. Pharmacodynamic parameters may also alter, depending on the hypothermic

  1. Population pharmacokinetics and dosing regimen design of milrinone in preterm infants

    PubMed Central

    Paradisis, Mary; Jiang, Xuemin; McLachlan, Andrew J; Evans, Nick; Kluckow, Martin; Osborn, David

    2007-01-01

    Aims To define the pharmacokinetics of milrinone in very preterm infants and determine an optimal dose regimen to prevent low systemic blood flow in the first 12 h after birth. Methods A prospective open‐labelled, dose‐escalation pharmacokinetic study was undertaken in two stages. In stage one, infants received milrinone at 0.25 μg/kg/min (n = 8) and 0.5 μg/kg/min (n = 11) infused from 3 to 24 h of age. Infants contributed 4–5 blood samples for concentration–time data which were analysed using a population modelling approach. A simulation study was used to explore the optimal dosing regimen to achieve target milrinone concentrations (180–300 ng/ml). This milrinone regimen was evaluated in stage two (n = 10). Results Infants (n = 29) born before 29 weeks gestation were enrolled. Milrinone pharmacokinetics were described using a one‐compartment model with first‐order elimination rate, with a population mean clearance (CV%) of 35 ml/h (24%) and volume of distribution of 512 ml (21%) and estimated half‐life of 10 h. The 0.25 and 0.5 μg/kg/min dosage regimens did not achieve optimal milrinone concentration‐time profiles to prevent early low systemic blood flow. Simulation studies predicted a loading infusion (0.75 μg/kg/min for 3 h) followed by maintenance infusion (0.2 μg/kg/min until 18 h of age) would provide an optimal milrinone concentration profile. This was confirmed in stage two of the study. Conclusion Population pharmacokinetic modelling in the preterm infant has established an optimal dose regimen for milrinone that increases the likelihood of achieving therapeutic aims and highlights the importance of pharmacokinetic studies in neonatal clinical pharmacology. PMID:16690639

  2. [Pharmacokinetics of digoxin in hyperthyroidism. Effect of methimazole].

    PubMed

    Izbicka, Maria; Gasińska, Teresa; Dec, Renata

    2010-01-01

    Cardiovascular abnormalities may be the only manifestations of overt hyperthyroidism. In patients with heart failure and atrial fibrillation digoxin can be beneficial in controlling the symptoms and signs, but hyperthyroid patients show an impaired response or even resistance to digoxin treatment. The aim of the study is to establish: 1. Are there any differences in the pharmacokinetics of a single oral dose of digoxin between hypertyroid and euthyroid patients? 2. Does simultaneous administration of digoxin and methimazole affect the pharmacokinetics of a single oral dose of dogoxin? 3. Does methimazole-induced euthyroidism change the pharmacokinetics of a single oral dose of digoxin? The subject of the study were 28 patients with hyperthyroidism and 15 healthy persons. We evaluated the pharmacokinetics of a single oral dose of digoxin. Moreover we evaluated pharmacokinetics of a single dose of digoxin after simultaneous administration of digoxin and methimazole in 12 patients and 12 methimazole treated patients werere-assessed once they had become euthyroid. Hyperthyroid patients showed significantly lower serum digoxin concentrations, shorter T1/2 beta and a significantly smaller area under the concentration curve (AUC) that the control group. Administration of methimazole did not affect digoxin pharmacokinetics. In hyperthyroid patients: 1. the pharmacokinetics of a single oral dose of digoxin does differ from that observed in healthy subjects. 2.methimazole do not alter digoxin pharmacokinetics.

  3. Effect of hepatic impairment on the pharmacokinetics of a single dose of cilostazol.

    PubMed

    Bramer, S L; Forbes, W P

    1999-01-01

    The pharmacokinetic profiles of cilostazol and its metabolites following a single oral dose of cilostazol 100 mg were compared between individuals with impaired and normal liver function. The study was conducted as a single-centre, open-label, single dose pharmacokinetic and tolerability trial. 12 patients with impaired and compensated liver function were compared with 12 volunteers with normal liver function. Participants in each group were matched for gender, age and weight. Of the 12 patients with hepatic impairment examined in this study, 10 had mild impairment (Child-Pugh class A) and 2 had moderate impairment (Child-Pugh class B). Blood and urine were collected up to 144 hours after drug administration. Pharmacokinetics were determined by noncompartmental methods. Protein binding did not differ between the groups (95.2% healthy volunteers, 94.6% hepatically impaired patients). Mean +/- SD unbound oral clearance of cilostazol decreased by 8.6% because of hepatic impairment (3380 +/- 1400 ml/min in healthy volunteers, 3260 +/- 2030 ml/min in hepatically impaired patients). Total urinary excretion of metabolites was significantly higher in healthy volunteers (26 vs 17% of dose). Overall, the pharmacokinetics of cilostazol and its metabolites, OPC-13213 and OPC-13015, were not substantially different in those with mild and moderate hepatic disease compared with values in healthy volunteers. Except for terminal-phase disposition half-life and apparent terminal-phase volume of distribution for cilostazol, the ratios of geometric means of pharmacokinetic parameters for plasma cilostazol, OPC-13213 and OPC-13015 in those with hepatic impairment versus healthy volunteers were close to 100%. Based on the results of the pharmacokinetic analysis, dose adjustment in patients with mild hepatic impairment is not necessary. However, caution should be exercised when cilostazol is administered to patients with moderate or severe hepatic impairment.

  4. Multiple-dose pharmacokinetics and safety of an ibuprofen-pseudoephedrine cold suspension in children.

    PubMed

    Gelotte, Cathy K; Prior, Mary Jane; Pendley, Charles; Zimmerman, Brenda; Lavins, Bernard J

    2010-07-01

    Two studies were conducted to characterize multiple-dose pharmacokinetics and potential drug interactions of ibuprofen and pseudoephedrine combined in a suspension and to evaluate safety of this combination in children with common cold, flu, or sinusitis. In the pharmacokinetic study, 24 healthy children aged 4-11 years were administered ibuprofen -pseudoephedrine suspension at 7.5 and 1.125 mg/kg, respectively, every 6 hours for 5 doses. Serial blood samples were drawn over 6 hours after final dose for assessment of steady-state pharmacokinetics. In the open-label, multicenter safety study, more than 100 children aged 2-11 years experiencing symptomatic rhinitis were enrolled. Ibuprofen -pseudoephedrine suspension was administered as needed at similar mg/kg doses every 6-8 hours for up to 3 days. Subjects enrolled in the pharmacokinetic study showed no accumulation of either drug; their weight-adjusted clearances were independent of age, and results were comparable with those from previous single-ingredient studies. For ibuprofen, oral clearance (Cl/F) was 77.5 + or - 16.4 mL/kg/h and volume of distribution (Vd/F) was 0.147 + or - 0.037 L/kg. For pseudoephedrine, Cl/F was 12.3 + or - 2.2 mL/kg/min and Vd/F was 2.52 + or - 0.47 L/kg. In the safety study, adverse events were reported for 18.4% of subjects; most were mild to moderate intensity. There was little difference in incidence of adverse events among different age and weight groups. In conclusion, administration of combined ibuprofen and pseudoephedrine in children demonstrated similar pharmacokinetics when compared with reports of the pharmacokinetics for the single-ingredient products, consistent with no apparent drug interactions. The combination suspension was generally well tolerated.

  5. Lack of sex-related differences in saquinavir pharmacokinetics in an HIV-seronegative cohort

    PubMed Central

    Robertson, Sarah M; Formentini, Elizabeth; Alfaro, Raul M; Natarajan, Ven; Falloon, Judith; Penzak, Scott R

    2006-01-01

    Aims To examine the influence of sex on steady-state saquinavir pharmacokinetics in HIV-seronegative volunteers administered saquinavir without a concomitant protease inhibitor. Methods Thirty-eight healthy volunteers (14 female) received saquinavir soft-gel capsules 1200 mg three times daily for 3 days to achieve steady-state conditions. Following administration of the 10th dose, blood was collected serially over 8 h for measurement of saquinavir plasma concentrations. Saquinavir pharmacokinetic parameter values were determined using noncompartmental methods and compared between males and females. CYP3A phenotype (using oral midazolam) and MDR-1 genotypes at positions 3435 and 2677 were determined for all subjects in order to characterize possible mechanisms for any observed sex-related differences. Results There was no significant difference in saquinavir AUC0−8 or any other pharmacokinetic parameter value between the sexes. These findings persisted after mathematically correcting for total body weight. The mean weight-normalized AUC0−8 was 29.9 (95% confidence interval 15.5, 44.3) and 29.8 (18.6, 40.9) ng h−1 ml−1 kg−1 for males and females, respectively. No significant difference in CYP3A phenotype was observed between the groups; likewise, the distribution of MDR-1 genotypes was similar for males and females. Conclusion In contrast to previous study findings, results from this investigation showed no difference in saquinavir pharmacokinetics between males and females. The discrepancy between our findings and those previously reported may be explained by the fact that we evaluated HIV-seronegative volunteers and administered saquinavir in the absence of concomitant protease inhibitors such as ritonavir. Caution must be exercised when extrapolating pharmacokinetic data from healthy volunteer studies (including sex-based pharmacokinetic differences) to HIV-infected populations or to patients receiving additional concurrent medications. PMID

  6. TU-F-18C-05: Evaluation of a Method to Calculate Patient-Oriented MGD Coefficients Using Estimates of Glandular Tissue Distribution

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Porras-Chaverri, M; University of Costa Rica, San Jose; Galavis, P

    Purpose: Evaluate mammographic mean glandular dose (MGD) coefficients for particular known tissue distributions using a novel formalism that incorporates the effect of the heterogeneous glandular tissue distribution, by comparing them with MGD coefficients derived from the corresponding anthropomorphic computer breast phantom. Methods: MGD coefficients were obtained using MCNP5 simulations with the currently used homogeneous assumption and the heterogeneously-layered breast (HLB) geometry and compared against those from the computer phantom (ground truth). The tissue distribution for the HLB geometry was estimated using glandularity map image pairs corrected for the presence of non-glandular fibrous tissue. Heterogeneity of tissue distribution was quantified usingmore » the glandular tissue distribution index, Idist. The phantom had 5 cm compressed breast thickness (MLO and CC views) and 29% whole breast glandular percentage. Results: Differences as high as 116% were found between the MGD coefficients with the homogeneous breast core assumption and those from the corresponding ground truth. Higher differences were found for cases with more heterogeneous distribution of glandular tissue. The Idist for all cases was in the [−0.8{sup −}+0.3] range. The use of the methods presented in this work results in better agreement with ground truth with an improvement as high as 105 pp. The decrease in difference across all phantom cases was in the [9{sup −}105] pp range, dependent on the distribution of glandular tissue and was larger for the cases with the highest Idist values. Conclusion: Our results suggest that the use of corrected glandularity image pairs, as well as the HLB geometry, improves the estimates of MGD conversion coefficients by accounting for the distribution of glandular tissue within the breast. The accuracy of this approach with respect to ground truth is highly dependent on the particular glandular tissue distribution studied. Predrag Bakic

  7. Visualizing spatial distribution of alectinib in murine brain using quantitative mass spectrometry imaging.

    PubMed

    Aikawa, Hiroaki; Hayashi, Mitsuhiro; Ryu, Shoraku; Yamashita, Makiko; Ohtsuka, Naoto; Nishidate, Masanobu; Fujiwara, Yasuhiro; Hamada, Akinobu

    2016-03-30

    In the development of anticancer drugs, drug concentration measurements in the target tissue have been thought to be crucial for predicting drug efficacy and safety. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is commonly used for determination of average drug concentrations; however, complete loss of spatial information in the target tissue occurs. Mass spectrometry imaging (MSI) has been recently applied as an innovative tool for detection of molecular distribution of pharmacological agents in heterogeneous targets. This study examined the intra-brain transitivity of alectinib, a novel anaplastic lymphoma kinase inhibitor, using a combination of matrix-assisted laser desorption ionization-MSI and LC-MS/MS techniques. We first analyzed the pharmacokinetic profiles in FVB mice and then examined the effect of the multidrug resistance protein-1 (MDR1) using Mdr1a/b knockout mice including quantitative distribution of alectinib in the brain. While no differences were observed between the mice for the plasma alectinib concentrations, diffuse alectinib distributions were found in the brain of the Mdr1a/b knockout versus FVB mice. These results indicate the potential for using quantitative MSI for clarifying drug distribution in the brain on a microscopic level, in addition to suggesting a possible use in designing studies for anticancer drug development and translational research.

