Science.gov

Sample records for pharmacokinetics tissue distribution

  1. Pharmacokinetics, oral bioavailability and tissue distribution of azithromycin in cats.

    PubMed

    Hunter, R P; Lynch, M J; Ericson, J F; Millas, W J; Fletcher, A M; Ryan, N I; Olson, J A

    1995-02-01

    Azithromycin is the first of a class of antibiotics classified as azalides. In an initial experiment four cats were given a single dose of azithromycin 5 mg/kg orally (p.o.), followed 2 weeks later by a single intravenous bolus (i.v.) dose of 5 mg/kg. Subsequently, six cats were given [14C]azithromycin p.o. in a single dose of 5.4 mg/kg for the study of tissue distribution and metabolism. In both experiments, serial blood samples were collected and the plasma assayed for unchanged azithromycin to determine various pharmacokinetic parameters. After p.o. administration, bioavailability was 58% and absorption rapid with a tmax of 0.85 +/- 0.72 h and a Cmax of 0.97 +/- 0.65 microgram/mL. The harmonic mean terminal t1/2 after i.v. administration was 35 h. Tissue half-lives varied from 13 h in fat to 72 h in cardiac muscle. Three metabolites were identified in bile. Unchanged azithromycin accounted for 100% of the total radioactivity in lung and skin tissues when assayed. In comparison with other species, the bioavailability in cats is higher than in humans but lower than in dogs. As in the dog, > 50% of the azithromycin-related material in feline bile was unchanged azithromycin. PMID:7752305

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

    SciTech Connect

    Cheung, W.K.

    1985-01-01

    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 was 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.

  3. In vivo gastroprotective effect along with pharmacokinetics, tissue distribution and metabolism of isoliquiritigenin in mice.

    PubMed

    Choi, Young Hee; Kim, You-Jin; Chae, Hee-Sung; Chin, Young-Won

    2015-05-01

    As numerous herbal products have been used as dietary supplements or functional foods, the demands of the pharmacokinetic and pharmacodynamic characteristics of active compounds are increasing in order to secure a consistent outcome (i.e., efficiency and safety). In this study, the pharmacokinetics including tissue distribution, metabolism, and protein binding of isoliquiritigenin, a chalcone found in Glycyrrhiza glabra, and its metabolite, liquiritigenin, at various doses in mice are reported. Also, correlations between the preferential tissue distribution and pharmacological effect of isoliquiritigenin in certain organs were investigated using the in vivo gastroprotective effect of isoliquiritigenin in mice with indomethacin-induced ulcer. The absorbed fraction of isoliquiritigenin was high, but the absolute bioavailability was low mainly due to its metabolism. In spite of the low bioavailability, the gastroprotective effect of isoliquiritigenin was attributed to its high distribution in the stomach. Isoliquiritigenin prevented the occurrence of gastric ulcers by indomethacin, which is associated with increased gastric mucous secretion because the pretreatment with isoliquiritigenin presumably counteracted the decreased cyclooxygenase 2 by indomethacin. This may suggest that the pharmacokinetic properties of isoliquiritigenin are useful to predict its efficacy as a gastroprotective agent in a target organ such as the stomach. PMID:25875506