  8. Visualizing spatial distribution of alectinib in murine brain using quantitative mass spectrometry imaging

    PubMed Central

    Aikawa, Hiroaki; Hayashi, Mitsuhiro; Ryu, Shoraku; Yamashita, Makiko; Ohtsuka, Naoto; Nishidate, Masanobu; Fujiwara, Yasuhiro; Hamada, Akinobu

    2016-01-01

    In the development of anticancer drugs, drug concentration measurements in the target tissue have been thought to be crucial for predicting drug efficacy and safety. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is commonly used for determination of average drug concentrations; however, complete loss of spatial information in the target tissue occurs. Mass spectrometry imaging (MSI) has been recently applied as an innovative tool for detection of molecular distribution of pharmacological agents in heterogeneous targets. This study examined the intra-brain transitivity of alectinib, a novel anaplastic lymphoma kinase inhibitor, using a combination of matrix-assisted laser desorption ionization–MSI and LC-MS/MS techniques. We first analyzed the pharmacokinetic profiles in FVB mice and then examined the effect of the multidrug resistance protein-1 (MDR1) using Mdr1a/b knockout mice including quantitative distribution of alectinib in the brain. While no differences were observed between the mice for the plasma alectinib concentrations, diffuse alectinib distributions were found in the brain of the Mdr1a/b knockout versus FVB mice. These results indicate the potential for using quantitative MSI for clarifying drug distribution in the brain on a microscopic level, in addition to suggesting a possible use in designing studies for anticancer drug development and translational research. PMID:27026287

  9. Single and Multiple Dose Pharmacokinetics of Maraviroc in Saliva, Semen, and Rectal Tissue of Healthy HIV-negative Men

    PubMed Central

    Patterson, Kristine B.; Malone, Stephanie A.; Shaheen, Nicholas J.; Asher Prince, Heather M.; Dumond, Julie B.; Spacek, Melissa B.; Heidt, Paris E.; Cohen, Myron S.; Kashuba, Angela D. M.

    2011-01-01

    Background. Antiretroviral pharmacology in seminal plasma (SP) and rectal tissue (RT) may provide insight into antiretroviral resistance and the prevention of sexual transmission of human immunodeficiency virus (HIV). Saliva may be of utility for noninvasively measuring adherence. Methods. A pharmacokinetic study was performed in 12 HIV-negative men receiving maraviroc 300 mg twice daily for 8 days. Seven time-matched pairs of blood plasma (BP) and saliva samples were collected over 12 h on day 1 (PK1) and days 7 and 8 (PK2). One RT sample from each subject was collected during PK1 and PK2. Two SP samples were collected from each subject during PK1, and 6 SP samples were collected from each subject during PK2. Results. SP AUCs were ∼50% lower than BP. However, protein binding in SP ranged from 4% to 25%, resulting in protein-free concentrations >2-fold higher than BP. RT AUCs were 7.5- to 26-fold higher than BP. Maraviroc saliva AUCs were ∼70% lower than BP, but saliva concentrations correlated with BP (r2 = 0.58). Conclusions. More pharmacologically available maraviroc was found in SP than BP. High RT concentrations are promising for preventing rectal HIV acquisition. Saliva correlation with BP suggests that this may be useful for monitoring adherence. Clinical Trials Registration. NCT00775294. PMID:21502084

  10. Pharmacokinetics of detomidine and its metabolites following intravenous and intramuscular administration in horses.

    PubMed

    Grimsrud, K N; Mama, K R; Thomasy, S M; Stanley, S D

    2009-04-01

    Detomidine is commonly used i.v. for sedation and analgesia in horses, but the pharmacokinetics and metabolism of this drug have not been well described. To describe the pharmacokinetics of detomidine and its metabolites, 3-hydroxy-detomidine (OH-detomidine) and detomidine 3-carboxylic acid (COOH-detomidine), after i.v. and i.m. administration of a single dose to horses. Eight horses were used in a balanced crossover design study. In Phase 1, 4 horses received a single dose of i.v. detomidine, administered 30 microg/kg bwt and 4 a single dose i.m. 30 microg/kg bwt. In Phase 2, treatments were reversed. Plasma detomidine, OH-detomidine and COOH-detomidine were measured at predetermined time points using liquid chromatography-mass spectrometry. Following i.v. administration, detomidine was distributed rapidly and eliminated with a half-life (t1/2(el)) of approximately 30 min. Following i.m. administration, detomidine was distributed and eliminated with t1/2(el) of approximately one hour. Following, i.v. administration, detomidine clearance had a mean, median and range of 12.41, 11.66 and 10.10-18.37 ml/min/kg bwt, respectively. Detomidine had a volume of distribution with the mean, median and range for i.v. administration of 470, 478 and 215-687 ml/kg bwt, respectively. OH-detomidine was detected sooner than COOH-detomidine; however, COOH-detomidine had a much greater area under the curve. These pharmacokinetic parameters provide information necessary for determination of peak plasma concentrations and clearance of detomidine in mature horses. The results suggest that, when a longer duration of plasma concentration is warranted, the i.m. route should be considered.

  11. Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV-infected infants and toddlers.

    PubMed

    Zhao, Wei; Cella, Massimo; Della Pasqua, Oscar; Burger, David; Jacqz-Aigrain, Evelyne

    2012-04-01

    Abacavir is used to treat HIV infection in both adults and children. The recommended paediatric dose is 8 mg kg(-1) twice daily up to a maximum of 300 mg twice daily. Weight was identified as the central covariate influencing pharmacokinetics of abacavir in children. A population pharmacokinetic model was developed to describe both once and twice daily pharmacokinetic profiles of abacavir in infants and toddlers. Standard dosage regimen is associated with large interindividual variability in abacavir concentrations. A maximum a posteriori probability Bayesian estimator of AUC(0-) (t) based on three time points (0, 1 or 2, and 3 h) is proposed to support area under the concentration-time curve (AUC) targeted individualized therapy in infants and toddlers. To develop a population pharmacokinetic model for abacavir in HIV-infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration-time curve (AUC) targeted dosage and individualize therapy. The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with first-order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross-validation and simulation-estimation method. The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 () h−1 (RSE 6.3%), apparent central volume of distribution 4.94 () (RSE 28.7%), apparent peripheral volume of distribution 8.12 () (RSE14.2%), apparent intercompartment clearance 1.25 () h−1 (RSE 16.9%) and absorption rate constant 0.758 h−1 (RSE 5.8%). The covariate analysis

  12. Pharmacokinetic drivers of toxicity for basic molecules: Strategy to lower pKa results in decreased tissue exposure and toxicity for a small molecule Met inhibitor

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Diaz, Dolores, E-mail: diaz.dolores@gene.com; Ford, Kevin A.; Hartley, Dylan P.

    Several toxicities are clearly driven by free drug concentrations in plasma, such as toxicities related to on-target exaggerated pharmacology or off-target pharmacological activity associated with receptors, enzymes or ion channels. However, there are examples in which organ toxicities appear to correlate better with total drug concentrations in the target tissues, rather than with free drug concentrations in plasma. Here we present a case study in which a small molecule Met inhibitor, GEN-203, with significant liver and bone marrow toxicity in preclinical species was modified with the intention of increasing the safety margin. GEN-203 is a lipophilic weak base as demonstratedmore » by its physicochemical and structural properties: high LogD (distribution coefficient) (4.3) and high measured pKa (7.45) due to the basic amine (N-ethyl-3-fluoro-4-aminopiperidine). The physicochemical properties of GEN-203 were hypothesized to drive the high distribution of this compound to tissues as evidenced by a moderately-high volume of distribution (Vd > 3 l/kg) in mouse and subsequent toxicities of the compound. Specifically, the basicity of GEN-203 was decreased through addition of a second fluorine in the 3-position of the aminopiperidine to yield GEN-890 (N-ethyl-3,3-difluoro-4-aminopiperidine), which decreased the volume of distribution of the compound in mouse (Vd = 1.0 l/kg), decreased its tissue drug concentrations and led to decreased toxicity in mice. This strategy suggests that when toxicity is driven by tissue drug concentrations, optimization of the physicochemical parameters that drive tissue distribution can result in decreased drug concentrations in tissues, resulting in lower toxicity and improved safety margins. -- Highlights: ► Lower pKa for a small molecule: reduced tissue drug levels and toxicity. ► New analysis tools to assess electrostatic effects and ionization are presented. ► Chemical and PK drivers of toxicity can be leveraged to improve safety.« less

  13. Metronidazole pharmacokinetics in patients with acute renal failure.

    PubMed

    Somogyi, A A; Kong, C B; Gurr, F W; Sabto, J; Spicer, W J; McLean, A J

    1984-02-01

    The pharmacokinetics and metabolism of intravenous metronidazole were studied in six patients with acute renal failure. In two of the patients a single dose (500 mg) of metronidazole was administered, whereas in four patients the steady-state pharmacokinetics were studied after four days therapy of 500 mg twice daily. Plasma concentrations of metronidazole and its hydroxy and acetic acid metabolites were measured by a specific and sensitive HPLC method. The volume of distribution was 0.65 +/- 0.13 l/kg (mean +/- S.D.), elimination half-life was 9.9 +/- 2.5 h and total plasma clearance was 55.5 +/- 17.7 ml/min. Renal clearance was almost non-existent (1.4 +/- 1.4 ml/min), whereas non-renal clearance was 54.0 +/- 18.2 ml/min. Steady-state plasma concentrations of metronidazole were 15.3 +/- 3.8 mg/l, the hydroxy metabolite were 17.4 +/- 2.0 mg/l and the acetic acid metabolite were 1.2 +/- 0.8 mg/l. In the patients studied, a dosing regimen of 500 mg twice daily resulted in therapeutically adequate blood levels of metronidazole.

  14. ADAM, a hands‐on patient simulator for teaching principles of drug disposition and compartmental pharmacokinetics

    PubMed Central

    Zuna, Ines

    2017-01-01

    Aims To design, construct and validate a pharmacokinetics simulator that offers students hands‐on opportunities to participate in the design, administration and analysis of oral and intravenous dosing regimens. Methods The Alberta Drug Administration Modeller (ADAM) is a mechanical patient in which peristaltic circulation of water through a network of silicone tubing and glass bottles creates a representation of the outcomes of drug absorption, distribution, metabolism and elimination. Changing peristaltic pump rates and volumes in bottles allows values for pharmacokinetic constants to be varied, thereby simulating differences in drug properties and in patient physiologies and pathologies. Following administration of methylene blue dye by oral or intravenous routes, plasma and/or urine samples are collected and drug concentrations are determined spectrophotometrically. The effectiveness of the simulator in enhancing student competence and confidence was assessed in two undergraduate laboratory classes. Results The simulator effectively models one‐ and two‐compartment drug behaviour in a mathematically‐robust and realistic manner. Data allow calculation of numerous pharmacokinetic constants, by traditional graphing methods or with curve‐fitting software. Students' competence in solving pharmacokinetic problems involving calculations and graphing improved significantly, while an increase in confidence and understanding was reported. Conclusions The ADAM is relatively inexpensive and straightforward to construct, and offers a realistic, hands‐on pharmacokinetics learning opportunity for students that effectively complements didactic lectures. PMID:28666308

  15. Pharmacokinetics of pancreatic polypeptide in man.

    PubMed

    Adrian, T E; Greenberg, G R; Besterman, H S; Bloom, S R

    1978-10-01

    Pure bovine pancreatic polypeptide (PP) was infused into 23 healthy subjects at doses of 1, 3, and 5 pmol/kg/min over 60 minutes and plasma PP was measured by radioimmunoassay. During the infusions mean plasma levels of 203 +/- 34, 575 +/- 73, and 930 +/- 48 pmol/l respectively were achieved. Mean disappearance half time on stopping the infusion was 6.9 +/- 0.3 min (mean +/- SEM). The metabolic clearance rate was 5.1 +/- 0.2 ml/kg/min (mean +/- SEM) and the apparent volume of distribution was calculated to be 51 +/- 3 ml/kg (mean +/- SEM). This study provides for the first time pharmacokinetic data for PP in man.

  16. Pharmacokinetics of pancreatic polypeptide in man.

    PubMed Central

    Adrian, T E; Greenberg, G R; Besterman, H S; Bloom, S R

    1978-01-01

    Pure bovine pancreatic polypeptide (PP) was infused into 23 healthy subjects at doses of 1, 3, and 5 pmol/kg/min over 60 minutes and plasma PP was measured by radioimmunoassay. During the infusions mean plasma levels of 203 +/- 34, 575 +/- 73, and 930 +/- 48 pmol/l respectively were achieved. Mean disappearance half time on stopping the infusion was 6.9 +/- 0.3 min (mean +/- SEM). The metabolic clearance rate was 5.1 +/- 0.2 ml/kg/min (mean +/- SEM) and the apparent volume of distribution was calculated to be 51 +/- 3 ml/kg (mean +/- SEM). This study provides for the first time pharmacokinetic data for PP in man. PMID:568585

  17. Population pharmacokinetics of abacavir in infants, toddlers and children.

    PubMed

    Zhao, Wei; Piana, Chiara; Danhof, Meindert; Burger, David; Della Pasqua, Oscar; Jacqz-Aigrain, Evelyne

    2013-06-01

    To characterize the pharmacokinetics of abacavir in infants, toddlers and children and to assess the influence of covariates on drug disposition across these populations. Abacavir concentration data from three clinical studies in human immunodeficiency virus-infected children (n = 69) were used for model building. The children received either a weight-normalized dose of 16 mg kg(-1) day(-1) or the World Health Organization recommended dose based on weight bands. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling VI. The influence of age, gender, bodyweight and formulation was evaluated. The final model was selected according to graphical and statistical criteria. A two-compartmental model with first-order absorption and first-order elimination best described the pharmacokinetics of abacavir. Bodyweight was identified as significant covariate influencing the apparent oral clearance and volume of distribution. Predicted steady-state maximal plasma concentration and area under the concentration-time curve from 0 to 12 h of the standard twice daily regimen were 2.5 mg l(-1) and 6.1 mg h l(-1) for toddlers and infants, and 3.6 mg l(-1) and 8.7 mg h l(-1) for children, respectively. Model-based predictions showed that equivalent systemic exposure was achieved after once and twice daily dosing regimens. There were no pharmacokinetic differences between the two formulations (tablet and solution). The model demonstrated good predictive performance for dosing prediction in individual patients and, as such, can be used to support therapeutic drug monitoring in conjunction with sparse sampling. The disposition of abacavir in children appears to be affected only by differences in size, irrespective of the patient's age. Maturation processes of abacavir metabolism in younger infants should be evaluated in further studies to demonstrate the potential impact of ontogeny. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012

  18. Population pharmacokinetics of abacavir in infants, toddlers and children

    PubMed Central

    Zhao, Wei; Piana, Chiara; Danhof, Meindert; Burger, David; Della Pasqua, Oscar; Jacqz-Aigrain, Evelyne

    2013-01-01

    Aims To characterize the pharmacokinetics of abacavir in infants, toddlers and children and to assess the influence of covariates on drug disposition across these populations. Methods Abacavir concentration data from three clinical studies in human immunodeficiency virus-infected children (n = 69) were used for model building. The children received either a weight-normalized dose of 16 mg kg−1 day−1 or the World Health Organization recommended dose based on weight bands. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling VI. The influence of age, gender, bodyweight and formulation was evaluated. The final model was selected according to graphical and statistical criteria. Results A two-compartmental model with first-order absorption and first-order elimination best described the pharmacokinetics of abacavir. Bodyweight was identified as significant covariate influencing the apparent oral clearance and volume of distribution. Predicted steady-state maximal plasma concentration and area under the concentration–time curve from 0 to 12 h of the standard twice daily regimen were 2.5 mg l−1 and 6.1 mg h l−1 for toddlers and infants, and 3.6 mg l−1 and 8.7 mg h l−1 for children, respectively. Model-based predictions showed that equivalent systemic exposure was achieved after once and twice daily dosing regimens. There were no pharmacokinetic differences between the two formulations (tablet and solution). The model demonstrated good predictive performance for dosing prediction in individual patients and, as such, can be used to support therapeutic drug monitoring in conjunction with sparse sampling. Conclusions The disposition of abacavir in children appears to be affected only by differences in size, irrespective of the patient's age. Maturation processes of abacavir metabolism in younger infants should be evaluated in further studies to demonstrate the potential impact of ontogeny. PMID:23126277

  19. Noncontact 3-D Speckle Contrast Diffuse Correlation Tomography of Tissue Blood Flow Distribution.

    PubMed

    Huang, Chong; Irwin, Daniel; Zhao, Mingjun; Shang, Yu; Agochukwu, Nneamaka; Wong, Lesley; Yu, Guoqiang

    2017-10-01

    Recent advancements in near-infrared diffuse correlation techniques and instrumentation have opened the path for versatile deep tissue microvasculature blood flow imaging systems. Despite this progress there remains a need for a completely noncontact, noninvasive device with high translatability from small/testing (animal) to large/target (human) subjects with trivial application on both. Accordingly, we discuss our newly developed setup which meets this demand, termed noncontact speckle contrast diffuse correlation tomography (nc_scDCT). The nc_scDCT provides fast, continuous, portable, noninvasive, and inexpensive acquisition of 3-D tomographic deep (up to 10 mm) tissue blood flow distributions with straightforward design and customization. The features presented include a finite-element-method implementation for incorporating complex tissue boundaries, fully noncontact hardware for avoiding tissue compression and interactions, rapid data collection with a diffuse speckle contrast method, reflectance-based design promoting experimental translation, extensibility to related techniques, and robust adjustable source and detector patterns and density for high resolution measurement with flexible regions of interest enabling unique application-specific setups. Validation is shown in the detection and characterization of both high and low contrasts in flow relative to the background using tissue phantoms with a pump-connected tube (high) and phantom spheres (low). Furthermore, in vivo validation of extracting spatiotemporal 3-D blood flow distributions and hyperemic response during forearm cuff occlusion is demonstrated. Finally, the success of instrument feasibility in clinical use is examined through the intraoperative imaging of mastectomy skin flap.

  20. Preparation and evaluation of enrofloxacin microspheres and tissue distribution in rats

    PubMed Central

    Yang, Fan; Kang, Jijun; Yang, Fang; Zhao, Zhensheng; Kong, Tao

    2015-01-01

    New enrofloxacin microspheres were formulated, and their physical properties, lung-targeting ability, and tissue distribution in rats were examined. The microspheres had a regular and round shape. The mean diameter was 10.06 µm, and the diameter of 89.93% of all microspheres ranged from 7.0 µm to 30.0 µm. Tissue distribution of the microspheres was evaluated along with a conventional enrofloxacin preparation after a single intravenous injection (7.5 mg of enrofloxacin/kg bw). The results showed that the elimination half-life (t1/2β) of enrofloxacin from lung was prolonged from 7.94 h for the conventional enrofloxacin to 13.28 h for the microspheres. Area under the lung concentration versus time curve from 0 h to ∞ (AUC0-∞) was increased from 11.66 h·µg/g to 508.00 h·µg/g. The peak concentration (Cmax) in lung was increased from 5.95 µg/g to 93.36 µg/g. Three lung-targeting parameters were further assessed and showed that the microspheres had remarkable lung-targeting capabilities. PMID:25643802

  1. Preparation and evaluation of enrofloxacin microspheres and tissue distribution in rats.

    PubMed

    Yang, Fan; Kang, Jijun; Yang, Fang; Zhao, Zhensheng; Kong, Tao; Zeng, Zhenling

    2015-01-01

    New enrofloxacin microspheres were formulated, and their physical properties, lung-targeting ability, and tissue distribution in rats were examined. The microspheres had a regular and round shape. The mean diameter was 10.06 µm, and the diameter of 89.93% of all microspheres ranged from 7.0 µm to 30.0 µm. Tissue distribution of the microspheres was evaluated along with a conventional enrofloxacin preparation after a single intravenous injection (7.5 mg of enrofloxacin/kg bw). The results showed that the elimination half-life (t1/2β) of enrofloxacin from lung was prolonged from 7.94 h for the conventional enrofloxacin to 13.28 h for the microspheres. Area under the lung concentration versus time curve from 0 h to ∞ (AUC00∞) was increased from 11.66 h·µg/g to 508.00 h·µg/g. The peak concentration (Cmax) in lung was increased from 5.95 µg/g to 93.36 µg/g. Three lung-targeting parameters were further assessed and showed that the microspheres had remarkable lung-targeting capabilities.

  2. Accumulation and distribution of selenium in mussel and shrimp tissues

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Fowler, S.W.; Benayoun, G.

    1976-09-01

    The tissue distribution of selenium in mussels and shrimp was examined and the bioaccumulation kinetics in the various tissues was elucidated with the aid of radio selenium. Mussels (Mytilus galloprovincialis) and shrimp (Lysmata seticaudata) collected near the Monaco port, were apportioned into several groups. One group of mussels and shrimp was maintained in sea water containing 0.8 ..mu..Ci/liter high specific activity Se-75. Three to four individuals were dissected and their tissues monitored for Se-75 content periodically. Another group of shrimp, maintained in flowing sea water, were fed ad libitum mussels that had previously accumulated Se-75 from sea water for severalmore » days. Shrimp were periodically dissected to follow tissue accumulation of ingested selenium. The highest concentrations of selenium were found in the exoskeleton, presumably due, in part, to the relatively large amount of isotope sorbed to its outer surface. Molts, cast by shrimp at various times throughout uptake, contained from 60 to 90% of the total Se-75 body burden. Direct uptake of water led to initially small fractions in internal tissues such as muscle and viscera compared to the relatively large fraction associated with the exoskeleton. With time percentages in internal tissues gradually increased relative to that in the exoskeleton. When Se-75 was accumulated through the food chain an opposite trend was noted with the Se-75 fraction in exoskeleton slowly increasing and that in viscera decreasing during the course of the experiment. All tissues examined readily accumulated the isotope and, in general, did not appear to have reached a steady state concentration after 63 days. The highest Se-75 concentrations were found in the visceral mass with lesser amounts in gills, muscle and mantle, in that order.« less

  3. Testing methods of pressure distribution of bra cups on breasts soft tissue

    NASA Astrophysics Data System (ADS)

    Musilova, B.; Nemcokova, R.; Svoboda, M.

    2017-10-01

    Objective of this study is to evaluate testing methods of pressure distribution of bra cups on breasts soft tissue, the system which do not affect the space between the wearer's body surface and bra cups and thus do not influence the geometry of the measured body surface and thus investigate the functional performance of brassieres. Two measuring systems were used for the pressure comfort evaluating: 1) The pressure distribution of a wearing bra during 20 minutes on women's breasts has been directly measured using pressure sensor, a dielectricum which is elastic polyurethane foam bra cups. Twelve points were measured in bra cups. 2) Simultaneously the change of temperature in the same points bra was tested with the help of noncontact system the thermal imager. The results indicate that both of those systems can identify different pressure distribution at different points. The same size of bra designing features bra cups made from the same material and which is define by the help of same standardised body dimensions (bust and underbust) can cause different value of a compression on different shape of a woman´s breast soft tissue.