  4. 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

  5. Pharmacokinetics, tissue distribution, and plasma protein binding study of chicoric acid by HPLC-MS/MS.

    PubMed

    Wang, Yutang; Xie, Guo; Liu, Qian; Duan, Xiang; Liu, Zhigang; Liu, Xuebo

    2016-09-15

    Chicoric acid is a major active constituent of Echinacea purpurea and has a variety of biological functions. In this study, a liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) approach was developed and validated for the determination of chicoric acid in rat plasma and various tissues using ferulic acid as an internal standard (IS). This method was successfully applied to pharmacokinetics, tissue distribution, and plasma protein binding (PPB) study of chicoric acid in Sprague-Dawley (SD) rats dosed with 50mg/kg by gastric gavage. The pharmacokinetic parameters were determined and showed a half-life (t1/2) of 4.53±1.44h, an apparent volume of mean residual time (MRT) of 18.58±4.43h, and an area under the curve (AUC) of 26.14 mghL(-1). The tissue distribution of chicoric acid in rats after gavage administration showed a decreasing tendency in different tissues (liver>lung>kidney>heart>spleen>brain). The PPB rates in rat plasma, human plasma, and bovine serum albumin were 98.3, 96.9, and 96.6%, respectively. These results provide insight for the further pharmacological investigation of chicoric acid. PMID:27479684

  6. Tissue distribution and physiologically based pharmacokinetics of antisense phosphorothioate oligonucleotide ISIS 1082 in rat.

    PubMed

    Peng, B; Andrews, J; Nestorov, I; Brennan, B; Nicklin, P; Rowland, M

    2001-02-01

    The aim of this study was to develop a whole body physiologically based model of the pharmacokinetics (PBPK) of the phosphorothioate oligonucleotide (PS-ODN) ISIS 1082 in vivo. Rats were administered an intravenous (i.v.) bolus dose of ISIS 1082 (10 mg/kg plus 3H tracer), and arterial blood and tissues were taken at specific times up to 72 hours. Radioactivity was measured in all samples. The parent compound was determined specifically in blood and tissues at 90 minutes and in liver and kidney also at 24 hours, using capillary gel electrophoresis (CGE). A whole body PBPK model was fitted to the combined blood and tissue radioactivity data using nonlinear regression analysis. CGE analysis indicated that the predominant species in plasma and all tissues is ISIS 1082, together with some n-1 and n-2 metabolites. Total radioactivity primarily reflects these species. The whole body model successfully described temporal events in all tissues. However, to adequately model the experimental data, all tissues had to be partitioned into vascular and extravascular spaces to accommodate the relatively slow distribution of ISIS 1082 out of blood because of a permeability rate limitation. ISIS 1082 distributes extensively into tissues, but the relative affinity varies enormously, being highest for kidney and liver and lowest for muscle and brain. A whole body PBPK model with a permeability rate limited tissue distribution was developed that adequately described events in both blood and tissue for an oligonucleotide. This model has the potential not only to characterize the events in individual tissues throughout the body for such compounds but also to scale across animal species, including human. PMID:11258618

  7. 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.

  8. Influence of co-administered danshensu on pharmacokinetic fate and tissue distribution of paeonol in rats.

    PubMed

    Li, Hua; Wang, Siwang; Zhang, Bangle; Xie, Yanhua; Wang, Jianbo; Yang, Qian; Cao, Wei; Hu, Jing; Duan, Linrui

    2012-01-01

    Cortex Moutan (root bark of Paeonia suffruticosa Andrew) and Radix Salviae miltiorrhizae (root and rhizome of Salvia miltiorrhiza Bunge) are two herbs widely used in traditional Chinese medicine (TCM) to treat cerebrovascular and cardiovascular diseases. In clinical practice, these two herbs are prescribed together. Studies on the pharmacokinetic interaction between the active constituents of these two herbs (paeonol and danshensu, respectively) can provide substantial foundation for understanding its mechanism and empirical evidence to support the clinical practice. A simple and sensitive high-performance liquid chromatographic (HPLC) method coupled with ultraviolet detector was developed for determination of paeonol in plasma and different tissues (heart, liver, spleen, lung, kidney, and brain) of male Sprague-Dawley rats. When co-administering danshensu, the peak plasma concentration of paeonol was decreased (p < 0.01), the mean residence time (MRT) was prolonged (p < 0.001), the volume of distribution (Vd/F) was increased (p < 0.001), and the concentrations of paeonol in heart, brain, and lung were dramatically increased (p < 0.01 or p < 0.001), compared with these values for rats administered paeonol alone. The results showed that the co-administration of danshensu could alter pharmacokinetic fate and tissue distribution of paeonol in rats, especially in heart and brain, providing substantial foundation for the investigation of the impact of danshensu on paeonol in clinical applications. PMID:21986818

  9. Pharmacokinetics, bioavailability, tissue distribution, excretion, and metabolite identification of methoxyflavones in Kaempferia parviflora extract in rats.