  4. Pharmacokinetics (PK), Pharmacodynamics (PD), and PK-PD Integration of Danofloxacin in Sheep Biological Fluids

    PubMed Central

    Aliabadi, F. Shojaee; Landoni, M. F.; Lees, P.

    2003-01-01

    The fluoroquinolone antimicrobial drug danofloxacin was administered to sheep intravenously (i.v.) and intramuscularly (i.m.) at a dose of 1.25 mg/kg of body weight in a two-period crossover study. The pharmacokinetic properties of danofloxacin in serum, inflamed tissue cage fluid (exudate), and noninflamed tissue cage fluid (transudate) were established by using a tissue cage model. The in vitro and ex vivo activities of danofloxacin in serum, exudate, and transudate against a pathogenic strain of Mannheimia haemolytica were established. Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the area under the curve (AUC)/MIC for serum, exudate, and transudate of 60.5, 85.6, and 45.7 h, respectively, after i.v. dosing and 55.9, 77.9, and 49.1 h, respectively, after i.m. dosing. After i.m. dosing, the maximum concentration/MIC ratios for serum, exudate, and transudate were 10.8, 3.0, and 1.6, respectively. The ex vivo growth inhibition data after i.m. dosing were fitted to the inhibitory sigmoid Emax equation to provide the values of AUC/MIC required to produce bacteriostasis, bactericidal activity, and elimination of bacteria. The respective values for serum were 17.8, 20.2, and 28.7 h, and slightly higher values were obtained for transudate and exudate. It is proposed that use of these data might provide a novel approach to the rational design of dosage schedules. PMID:12543670

  5. Effect of age and sex on lacosamide pharmacokinetics in healthy adult subjects and adults with focal epilepsy.

    PubMed

    Schaefer, Carina; Cawello, Willi; Waitzinger, Josef; Elshoff, Jan-Peer

    2015-04-01

    Age- and sex-related differences in body composition could affect the pharmacokinetic parameters of administered drugs. The purpose of this post hoc analysis was to investigate the influences of age and sex on the pharmacokinetics of lacosamide. This post hoc analysis used pharmacokinetic data taken at steady state from (i) two phase I studies of oral lacosamide in healthy adult subjects (n = 66), and (ii) a population pharmacokinetic analysis carried out using data from two phase III studies of adjunctive oral lacosamide in adults (n = 565) with focal epilepsy taking 1-3 concomitant anti-epileptic drugs. Phase I data were stratified by age and sex as 'younger female' (aged 18-40 years), 'younger male' (aged 18-45 years) or 'elderly male/female' (aged ≥65 years), then normalized by body weight (lean body weight or fat-free mass), height or volume of distribution, and analysed using non-compartmental analysis. Population pharmacokinetic data were stratified by sex and analysed using a one-compartment model. Minor numerical differences between lacosamide exposure [the area under the concentration-time curve at steady state over the dosage interval (AUCτ,ss)] and the maximum plasma concentration at steady state (C max,ss) in subjects of different ages or sexes were noted. The differences could be explained by a scaling factor between the drug applied and the plasma concentration. Following normalization by lean body weight or volume of distribution, an analysis of relative bioavailability resulted in 90 % confidence intervals of the ratios for AUCτ,ss and C max,ss for age (elderly to younger) or sex (male to female) falling within the range accepted for equivalence (80-125 %); without normalization, the 90 % confidence intervals were outside this range. Minor numerical differences in lacosamide plasma concentrations were noted in the comparison between male and female patients (aged 16-71 years) with focal epilepsy. Simulations using different body weights

  6. Pharmacokinetics of oral amantadine in greyhound dogs.

    PubMed

    Norkus, C; Rankin, D; Warner, M; KuKanich, B

    2015-06-01

    This study reports the pharmacokinetics of amantadine in greyhound dogs after oral administration. Five healthy greyhound dogs were used. A single oral dose of 100 mg amantadine hydrochloride (mean dose 2.8 mg/kg as amantadine hydrochloride) was administered to nonfasted subjects. Blood samples were collected at predetermined time points from 0 to 24 h after administration, and plasma concentrations of amantadine were measured by liquid chromatography with triple quadrupole mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Amantadine was well tolerated in all dogs with no adverse effects observed. The mean (range) amantadine CMAX was 275 ng/mL (225-351 ng/mL) at 2.6 h (1-4 h) with a terminal half-life of 4.96 h (4.11-6.59 h). The results of this study can be used to design dosages to assess multidose pharmacokinetics and dosages designed to achieve targeted concentrations in order to assess the clinical effects of amantadine in a variety of conditions including chronic pain. Further studies should also assess the pharmacokinetics of amantadine in other dog breeds or using population pharmacokinetics studies including multiple dog breeds to assess potential breed-specific differences in the pharmacokinetics of amantadine in dogs. © 2014 John Wiley & Sons Ltd.

  7. Diclofenac and metabolite pharmacokinetics in children.

    PubMed

    van der Marel, Caroline D; Anderson, Brian J; Rømsing, Janne; Jacqz-Aigrain, Evelyne; Tibboel, Dick

    2004-06-01

    Data concerning metabolism of diclofenac in children are limited to intravenous and enteric coated oral formulations. There are no data examining diclofenac or its hydroxyl metabolite pharmacokinetics after rectal administration in children. Infants (n = 26) undergoing tonsillectomy were given diclofenac 2 mg.kg(-1) followed by 1 mg.kg(-1) 8 h as suppository formulation for postoperative analgesia. Serum was assayed for diclofenac, 4'-hydroxydiclofenac and 5'-hydroxydiclofenac concentrations during the procedure and 1, 2 and 4 h postoperatively. The formation clearances of diclofenac to hydroxyl metabolites were estimated using nonlinear mixed effects models. A single compartment, first order absorption and first order elimination model was used to describe diclofenac pharmacokinetics. Published data from 11 children given enteric-coated diclofenac tablets were used to assess relative bioavailability. Mean (sd) age and weight of the patients were 4.5 (1.5) years and 20.5 (4.1) kg. The formation clearance to 4'-hydroxydiclofenac (% CV) and to 5'-hydroxydiclofenac were 8.41 (8.1) and 3.41 (113) l.h(-1) respectively, standardized to a 70 kg person using allometric '1/4 power' models. Clearance by other routes contributed 33.0 (64) l.h(-1) 70 kg(-1). Elimination clearance of hydroxyl metabolites was fixed at 27.5 l.h(-1) 70 kg(-1). The volumes of distribution of parent diclofenac and its hydroxyl metabolite were 22.8 (19.0) and 45.3 (l.70) kg(-1). The suppository formulation had an absorption half-life of 0.613 (33.2) h with a lag time of 0.188 (24.9) h. Interoccasion variability of formation clearance to 4'-hydroxydiclofenac, diclofenac volume of distribution, absorption half-time and lag time for the suppository was 36%, 55%, 14% and 119%, respectively. The relative bioavailability of the suppository compared with an enteric-coated tablet was 1.26. The formation clearance of the active metabolite 4'-hydroxydiclofenac contributed 19% of total clearance (44.82 l.h(-1

  8. Scale-up of a physiologically-based pharmacokinetic model to predict the disposition of monoclonal antibodies in monkeys.

    PubMed

    Glassman, Patrick M; Chen, Yang; Balthasar, Joseph P

    2015-10-01

    Preclinical assessment of monoclonal antibody (mAb) disposition during drug development often includes investigations in non-human primate models. In many cases, mAb exhibit non-linear disposition that relates to mAb-target binding [i.e., target-mediated disposition (TMD)]. The goal of this work was to develop a physiologically-based pharmacokinetic (PBPK) model to predict non-linear mAb disposition in plasma and in tissues in monkeys. Physiological parameters for monkeys were collected from several sources, and plasma data for several mAbs associated with linear pharmacokinetics were digitized from prior literature reports. The digitized data displayed great variability; therefore, parameters describing inter-antibody variability in the rates of pinocytosis and convection were estimated. For prediction of the disposition of individual antibodies, we incorporated tissue concentrations of target proteins, where concentrations were estimated based on categorical immunohistochemistry scores, and with assumed localization of target within the interstitial space of each organ. Kinetics of target-mAb binding and target turnover, in the presence or absence of mAb, were implemented. The model was then employed to predict concentration versus time data, via Monte Carlo simulation, for two mAb that have been shown to exhibit TMD (2F8 and tocilizumab). Model predictions, performed a priori with no parameter fitting, were found to provide good prediction of dose-dependencies in plasma clearance, the areas under plasma concentration versu time curves, and the time-course of plasma concentration data. This PBPK model may find utility in predicting plasma and tissue concentration versus time data and, potentially, the time-course of receptor occupancy (i.e., mAb-target binding) to support the design and interpretation of preclinical pharmacokinetic-pharmacodynamic investigations in non-human primates.

  9. Distribution of the lingual lymphoid tissue in domestic ruminants.

    PubMed

    Breugelmans, S; Casteleyn, C; Simoens, P; Van den Broeck, W

    2011-12-01

    The distribution and organisation of the intralingual lymphoid tissue was studied in sheep, goat and cattle. For each species, the tongues of two animals were harvested and divided in sample blocks extending over the total surface of the tongue. With 2.5 mm intervals, ten serial histological sections were made for conventional histological staining (haematoxylin-eosin, Van Gieson, Masson's trichrome) and immunohistochemical staining of lymphoid cells (anti-CD3, anti-CD21, anti-CD45). Lymphocytes were scattered in the subepithelial propria-submucosa and in the connective tissue cores of the lingual papillae. The connective tissue cores of fungiform papillae, including those located on the lingual apex, and vallate papillae showed relatively more lymphocytes than the propria-submucosa. Lymphoid cell aggregations were even more abundant beneath the grooves surrounding the vallate papillae in small ruminants. In cattle, a well-organised lingual tonsil was additionally found at the root of the tongue. CD3-positive lymphocytes were observed in all species examined. CD21-positive lymphocytes were numerous in the lymphoid nodules of the bovine lingual tonsil but very scarce in the ovine and caprine tongues. Therefore, the lymphoid cell aggregations in the tongues of small ruminants should not be referred to by the term 'lingual tonsil'. © 2011 Blackwell Verlag GmbH.

  10. Pharmacokinetics-on-a-Chip Using Label-Free SERS Technique for Programmable Dual-Drug Analysis.

    PubMed

    Fei, Jiayuan; Wu, Lei; Zhang, Yizhi; Zong, Shenfei; Wang, Zhuyuan; Cui, Yiping

    2017-06-23

    Synergistic effects of dual or multiple drugs have attracted great attention in medical fields, especially in cancer therapies. We provide a programmable microfluidic platform for pharmacokinetic detection of multiple drugs in multiple cells. The well-designed microfluidic platform includes two 2 × 3 microarrays of cell chambers, two gradient generators, and several pneumatic valves. Through the combined use of valves and gradient generators, each chamber can be controlled to infuse different kinds of living cells and drugs with specific concentrations as needed. In our experiments, 6-mercaptopurine (6MP) and methimazole (MMI) were chosen as two drug models and their pharmacokinetic parameters in different living cells were monitored through intracellular SERS spectra, which reflected the molecular structure of these drugs. The dynamic change of SERS fingerprints from 6MP and MMI molecules were recorded during drug metabolism in living cells. The results indicated that both 6MP and MMI molecules were diffused into the cells within 4 min and excreted out after 36 h. Moreover, the intracellular distribution of these drugs was monitored through SERS mapping. Thus, our microfluidic platform simultaneously accomplishes the functions to monitor pharmacokinetic action, distribution, and fingerprint of multiple drugs in multiple cells. Owing to its real-time, rapid-speed, high-precision, and programmable capability of multiple-drug and multicell analysis, such a microfluidic platform has great potential in drug design and development.