    PubMed

    Mekjaruskul, Catheleeya; Jay, Michael; Sripanidkulchai, Bungorn

    2012-12-01

    Kaempferia parviflora (KP) is an herbal plant in the family of Zingiberaceae. KP mainly contains methoxyflavones, especially 5,7-dimethoxyflavone (DMF), 5,7,4'-trimethoxyflavone (TMF), and 3,5,7,3',4'-pentamethoxyflavone (PMF). The present study was designed to characterize the pharmacokinetics, including bioavailability, distribution, excretion, and identification of metabolites after administration of a KP ethanolic extract. Male rats were orally or intravenously administered a 250 mg/kg concentration of a KP extract, and blood samples were obtained at selected times to determine pharmacokinetic parameters of PMF, TMF, and DMF. For distribution and excretion studies, the organs, urine, and feces samples were collected at various times after oral administration of a larger (750 mg/kg) dose of KP extract. Methoxyflavones in the biological samples were quantified by high-performance liquid chromatography-UV, and the metabolites in urine and feces were further identified by using liquid chromatography-tandem mass spectrometry. After oral administration, concentrations of the three methoxyflavones quickly approached their maximal concentration, ranging from 0.55 to 0.88 μg/ml within 1 to 2 h after administration, and then were gradually excreted with half-lives of 3 to 6 h. The methoxyflavones showed low oral bioavailability of 1 to 4%. Three methoxyflavones were detected at their highest levels in liver followed by kidney. They were also found in lung, testes, and brain. After absorption, organ distribution, and metabolism, the components of KP were mainly eliminated through urine in the forms of demethylated, sulfated, and glucuronidated products and as demethylated metabolites in the feces. The parent compounds were found to have 0.79, 1.76, and 3.10% dose recovery in urine and 1.06, 1.77, and 0.96% dose recovery in feces for PMF, TMF, and DMF, respectively. These studies are the first to describe the pharmacokinetics of KP extract to provide the information on

  10. Tissue Distribution, Excretion and Pharmacokinetics of the Environmental Pollutant Dibenzo[def,p]chrysene in Mice.

    PubMed

    Sun, Yuan-Wan; El-Bayoumy, Karam; Aliaga, Cesar; Awad, Alaa S; Gowda, Krishne; Amin, Shantu; Chen, Kun-Ming

    2015-07-20

    Dibenzo[def,p]chrysene (DBP), a representative example of the class of polycyclic aromatic hydrocarbon (PAH), is known to induce tumors in multiple organ sites including the ovary, lung, mammary glands, and oral cavity in rodents. The goal of this study was to test the hypothesis that the levels of DBP and its metabolites that reach and retain the levels for an extended time in the target organs as well as the capacity of these organs to metabolize this carcinogen to active metabolites that can damage DNA may account for its tissue selective tumorigenicity. Therefore, we used the radiolabeled [(3)H] DBP to accurately assess the tissue distribution, excretion, and pharmacokinetics of this carcinogen. We also compared the levels of DBPDE-DNA adducts in a select target organ (ovary) and nontarget organs (kidney and liver) in mice treated orally with DBP. Our results showed that after 1 week, 91.40 ± 7.23% of the radioactivity was recovered in the feces; the corresponding value excreted in the urine was less than 2% after 1 week. After 24 h, the stomach had the highest radioactivity followed by the intestine and the liver; however, after 1 week, levels of the radioactivity in these organs were the lowest among tissues examined including the ovary and liver; the pharmacokinetic analysis of DBP was conducted using a one compartment open model. The level of (-)-anti-trans-DBPDE-dA in the ovaries (8.91 ± 0.08 adducts/10(7) dA) was significantly higher (p < 0.01) than the levels of adducts in kidneys (0.69 ± 0.09 adducts/10(7) dA) and livers (0.63 ± 0.11 adducts/10(7) dA). Collectively, the results of the tissue distribution and pharmacokinetic analysis may not fully support our hypothesis, but the capacity of the target organs vs nontarget organs to metabolize DBP to active intermediates that can damage DNA may account for its tissue selective tumorigenicity. PMID:26034881