  11. Pharmacokinetics of Curcumin Diethyl Disuccinate, a Prodrug of Curcumin, in Wistar Rats.

    PubMed

    Bangphumi, Kunan; Kittiviriyakul, Chuleeporn; Towiwat, Pasarapa; Rojsitthisak, Pornchai; Khemawoot, Phisit

    2016-12-01

    Curcumin is the major bioactive component of turmeric, but has poor oral bioavailability that limits its clinical applications. To improve the in vitro solubility and alkaline stability, we developed a prodrug of curcumin by succinylation to obtain curcumin diethyl disuccinate, with the goal of improving the oral bioavailability of curcumin. The in vivo pharmacokinetic profile of curcumin diethyl disuccinate was compared with that of curcumin in male Wistar rats. Doses of curcumin 20 mg/kg intravenous or 40 mg/kg oral were used as standard regimens for comparison with the prodrug at equivalent doses in healthy adult rats. Blood, tissues, urine, and faeces were collected from time zero to 48 h after dosing to determine the prodrug level, curcumin level and a major metabolite by liquid chromatography-tandem spectrometry. The absolute oral bioavailability of curcumin diethyl disuccinate was not significantly improved compared with curcumin, with both compounds having oral bioavailability of curcumin less than 1 %. The major metabolic pathway of the prodrug was rapid hydrolysis to obtain curcumin, followed by glucuronidation. Interestingly, curcumin diethyl disuccinate gave superior tissue distribution with higher tissue to plasma ratio of curcumin and curcumin glucuronide in several organs after intravenous dosing at 1 and 4 h. The primary elimination route of curcumin glucuronide occurred via biliary and faecal excretion, with evidence of an entry into the enterohepatic circulation. Curcumin diethyl disuccinate did not significantly improve the oral bioavailability of curcumin due to first pass metabolism in the gastrointestinal tract. Further studies on reduction of first pass metabolism are required to optimise delivery of curcumin using a prodrug approach.

  12. Pharmacokinetics and metabolism of hydroxytyrosol, a natural antioxidant from olive oil.

    PubMed

    D'Angelo, S; Manna, C; Migliardi, V; Mazzoni, O; Morrica, P; Capasso, G; Pontoni, G; Galletti, P; Zappia, V

    2001-11-01

    3,4-Dihydroxyphenylethanol (DOPET) is the major o-diphenol detectable in extra virgin olive oil, either in free or esterified form. Despite its relevant biological effects, mainly related to its antioxidant properties, little data have been reported so far on its toxicity and metabolism. The aim of the present work is to evaluate DOPET toxicity and to investigate its molecular pharmacokinetics by using the (14)C-labeled diphenol. When orally administered to rats, the molecule does not show appreciable toxicity up to 2 g/kg b.wt. To identify and quantify its metabolites, [(14)C]DOPET has been synthesized and intravenously injected in rats. The pharmacokinetic analysis indicates a fast and extensive uptake of the molecule by the organs and tissues investigated, with a preferential renal uptake. Moreover, 90% of the administered radioactivity is excreted in urine collected up to 5 h after injection, and about 5% is detectable in feces and gastrointestinal content. The characterization of the labeled metabolites, extracted from the organs and urine, has been performed by high-pressure liquid chromatography analysis. In all the investigated tissues, DOPET is enzymatically converted in four oxidized and/or methylated derivatives. Moreover, a significant fraction of total radioactivity is associated with the sulfo-conjugated forms, which also represent the major urinary excretion products. On the basis of the reported results, an intracellular metabolic pathway of exogenously administered DOPET, implying the involvement of catechol-O-methyltransferase, alcohol dehydrogenase, aldehyde dehydrogenase, and phenolsulfotransferase, has been proposed.

  13. Influence of biophase distribution and P-glycoprotein interaction on pharmacokinetic-pharmacodynamic modelling of the effects of morphine on the EEG

    PubMed Central

    Groenendaal, D; Freijer, J; de Mik, D; Bouw, M R; Danhof, M; de Lange, E C M

    2007-01-01

    Background and purpose: The aim was to investigate the influence of biophase distribution including P-glycoprotein (Pgp) function on the pharmacokinetic-pharmacodynamic correlations of morphine's actions in rat brain. Experimental approach: Male rats received a 10-min infusion of morphine as 4 mg kg−1, combined with a continuous infusion of the Pgp inhibitor GF120918 or vehicle, 10 or 40 mg kg−1. EEG signals were recorded continuously and blood samples were collected. Key results: Profound hysteresis was observed between morphine blood concentrations and effects on the EEG. Only the termination of the EEG effect was influenced by GF120918. Biophase distribution was best described with an extended catenary biophase distribution model, with a sequential transfer and effect compartment. The rate constant for transport through the transfer compartment (k1e) was 0.038 min−1, being unaffected by GF120918. In contrast, the rate constant for the loss from the effect compartment (keo) decreased 60% after GF120918. The EEG effect was directly related to concentrations in the effect compartment using the sigmoidal Emax model. The values of the pharmacodynamic parameters E0, Emax, EC50 and Hill factor were 45.0 μV, 44.5 μV, 451 ng ml−1 and 2.3, respectively. Conclusions and implications: The effects of GF120918 on the distribution kinetics of morphine in the effect compartment were consistent with the distribution in brain extracellular fluid (ECF) as estimated by intracerebral microdialysis. However, the time-course of morphine concentrations at the site of action in the brain, as deduced from the biophase model, is distinctly different from the brain ECF concentrations. PMID:17471181

  14. Oxaliplatin in patients with metastatic colorectal cancer: efficacy and pharmacokinetics parameters.

    PubMed

    Burz, C; Berindan-Neagoe, I; Balacescu, O; Todor, N; Pelau, D; Floares, C; Kacso, G; Tanaselia, C; Ursu, M; Vlase, L; Leucuta, S E; Cristea, V; Irimie, A

    2010-01-01

    The aim of this study was to investigate the efficiency of the FOLFOX-4 regimen and to evaluate the pharmacokinetics of oxaliplatin in untreated patients with metastatic colorectal cancer. 43 patients were enrolled in the study. Patients received oxaliplatin 85 mg/m(2) as 2-h i.v. infusion, on day 1, and bolus 5-fluorouracil (5FU) 400 mg/m(2) plus leucovorin (LV) 200 mg/m(2) followed by 5FU 600 mg/m(2) as 22-h infusion on day 1 and 2, every 2 weeks. The pharmacokinetics of oxaliplatin evaluated in 4 patients was performed in blood, plasma and ultrafiltered plasma (UFT) by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The overall response rate and the median time to progression (TTP) were 53.49% and 7.1 months, respectively. Grade 3-4 toxic effects were observed in 11 (25.5%) patients. Grade 3 neuropathy was observed in 13.95% of the cases. In univariate analysis only Eastern Cooperative Oncology Group (ECOG) performance status (PS) was correlated with response. No correlation was found between grade 3-4 adverse events and the patient characteristics. The area under the time-concentration curve (AUC) in UFT was 4.8 + or - 0.72 standard deviation (SD) microg h/ml and the total clearance 30.17 + or - 7.75 l/min. The values for volume of distribution and the maximum concentration were 567 + or - 20 liters and 0.38 + or - 0.17 ug/ml, respectively. FOLFOX-4 was an effective regimen with good tolerability in previously untreated metastatic colorectal cancer patients. The pharmacokinetics of oxaliplatin was triphasic with a short initial distribution phase and a long terminal elimination phase.

  15. Population pharmacokinetics of bupivacaine in combined lumbar and sciatic nerve block

    PubMed Central

    Eljebari, Hanene; Jebabli, Nadia; Salouage, Issam; Gaies, Emna; Lakhal, Mohamed; Boussofara, Mehdi; Klouz, Anis

    2014-01-01

    Objectives: The primary aim of this study was to establish the population pharmacokinetic (PPK) model of bupivacaine after combined lumbar plexus and sciatic nerve blocks and secondary aim is to assess the effect of patient's characteristics including age, body weight and sex on pharmacokinetic parameters. Materials and Methods: A total of 31 patients scheduled for elective lower extremity surgery with combined lumbar and sciatic nerve block using plain bupivacaine 0.5% were included. The total bupivacaine plasma concentrations were measured before injection and after two blocks placement and at selected time points. Monitoring of bupivacaine was made by high performance liquid chromatography (HPLC) with ultraviolet detection. Non-linear mixed effects modeling was used to analyze the PPK of bupivacaine. Results: One compartment model with first order absorption, two input compartments and a central elimination was selected. The Shapiro-Wilks test of normality for normalized prediction distribution errors for this model (P = 0.156) showed this as a valid model. The selected model predicts a population clearance of 930 ml/min (residual standard error [RSE] = 15.48%, IC 95% = 930 ± 282.24) with inter individual variability of 75.29%. The central volume of distribution was 134 l (RSE = 12.76%, IC = 134 ± 33.51 L) with inter individual variability of 63.40%. The absorption of bupivacaine in two sites Ka1 and Ka2 were 0.00462/min for the lumbar site and 0.292/min for the sciatic site. Age, body weight and sex have no effect on the bupivacaine pharmacokinetics in this studied population. Conclusion: The developed model helps us to assess the systemic absorption of bupivacaine at two injections sites. PMID:24741194

  16. Obesity alters adipose tissue macrophage iron content and tissue iron distribution.

    PubMed

    Orr, Jeb S; Kennedy, Arion; Anderson-Baucum, Emily K; Webb, Corey D; Fordahl, Steve C; Erikson, Keith M; Zhang, Yaofang; Etzerodt, Anders; Moestrup, Søren K; Hasty, Alyssa H

    2014-02-01

    Adipose tissue (AT) expansion is accompanied by the infiltration and accumulation of AT macrophages (ATMs), as well as a shift in ATM polarization. Several studies have implicated recruited M1 ATMs in the metabolic consequences of obesity; however, little is known regarding the role of alternatively activated resident M2 ATMs in AT homeostasis or how their function is altered in obesity. Herein, we report the discovery of a population of alternatively activated ATMs with elevated cellular iron content and an iron-recycling gene expression profile. These iron-rich ATMs are referred to as MFe(hi), and the remaining ATMs are referred to as MFe(lo). In lean mice, ~25% of the ATMs are MFe(hi); this percentage decreases in obesity owing to the recruitment of MFe(lo) macrophages. Similar to MFe(lo) cells, MFe(hi) ATMs undergo an inflammatory shift in obesity. In vivo, obesity reduces the iron content of MFe(hi) ATMs and the gene expression of iron importers as well as the iron exporter, ferroportin, suggesting an impaired ability to handle iron. In vitro, exposure of primary peritoneal macrophages to saturated fatty acids also alters iron metabolism gene expression. Finally, the impaired MFe(hi) iron handling coincides with adipocyte iron overload in obese mice. In conclusion, in obesity, iron distribution is altered both at the cellular and tissue levels, with AT playing a predominant role in this change. An increased availability of fatty acids during obesity may contribute to the observed changes in MFe(hi) ATM phenotype and their reduced capacity to handle iron.

  17. Distribution of hexadecenoic, octadecenoic and octadecadienoic acid isomers in human tissue lipids.

    PubMed

    Adlof, R O; Emken, E A

    1986-09-01

    The trans 16:1, 18:1 and 18:2 fatty acid composition of various human organ lipids was studied to determine if isomers accumulated in specific tissues. "Trans" isomers are defined as those fatty acids containing one or more trans double bonds. Adipose, kidney, brain, heart and liver tissue lipids were analyzed. Gas chromatography with a 100-SP2560 capillary column was used to characterize the various positional and/or geometrical isomers. The distribution of trans 16:1 and 18:1 isomers ranged from 0.3% in the brain to 4.0% in adipose tissue, while trans 18:2 isomers ranged from 0.0% in the brain to 0.4% in adipose tissue. No trans 18:3 isomers were detected. Positional isomer ratios for cis 16:1 (delta 9 vs delta 7) and cis 18:1 (delta 11 vs delta 9) were also determined. Since these ratios are reproducible from one individual to the next, they might be useful for diagnosis of human metabolic disorders.

  18. Pharmacokinetic Modeling of Manganese III. Physiological Approaches Accounting for Background and Tracer Kinetics

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Teeguarden, Justin G.; Gearhart, Jeffrey; Clewell, III, H. J.

    2007-01-01

    Manganese (Mn) is an essential nutrient. Mn deficiency is associated with altered lipid (Kawano et al. 1987) and carbohydrate metabolism (Baly et al. 1984; Baly et al. 1985), abnormal skeletal cartilage development (Keen et al. 2000), decreased reproductive capacity, and brain dysfunction. Occupational and accidental inhalation exposures to aerosols containing high concentrations of Mn produce neurological symptoms with Parkinson-like characteristics in workers. At present, there is also concern about use of the manganese-containing compound, methylcyclopentadienyl manganese tricarbonyl (MMT), in unleaded gasoline as an octane enhancer. Combustion of MMT produces aerosols containing a mixture of manganese salts (Lynam et al. 1999).more » These Mn particulates may be inhaled at low concentrations by the general public in areas using MMT. Risk assessments for essential elements need to acknowledge that risks occur with either excesses or deficiencies and the presence of significant amounts of these nutrients in the body even in the absence of any exogenous exposures. With Mn there is an added complication, i.e., the primary risk is associated with inhalation while Mn is an essential dietary nutrient. Exposure standards for inhaled Mn will need to consider the substantial background uptake from normal ingestion. Andersen et al. (1999) suggested a generic approach for essential nutrient risk assessment. An acceptable exposure limit could be based on some ‘tolerable’ change in tissue concentration in normal and exposed individuals, i.e., a change somewhere from 10 to 25 % of the individual variation in tissue concentration seen in a large human population. A reliable multi-route, multi-species pharmacokinetic model would be necessary for the implementation of this type of dosimetry-based risk assessment approach for Mn. Physiologically-based pharmacokinetic (PBPK) models for various xenobiotics have proven valuable in contributing to a variety of chemical specific

  19. Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition.

    PubMed

    Zhang, Xiaoping; Nieforth, Keith; Lang, Jean-Marie; Rouzier-Panis, Regine; Reynes, Jacques; Dorr, Albert; Kolis, Stanley; Stiles, Mark R; Kinchelow, Tosca; Patel, Indravadan H

    2002-07-01

    Enfuvirtide (T-20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41-mediated viral fusion to host cells. The objectives of this study were to develop a structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies. Twelve patients with HIV infection received 4 single doses of enfuvirtide separated by a 1-week washout period in an open-label, randomized, 4-way crossover fashion. The doses studied were 90 mg (intravenous) and 45 mg, 90 mg, and 180 mg (subcutaneous). Serial blood samples were collected up to 48 hours after each dose. Plasma enfuvirtide concentrations were measured with use of a validated liquid chromatography-tandem mass spectrometry method. Enfuvirtide plasma concentration-time data after subcutaneous administration were well described by an inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment. The model-derived mean pharmacokinetic parameters (+/-SD) were volume of distribution of the central compartment (3.8 +/- 0.8 L), volume of distribution of the peripheral compartment (1.7 +/- 0.6 L), total clearance (1.44 +/- 0.30 L/h), intercompartmental distribution (2.3 +/- 1.1 L/h), bioavailability (89% +/- 11%), and mean absorption time (7.26 hours, 8.65 hours, and 9.79 hours for the 45-mg, 90-mg, and 180-mg dose groups, respectively). The terminal half-life increased from 3.46 to 4.35 hours for the subcutaneous dose range from 45 to 180 mg. An inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment was appropriate to describe complex

  20. 4-Hydroxyanisole: human pharmacokinetics.

    PubMed

    Belcher, H J; Barsted, C G; Dawson, C M

    1990-12-01

    The pharmacokinetic behaviour of 4-hydroxyanisole (4HA) has been studied in ten female patients with recurrent malignant melanoma confined to the lower limb. Ten grams of 4HA was infused twice each day via a catheter placed in the common femoral artery for a maximum of 4 days. Blood samples were collected after the first and fourth infusions in all patients and the serum 4HA concentration assayed. Following infusion, the serum 4HA concentration declined in two phases, the half-lives (t1/2) of the distribution and elimination phases being 6.3 and 70.9 min, respectively. The serum 4HA concentrations and area under the curve (AUC) declined significantly between the first and fourth infusions. There was a significant rise in the apparent volume of distribution (VD) of 4HA between these times but no change in the t1/2 of the elimination phase or the clearance rate. It is concluded that there is no evidence that enzyme induction influences the clearance of 4-hydroxyanisole from the bloodstream in the short-term. However, it may be appropriate to adjust dosage regimens to take account of the change in VD that occurs with time.

  1. A Pharmacokinetics, Efficacy, and Safety Study of Gadoterate Meglumine in Pediatric Subjects Aged Younger Than 2 Years

    PubMed Central

    Scala, Mario; Koob, Meriam; de Buttet, Sophie; Bourrinet, Philippe; Felices, Mathieu; Jurkiewicz, Elzbieta

    2018-01-01

    Objectives The primary objective of this study was to investigate the pharmacokinetic profile of gadoterate meglumine in pediatric patients younger than 2 years; the secondary objectives were to document its efficacy and safety. Material and Methods This was a Phase IV open-label, prospective study conducted in 9 centers (4 countries). Forty-five patients younger than 2 years with normal estimated glomerular filtration rate and scheduled to undergo routine gadolinium-enhanced magnetic resonance imaging (MRI) of any organ were included and received a single intravenous injection of gadoterate meglumine (0.1 mmol/kg). To perform the population pharmacokinetics analysis, 3 blood samples per subject were drawn during 3 time windows at time points allocated by randomization. Results Gadoterate meglumine concentrations were best fitted using a 2-compartmental model with linear elimination from central compartment. The median total clearance adjusted to body weight was estimated at 0.06 L/h per kg and increased with estimated glomerular filtration rate according to a power model. The median volume of distribution at steady state (Vss) adjusted to body weight was estimated at 0.047 L/kg. Estimated median terminal half-life (t1/2β) was 1.35 h, and the median systemic exposure (area under the curve) was 1591 μmol h/L. Efficacy was assessed by comparing precontrast +postcontrast images to precontrast images in a subset of 28 subjects who underwent an MRI examination of brain, spine, and associated tissues. A total of 28 lesions were identified and analyzed in 15 subjects with precontrast images versus 30 lesions in 16 subjects with precontrast + postcontrast images. Lesion visualization was improved with a mean (SD) increase in scores at subject level of 0.7 (1.0) for lesion border delineation, 0.9 (1.6) for internal morphology, and 3.1 (3.2) for contrast enhancement. Twenty-six adverse events occurred postinjection in 13 subjects (28.9%), including 3 serious reported in 1

  2. A Pharmacokinetics, Efficacy, and Safety Study of Gadoterate Meglumine in Pediatric Subjects Aged Younger Than 2 Years.

    PubMed

    Scala, Mario; Koob, Meriam; de Buttet, Sophie; Bourrinet, Philippe; Felices, Mathieu; Jurkiewicz, Elzbieta

    2018-02-01

    The primary objective of this study was to investigate the pharmacokinetic profile of gadoterate meglumine in pediatric patients younger than 2 years; the secondary objectives were to document its efficacy and safety. This was a Phase IV open-label, prospective study conducted in 9 centers (4 countries). Forty-five patients younger than 2 years with normal estimated glomerular filtration rate and scheduled to undergo routine gadolinium-enhanced magnetic resonance imaging (MRI) of any organ were included and received a single intravenous injection of gadoterate meglumine (0.1 mmol/kg). To perform the population pharmacokinetics analysis, 3 blood samples per subject were drawn during 3 time windows at time points allocated by randomization. Gadoterate meglumine concentrations were best fitted using a 2-compartmental model with linear elimination from central compartment. The median total clearance adjusted to body weight was estimated at 0.06 L/h per kg and increased with estimated glomerular filtration rate according to a power model. The median volume of distribution at steady state (Vss) adjusted to body weight was estimated at 0.047 L/kg. Estimated median terminal half-life (t1/2β) was 1.35 h, and the median systemic exposure (area under the curve) was 1591 μmol h/L. Efficacy was assessed by comparing precontrast +postcontrast images to precontrast images in a subset of 28 subjects who underwent an MRI examination of brain, spine, and associated tissues. A total of 28 lesions were identified and analyzed in 15 subjects with precontrast images versus 30 lesions in 16 subjects with precontrast + postcontrast images. Lesion visualization was improved with a mean (SD) increase in scores at subject level of 0.7 (1.0) for lesion border delineation, 0.9 (1.6) for internal morphology, and 3.1 (3.2) for contrast enhancement. Twenty-six adverse events occurred postinjection in 13 subjects (28.9%), including 3 serious reported in 1 subject (2.2%). One subject (2

  3. Distribution of Interleukin-22-secreting Immune Cells in Conjunctival Associated Lymphoid Tissue.

    PubMed

    Yoon, Chang Ho; Lee, Daeseung; Jeong, Hyun Jeong; Ryu, Jin Suk; Kim, Mee Kum

    2018-04-01

    Interleukin (IL)-22 is a cytokine involved in epithelial cell regeneration. Currently, no research studies have analyzed the distribution of the three distinct IL-22-secreting cell populations in human or mouse conjunctiva. This study investigated the distribution of the three main populations of IL-22-secreting immune cells, αβ Th cells, γδ T cells, or innate cells (innate lymphoid cells [ILCs] or natural killer cells), in conjunctival associated lymphoid tissues (CALTs) in human and mouse models. We collected discarded cadaveric bulbar conjunctival tissue specimens after preservation of the corneo-limbal tissue for keratoplasty from four enucleated eyes of the domestic donor. The bulbar conjunctiva tissue, including the cornea from normal (n = 27) or abraded (n = 4) B6 mice, were excised and pooled in RPMI 1640 media. After the lymphoid cells were gated in forward and side scattering, the αβ Th cells, γδ T cells, or innate lymphoid cells were positively or negatively gated using anti-CD3, anti-γδ TCR, and anti-IL-22 antibodies, with a FACSCanto flow cytometer. In normal human conjunctiva, the percentage and number of cells were highest in αβ Th cells, followed by γδ T cells and CD3- γδ TCR- IL-22+ innate cells (presumed ILCs, pILCs) (Kruskal-Wallis test, p = 0.012). In normal mice keratoconjunctiva, the percentage and total number were highest in γδ T cells, followed by αβ Th cells and pILCs (Kruskal-Wallis test, p = 0.0004); in corneal abraded mice, the population of αβ Th cells and pILCs tended to increase. This study suggests that three distinctive populations of IL-22-secreting immune cells are present in CALTs of both humans and mice, and the proportions of IL-22+αβ Th cells, γδ T cells, and pILCs in CALTs in humans might be differently distributed from those in normal mice. © 2018 The Korean Ophthalmological Society.

  4. Microanalysis and preliminary pharmacokinetic studies of a sulfated polysaccharide from Laminaria japonica

    NASA Astrophysics Data System (ADS)

    Zhang, Wenjing; Sun, Delin; Zhao, Xia; Jin, Weihua; Wang, Jing; Zhang, Quanbin

    2016-01-01

    A rapid, sensitive and reproducible high performance liquid chromatography (HPLC) method with post-column fluorescence derivatization has been developed to determine the amount of low-molecular-weight sulfated polysaccharide (GFS) in vivo. The metabolism of GFS has been shown to fit a two component model following its administration by intravenous injection, and its pharmacokinetic parameters were determined to be as follows: half-time of distribution phase ( t 1/2α)=11.24±2.93 min, half-time of elimination phase ( t 1/2β)=98.20±25.78 min, maximum concentration ( C max)=110.53 μg/mL and peak time ( T max)=5 min. The pharmacokinetic behavior of GFS was also investigated following intragastric administration. However, the concentration of GFS found in serum was too low for detection, and GFS could only be detected for up to 2 h after intragastric administration (200 mg/kg body weight). Thus, the bioavailability of GFS was low following intragastric administration because of the metabolism of GFS. In conclusion, HPLC with postcolumn derivatization could be used for quantitative microanalysis and pharmacokinetic studies to determine the presence of polysaccharides in the serum following intravenous injection.