  11. Pharmacokinetics and tissue distribution of two novel isomerism anticancer platinum compounds.

    PubMed

    He, Donglin; Yin, Shuhui; Han, Fuguo; Zhu, Jingjie; Shi, Yun; Tong, Zhiyuan; Liu, Qingfei

    2016-11-01

    LLC-0601(S,S) and LLC-0601(R,R) are two novel synthesized isomerism platinum compounds both with encouraging anticancer activity. However, the previous study showed that toxicity of LLC-0601(R,R) was much higher than that of LLC-0601(S,S) with higher body weight loss and mortality rate of tested rats. This paper is focused on the comparison of the two compounds with their pharmacokinetic (PK) profiles in rats and tissue distribution in mice after intravenous administration. The atomic absorption spectrometry (AAS) method was successfully developed and applied for the determination of platinum in plasma and tissues. The results showed that main PK parameters such as half-life, AUC and MRT of the two compounds had no significant difference after intravenous administration to rats (p  > 0.05). The tissue distribution after intravenous administration to mice showed that the concentration of LLC-0601(R,R) in heart at 0.083 h was higher than that of LLC-0601(S,S) (p  < 0.05) and it was the same case for AUC5min-4 h (p  < 0.05). Different distribution of the two compounds in heart was possibly the main reason of different toxicity and more in-depth research on the metabolites and other mechanism are needed to investigate the toxicity. PMID:27042965

  12. Pharmacokinetics and tissue distribution study of Isovitexin in rats by HPLC-MS/MS.

    PubMed

    Li, Yaxin; Zhang, Yanqing; Yang, Tan; Li, Hui; Guo, Jiang; Zhao, Qiqing; Xie, Junbo

    2015-06-01

    A sensitive and credible high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was established and validated for the determination of isovitexin in rat plasma and various tissues (including heart, liver, lung, kidney, stomach, intestine, muscle, brain and cerebellum). The samples were prepared with methanol by liquid-liquid extraction, and puerarin was used as the internal standard. The chromatographic separation was carried out on an Agilent Poroshell 120 EC-C18 column (4.6mm×50mm, 2.7μm) with a mobile phase consisting of acetonitrile and 0.1% formic acid (21:79, v/v). The MS analysis was performed by multiple reaction monitoring (MRM) with electronic spray ionization source (ESI(-)) for quantitative response of isovitexin (431.0→311.0) and puerarin (415.1→295.0). The linearity of isovitexin in all the biosamples was good, with correlation coefficients greater than 0.9912 within the corresponding concentration range. The intra- and inter-day precisions in plasma and various tissues were less than 11.80%, and the accuracy (RE %) ranged from -4.89% to 4.78%. The extraction recoveries were in the range of 72.70%-90.81%. The present method was successfully applied to pharmacokinetics and tissue distribution of isovitexin in rats after tail vein injection with 2.0mg/kg of the compound. The pharmacokinetic parameters were demonstrated as followed: the half-life (t1/2) was 1.05±0.325h, the apparent volume of mean residual time (MRT) was 1.229±0.429h, and the area under the curve (AUC) was 11.39±5.05μg/mL/h. The results of tissue distribution showed that the main tissue depots for isovitexin in rats were kidney, intestine and liver. The results provided a meaningful insight for the further pharmacological investigation of isovitexin. PMID:25902051

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  14. Pharmacokinetics in rats and tissue distribution in mouse of berberrubine by UPLC-MS/MS.