  5. Incorporation of lysosomal sequestration in the mechanistic model for prediction of tissue distribution of basic drugs.

    PubMed

    Assmus, Frauke; Houston, J Brian; Galetin, Aleksandra

    2017-11-15

    The prediction of tissue-to-plasma water partition coefficients (Kpu) from in vitro and in silico data using the tissue-composition based model (Rodgers & Rowland, J Pharm Sci. 2005, 94(6):1237-48.) is well established. However, distribution of basic drugs, in particular into lysosome-rich lung tissue, tends to be under-predicted by this approach. The aim of this study was to develop an extended mechanistic model for the prediction of Kpu which accounts for lysosomal sequestration and the contribution of different cell types in the tissue of interest. The extended model is based on compound-specific physicochemical properties and tissue composition data to describe drug ionization, distribution into tissue water and drug binding to neutral lipids, neutral phospholipids and acidic phospholipids in tissues, including lysosomes. Physiological data on the types of cells contributing to lung, kidney and liver, their lysosomal content and lysosomal pH were collated from the literature. The predictive power of the extended mechanistic model was evaluated using a dataset of 28 basic drugs (pK a ≥7.8, 17 β-blockers, 11 structurally diverse drugs) for which experimentally determined Kpu data in rat tissue have been reported. Accounting for the lysosomal sequestration in the extended mechanistic model improved the accuracy of Kpu predictions in lung compared to the original Rodgers model (56% drugs within 2-fold or 88% within 3-fold of observed values). Reduction in the extent of Kpu under-prediction was also evident in liver and kidney. However, consideration of lysosomal sequestration increased the occurrence of over-predictions, yielding overall comparable model performances for kidney and liver, with 68% and 54% of Kpu values within 2-fold error, respectively. High lysosomal concentration ratios relative to cytosol (>1000-fold) were predicted for the drugs investigated; the extent differed depending on the lysosomal pH and concentration of acidic phospholipids among

  6. Compartmental analysis and its manifold applications to pharmacokinetics.

    PubMed

    Rescigno, Aldo

    2010-03-01

    In this paper, I show how the concept of compartment evolved from the simple dilution of a substance in a physiological volume to its distribution in a network of interconnected spaces. The differential equations describing the fate of a substance in a living being can be solved, qualitatively and quantitatively, with the help of a number of mathematical techniques. A number of parameters of pharmacokinetic interest can be computed from the experimental data; often, the data available are not sufficient to determine some parameters, but it is possible to determine their range.

  7. Pharmacokinetic modeling in aquatic animals. 1. Models and concepts

    USGS Publications Warehouse

    Barron, M.G.; Stehly, Guy R.; Hayton, W.L.

    1990-01-01

    While clinical and toxicological applications of pharmacokinetics have continued to evolve both conceptually and experimentally, pharmacokinetics modeling in aquatic animals has not progressed accordingly. In this paper we present methods and concepts of pharmacokinetic modeling in aquatic animals using multicompartmental, clearance-based, non-compartmental and physiologically-based pharmacokinetic models. These models should be considered as alternatives to traditional approaches, which assume that the animal acts as a single homogeneous compartment based on apparent monoexponential elimination.

  8. Correlation of tissue-plasma partition coefficients between normal tissues and subcutaneous xenografts of human tumor cell lines in mouse as a prediction tool of drug penetration in tumors.

    PubMed

    Poulin, Patrick; Hop, Cornelis Eca; Salphati, Laurent; Liederer, Bianca M

    2013-04-01

    Understanding drug distribution and accumulation in tumors would be informative in the assessment of efficacy in targeted therapy; however, existing methods for predicting tissue drug distribution focus on normal tissues and do not incorporate tumors. The main objective of this study was to describe the relationships between tissue-plasma concentration ratios (Kp ) of normal tissues and those of subcutaneous xenograft tumors under nonsteady-state conditions, and establish regression equations that could potentially be used for the prediction of drug levels in several human tumor xenografts in mouse, based solely on a Kp value determined in a normal tissue (e.g., muscle). A dataset of 17 compounds was collected from the literature and from Genentech. Tissue and plasma concentration data in mouse were obtained following oral gavage or intraperitoneal administration. Linear regression analyses were performed between Kp values in several normal tissues (muscle, lung, liver, or brain) and those in human tumor xenografts (CL6, EBC-1, HT-29, PC3, U-87, MCF-7-neo-Her2, or BT474M1.1). The tissue-plasma ratios in normal tissues reasonably correlated with the tumor-plasma ratios in CL6, EBC-1, HT-29, U-87, BT474M1.1, and MCF-7-neo-Her2 xenografts (r(2) in the range 0.62-1) but not with the PC3 xenograft. In general, muscle and lung exhibited the strongest correlation with tumor xenografts, followed by liver. Regression coefficients from brain were low, except between brain and the glioblastoma U-87 xenograft (r(2) in the range 0.62-0.94). Furthermore, reasonably strong correlations were observed between muscle and lung and between muscle and liver (r(2) in the range 0.67-0.96). The slopes of the regressions differed depending on the class of drug (strong vs. weak base) and type of tissue (brain vs. other tissues and tumors). Overall, this study will contribute to our understanding of tissue-plasma partition coefficients for tumors and facilitate the use of physiologically

  9. Tissue distribution and developmental expression of type XVI collagen in the mouse.

    PubMed

    Lai, C H; Chu, M L

    1996-04-01

    The expression of a recently identified collagen, alpha 1 (XVI), in adult mouse tissue and developing mouse embryo was examined by immunohistochemistry and in situ hybridization. A polyclonal antiserum was raised against a recombinant fusion protein, which contained a segment of 161 amino acids in the N-terminal noncollagenous domain of the human alpha 1 (XVI) collagen. Immunoprecipitation of metabolically labelled human or mouse fibroblast cell lysates with this antibody revealed a major, bacterial collagenase sensitive polypeptide of approximately 210 kDa. The size agrees with the prediction from the full-length cDNA. Immunofluorescence examination of adult mouse tissues using the affinity purified antibody revealed a rather broad distribution of the protein. The heart, kidney, intestine, ovary, testis, eye, arterial walls and smooth muscles all exhibited significant levels of expression, while the skeletal muscle, lung and brain showed very restricted and low signals. During development, no significant expression of the mRNA or protein was observed in embryo of day 8 of gestation, but strong signals was detected in placental trophoblasts. Expression in embryos was detectable first after day 11 of gestation with weak positive signals appearing in the heart. In later stages of development, stronger RNA hybridizations were observed in a variety of tissues, particularly in atrial and ventricular walls of the developing heart, spinal root neural fibers and skin. These data demonstrate that type XVI collagen represents another collagenous component widely distributed in the extracellular matrix and may contribute to the structural integrity of various tissues.

  10. Simultaneous determination of osthole, bergapten and isopimpinellin in rat plasma and tissues by liquid chromatography-tandem mass spectrometry.

    PubMed

    Li, Jing; Ma, Bo; Zhang, Qi; Yang, Xiaojing; Sun, Jingjing; Tang, Bowen; Cui, Guangbo; Yao, Di; Liu, Lei; Gu, Guiying; Zhu, Jianwei; Wei, Ping; Ouyang, Pingkai

    2014-11-01

    A highly selective and sensitive method for simultaneous quantitation of osthole, bergapten and isopimpinellin in rat plasma and tissues was developed by liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS). After liquid-liquid extraction of samples with methyl tert-butyl ether, the analytes and dextrorphan (internal standard, IS) were separated by a Hypersil GOLD AQ C18 column with gradient elution of acetonitrile and water containing 0.5‰ formic acid. Three determinands were detected using an electrospray ionization (ESI) tandem mass spectrometry in the multiple reaction monitoring (MRM) modes with positive electrospray ionization. Calibration curves were recovered over the concentration ranges of 1-200 ng/ml, 1-500 ng/ml, 0.25-200 ng/ml for osthole, bergapten and isopimpinellin in plasma; 1-100 ng/ml, 1-500 ng/ml, 0.5-100 ng/ml for osthole, bergapten and isopimpinellin in tissues, respectively. The intra-day precision (R.S.D.) was within 13.90% and the intra-day accuracy (R.E.) was within -6.27 to 6.84% in all biological matrixes. The inter-day precision (R.S.D.) was less than 13.66% and the inter-day accuracy (R.E.) was within -10.64 to 13.04%. Then the method was successfully applied to investigate plasma pharmacokinetic study and tissue distribution of osthole, bergapten and isopimpinellin in rats after oral administration of Fructus Cnidii extraction, especially for testis/uterus tissue distribution. The results demonstrated that osthole, bergapten and isopimpinellin were absorbed and eliminated rapidly with wide distributions in rats. Distribution data of these three bioactive components in testis/uterus tissues could offer useful information for the further preclinical and clinical studies of Fructus Cnidii in the treatment of genital system disease. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Cannabinoid Disposition After Human Intraperitoneal Use: An Insight Into Intraperitoneal Pharmacokinetic Properties in Metastatic Cancer.

    PubMed

    Lucas, Catherine J; Galettis, Peter; Song, Shuzhen; Solowij, Nadia; Reuter, Stephanie E; Schneider, Jennifer; Martin, Jennifer H

    2018-01-06

    Medicinal cannabis is prescribed under the provision of a controlled drug in the Australian Poisons Standard. However, multiple laws must be navigated in order for patients to obtain access and imported products can be expensive. Dose-response information for both efficacy and toxicity pertaining to medicinal cannabis is lacking. The pharmacokinetic properties of cannabis administered by traditional routes has been described but to date, there is no literature on the pharmacokinetic properties of an intraperitoneal cannabinoid emulsion. A cachectic 56-year-old female with stage IV ovarian cancer and peritoneal metastases presented to hospital with fevers, abdominal distension and severe pain, vomiting, anorexia, dehydration and confusion. The patient reported receiving an intraperitoneal injection, purported to contain 12 g of mixed cannabinoid (administered by a deregistered medical practitioner) two days prior to presentation. Additionally, cannabis oil oral capsules were administered in the hours prior to hospital admission. THC concentrations were consistent with the clinical state but not with the known pharmacokinetic properties of cannabis nor of intraperitoneal absorption. THC concentrations at the time of presentation were predicted to be ~60 ng/mL. Evidence suggests that blood THC concentrations >5 ng/mL are associated with substantial cognitive and psychomotor impairment. The predicted time for concentrations to drop <5 ng/mL was 49 days after administration. The unusual pharmacokinetic properties of the case suggest that there is a large amount unknown about cannabis pharmacokinetic properties. The pharmacokinetic properties of a large amount of a lipid soluble compound given intraperitoneally gave insights into the absorption and distribution of cannabinoids, particularly in the setting of metastatic malignancy. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

  12. Whole-body tissue distribution of total radioactivity in rats after oral administration of [¹⁴C]-bilastine.

    PubMed

    Lucero, María Luisa; Patterson, Andrew B

    2012-06-01

    This study evaluated the tissue distribution of total radioactivity in male albino, male pigmented, and time-mated female albino rats after oral administration of a single dose of [¹⁴C]-bilastine (20 mg/kg). Although only 1 animal was analyzed at each time point, there were apparent differences in bilastine distribution. Radioactivity was distributed to only a few tissues at low levels in male rats, whereas distribution was more extensive and at higher levels in female rats. This may be a simple sex-related difference. In each group and at each time point, concentrations of radioactivity were high in the liver and kidney, reflecting the role of these organs in the elimination process. In male albino rats, no radioactivity was measurable by 72 hours postdose. In male pigmented rats, only the eye and uveal tract had measurable levels of radioactivity at 24 hours. Measureable levels of radioactivity were retained in these tissues at the final sampling time point (336 hours postdose), indicating a degree of melanin-associated binding. In time-mated female rats, but not in albino or pigmented male rats, there was evidence of low-level passage of radioactivity across the placental barrier into fetal tissues as well as low-level transfer of radioactivity into the brain.

  13. Sex differences in the pharmacokinetics of antidepressants: influence of female sex hormones and oral contraceptives.

    PubMed

    Damoiseaux, Valérie A; Proost, Johannes H; Jiawan, Vincent C R; Melgert, Barbro N

    2014-06-01

    Women are twice as likely to develop depression as men. Moreover, the symptoms they experience also show sex differences: women tend to develop depression at an earlier age and show more severe symptoms than men. Likewise, the response to antidepressant pharmacotherapy appears to have sex differences. These differences can partially be explained by differences in pharmacokinetic properties (i.e., absorption, distribution, metabolism, and excretion) of drugs in males and females. More recent research has shown that sex hormones may influence all these previously named pharmacokinetic processes. As concentrations of sex hormones vary throughout the female lifespan, these hormonal variations can have effects on therapeutic responses to antidepressants as well as the occurrence of adverse events. The purpose of this paper is therefore to review the literature reporting on the effects of female sex hormones on the pharmacokinetics of antidepressants and to discuss and evaluate the implications of changes in levels of sex hormones throughout life for the treatment of depression.

  14. Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints.

    PubMed

    de Velde, Femke; de Winter, Brenda C M; Koch, Birgit C P; van Gelder, Teun; Mouton, Johan W

    2016-10-01

    To describe the population pharmacokinetics of oral amoxicillin and to compare the PTA of current dosing regimens. Two groups, each with 14 healthy male volunteers, received oral amoxicillin/clavulanic acid tablets on two separate days 1 week apart. One group received 875/125 mg twice daily and 500/125 mg three times daily and the other group 500/125 mg twice daily and 250/125 mg three times daily. A total of 1428 amoxicillin blood samples were collected before and after administration. We analysed the concentration-time profiles using a non-compartmental pharmacokinetic method (PKSolver) and a population pharmacokinetic method (NONMEM). The PTA was computed using Monte Carlo simulations for several dosing regimens. AUC0-24 and Cmax increased non-linearly with dose. The final model included the following components: Savic's transit compartment model, Michaelis-Menten absorption, two distribution compartments and first-order elimination. The mean central volume of distribution was 27.7 L and mean clearance was 21.3 L/h. We included variability for the central volume of distribution (34.4%), clearance (25.8%), transit compartment model parameters and Michaelis-Menten absorption parameters. For 40% fT>MIC and >97.5% PTA, the breakpoints were 0.125 mg/L (500 mg twice daily), 0.25 mg/L (250 mg three times daily and 875 mg twice daily), 0.5 mg/L (500 mg three times daily) and 1 mg/L (750, 875 or 1000 mg three times daily and 500 mg four times daily). The amoxicillin absorption rate appears to be saturable. The PTAs of high-dose as well as twice-daily regimens are less favourable than regimens with lower doses and higher frequency. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  15. Distribution of Hydroxychloroquine in Lymphoid Tissue in a Rabbit Model for HIV Infection

    PubMed Central

    González-Hernández, Iliana; Aguirre-Cruz, Lucinda; Sotelo, Julio; López-Arellano, Raquel; Morales-Hipólito, Adriana

    2014-01-01

    Hydroxychloroquine has been proposed for HIV treatment; however, little is known about its disposition in the lymphatic system, where replication takes place. Therefore, its distribution in lymphoid tissues (Peyer's patches and popliteal, submandibular, femoral, splenic, and prescapular lymph nodes) was evaluated and compared with that in blood. Results showed a high affinity of hydroxychloroquine for all of these tissues, with higher affinity for the splenic and submandibular lymph nodes, suggesting its potential use as a coadjuvant in HIV therapy. PMID:24145523

  16. Pharmacokinetics and Pharmacodynamics of Piperacillin-Tazobactam in 42 Patients Treated with Concomitant CRRT

    PubMed Central

    Bauer, Seth R.; Salem, Charbel; Connor, Michael J.; Groszek, Joseph; Taylor, Maria E.; Wei, Peilin; Tolwani, Ashita J.

    2012-01-01

    Summary Background and objectives Current recommendations for piperacillin-tazobactam dosing in patients receiving continuous renal replacement therapy originate from studies with relatively few patients and lower continuous renal replacement therapy doses than commonly used today. This study measured the pharmacokinetic and pharmacodynamic characteristics of piperacillin-tazobactam in patients treated with continuous renal replacement therapy using contemporary equipment and prescriptions. Design, setting, participants, & measurements A multicenter prospective observational study in the intensive care units of two academic medical centers was performed, enrolling patients with AKI or ESRD receiving piperacillin-tazobactam while being treated with continuous renal replacement therapy. Pregnant women, children, and patients with end stage liver disease were excluded from enrollment. Plasma and continuous renal replacement therapy effluent samples were analyzed for piperacillin and tazobactam levels using HPLC. Pharmacokinetic and pharmacodynamic parameters were calculated using standard equations. Multivariate analyses were used to examine the association of patient and continuous renal replacement therapy characteristics with piperacillin pharmacokinetic parameters. Results Forty-two of fifty-five subjects enrolled had complete sampling. Volume of distribution (median=0.38 L/kg, intraquartile range=0.20 L/kg) and elimination rate constants (median=0.104 h−1, intraquartile range=0.052 h−1) were highly variable, and clinical parameters could explain only a small fraction of the large variability in pharmacokinetic parameters. Probability of target attainment for piperacillin was 83% for total drug but only 77% when the unbound fraction was considered. Conclusions There is significant patient to patient variability in pharmacokinetic/pharmacodynamic parameters in patients receiving continuous renal replacement therapy. Many patients did not achieve pharmacodynamic

  17. Prediction of a Therapeutic Dose for Buagafuran, a Potent Anxiolytic Agent by Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Starting from Pharmacokinetics in Rats and Human.

    PubMed

    Yang, Fen; Wang, Baolian; Liu, Zhihao; Xia, Xuejun; Wang, Weijun; Yin, Dali; Sheng, Li; Li, Yan

    2017-01-01

    Physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) models can contribute to animal-to-human extrapolation and therapeutic dose predictions. Buagafuran is a novel anxiolytic agent and phase I clinical trials of buagafuran have been completed. In this paper, a potentially effective dose for buagafuran of 30 mg t.i.d. in human was estimated based on the human brain concentration predicted by a PBPK/PD modeling. The software GastroPlus TM was used to build the PBPK/PD model for buagafuran in rat which related the brain tissue concentrations of buagafuran and the times of animals entering the open arms in the pharmacological model of elevated plus-maze. Buagafuran concentrations in human plasma were fitted and brain tissue concentrations were predicted by using a human PBPK model in which the predicted plasma profiles were in good agreement with observations. The results provided supportive data for the rational use of buagafuran in clinic.

  18. PHARMACOKINETIC AND PHARMACODYNAMIC INTERACTION FOR A BINARY MIXTURE OF CHLORPYRIFOS AND DIAZINON IN THE RAT

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Timchalk, Chuck; Poet, Torka S.; Hinman, Melissa N.

    2005-05-15

    Chlorpyrifos (CPF) and diazinon (DZN) are two commonly used organophosphorus (OP) insecticides and potential exists for concurrent exposures. The primary neurotoxic effects from OP pesticide exposures result from the inhibition of acetylcholinesterase (AChE) by their oxon metabolites. The pharmacokinetic and pharmacodynamic impact of acute binary exposures to CPF and DZN in rats were evaluated in this study. Rats were orally administered CPF, DZN or a CPF/DZN mixture (0, 15, 30 or 60 mg/kg) and blood (plasma and RBC), and brain were collected at 0, 3, 6, 12 and 24 h post-dosing, urine was also collected at 24 h. Chlorpyrifos, DZNmore » and their respective metabolites 3,5,6-trichloro-2-pyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP) were quantified in blood and/or urine and cholinesterase (ChE) inhibition was measured in brain, RBCs and plasma. Co-exposure to CPF/DZN at 15/15 mg/kg, did not appreciably alter the pharmacokinetics of CPF, DZN or their metabolites in blood; whereas, a 60/60 mg/kg dose resulted in a transient increase in Cmax, AUC, and decreased clearance of both compounds, likely due to competition between CPF and DZN for CYP450 metabolism. At lower doses, most likely to be encountered in occupational or environmental exposures, the pharmacokinetics were linear. A dose-dependent inhibition of ChE was noted in tissues for both the single and co-exposures. The overall potency for ChE inhibition was greater for CPF than DZN and the binary mixture response appeared to be strongly influenced by CPF. A comparison of the ChE binary response at the low dose (15 mg/kg), where there were no apparent pharmacokinetic interactions, suggested that the overall ChE response was additive. These are the first reported experiments we are aware of that characterize both the pharmacokinetic and pharmacodynamic interactions between CPF and DZN in the rat, and will be used to further develop a binary physiologically based pharmacokinetic and

  19. ADAM, a hands-on patient simulator for teaching principles of drug disposition and compartmental pharmacokinetics.

    PubMed

    Zuna, Ines; Holt, Andrew

    2017-11-01

    To design, construct and validate a pharmacokinetics simulator that offers students hands-on opportunities to participate in the design, administration and analysis of oral and intravenous dosing regimens. The Alberta Drug Administration Modeller (ADAM) is a mechanical patient in which peristaltic circulation of water through a network of silicone tubing and glass bottles creates a representation of the outcomes of drug absorption, distribution, metabolism and elimination. Changing peristaltic pump rates and volumes in bottles allows values for pharmacokinetic constants to be varied, thereby simulating differences in drug properties and in patient physiologies and pathologies. Following administration of methylene blue dye by oral or intravenous routes, plasma and/or urine samples are collected and drug concentrations are determined spectrophotometrically. The effectiveness of the simulator in enhancing student competence and confidence was assessed in two undergraduate laboratory classes. The simulator effectively models one- and two-compartment drug behaviour in a mathematically-robust and realistic manner. Data allow calculation of numerous pharmacokinetic constants, by traditional graphing methods or with curve-fitting software. Students' competence in solving pharmacokinetic problems involving calculations and graphing improved significantly, while an increase in confidence and understanding was reported. The ADAM is relatively inexpensive and straightforward to construct, and offers a realistic, hands-on pharmacokinetics learning opportunity for students that effectively complements didactic lectures. © 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

  20. Biodistribution and Pharmacokinetic Analysis of Combination Lonidamine and Paclitaxel Delivery in an Orthotopic Animal Model of Multi-drug Resistant Breast Cancer Using EGFR-Targeted Polymeric Nanoparticles

    PubMed Central

    Milane, Lara; Duan, Zhen-feng; Amiji, Mansoor

    2011-01-01

    The aim of this study was to assess the biodistribution and pharmacokinetics of epidermal growth factor receptor (EGFR)-targeted polymer blend nanoparticles loaded with the anticancer drugs lonidamine and paclitaxel. Plasma, tumor, and tissue distribution profiles were quantified in an orthotopic animal model of multi-drug resistant (MDR) breast cancer and were compared to treatment with non-targeted nanoparticles and to treatment with drug solution. Poly(D,L-lactide-co-glycolide)/poly(ethylene glycol)/EGFR targeting peptide (PLGA/PEG/EFGR peptide) construct was synthesized for incorporation in poly(ε-caprolactone) (PCL) particles to achieve active EGFR targeting. An isocratic HPLC method was developed to quantify lonidamine and paclitaxel in mice plasma, tumors, and vital organs. The targeted nanoparticles demonstrated superior pharmacokinetic profile relative to drug solution and non-targeted nanoparticles, particularly for lonidamine delivery. The first target site of accumulation is the liver, followed by the kidneys, and then the tumor mass; maximal tumor accumulation occurs at 3 hours post-administration. Lonidamine/paclitaxel combination therapy administered via EGFR-targeted polymer blend nanocarriers may become a viable platform for the future treatment of MDR cancer. PMID:21220050