    PubMed

    Wang, Xianqin; Wang, Shuanghu; Ma, Jianshe; Ye, Tao; Lu, Mengrou; Fan, Miao; Deng, Mingjie; Hu, Lufeng; Gao, Zhimou

    2015-11-10

    Berberrubine is an isoquinoline alkaloid isolated from Berberis vulgaris L, and it is readily derived from berberine. In this study, a sensitive and selective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of berberrubine in rat plasma and mouse tissue has been developed. Magnoflorine was employed as an internal standard (IS), and liquid-liquid extraction by ethyl acetate was used for sample preparation. Chromatographic separation was achieved on a UPLC BEH C18 column (2.1mm×100mm, 1.7μm) with 0.1% formic acid and acetonitrile as the mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; multiple reactions monitoring (MRM) mode was used for quantification using target fragment ions m/z 322.0→307.0 for berberrubine and m/z 342.8→298.2 for IS. Calibration plots were linear in the range of 2-2000ng/mL for berberrubine in rat plasma and mouse tissue. Mean recoveries of berberrubine in rat plasma ranged from 79.6% to 84.8%. Intra-day and inter-day precision were less than 11%. The accuracy ranged from 93.6% to 106.8%. The method has also been successfully applied in pharmacokinetics and tissue distribution study of berberrubine. The absolute bioavailability of berberrubine was determined to be 31.6%. The results also show that berberrubine is rapidly absorbed and widely distributed in various tissues. The level of berberrubine in liver is highest, and followed by kidney, spleen and heart. Furthermore, the concentration of berberrubine in various tissues could also be predicted by a BP-ANN model. PMID:26279368

  15. Pharmacokinetics, tissue distribution, and the lactone/carboxylate equilibrium of hydroxycamptothecin delivered via aerosol in mice.

    PubMed

    Hu, Wei; Zhang, Chao; Hu, Wenjin; Fang, Yun; Hou, Wenjie

    2012-10-01

    Aerosol delivery is a route which is advantageous to the therapy of pulmonary diseases, such as lung cancer. The pharmacokinetics and tissue distribution after aerosol delivery of carboxylate form of hydroxycamptothecin (C-HCPT) were investigated. The concentrations of the three different types (lactone, carboxylate and the total of both forms) of HCPT were measured by HPLC analysis. The initial experiment showed no evident difference between lactone and carboxylate in the lungs during the aerosol treatment, compared with the HCPT content in plasma. The AUC(inf) value of lactone in the lungs was higher than that of carboxylate, which was 138,176.00 min ng g⁻¹ and 128,460.00 min ng g⁻¹, respectively. Meanwhile, AUC(inf) in the plasma during the entire treatment indicated that the lactone content was always at a lower level, and the carboxylate form tended to predominate, as shown by the lactone/carboxylate (L/C) equilibrium. The tissue distribution results showed that the lactone proportion in the liver increased up to the maximum value of 69.69% after aerosol administration, whereas the mean L/C equilibrium index for the liver was 2.07±1.06, and the C(max) and AUC(0-∞) values of the total HCPT were highest in the tissues. Based on these results we speculated that the initial wholly carboxylate form of the HCPT atomized liquid did not influence the transformation to lactone form. Moreover, the deposition of the total HCPT and lactone was higher in the lungs and other tissues than in the plasma after the aerosol treatment. This study will be beneficial to the therapy of pulmonary carcinoma. PMID:22858157

  16. Pharmacokinetics and tissue distribution of spinosin after intravenous administration in rats.

    PubMed

    Li, Yu-Juan; Dai, Yue-Han; Yu, Ye-Ling; Li, Yan; Deng, Yu-Lin

    2007-08-01

    Spinosin is the major effective single constituent in the traditional Chinese herb Semen Ziziphi Spinosae, which is used for sedation and hypnosis. For the further use of spinosin in treating insomnia, the pharmacokinetics and tissue distribution of spinosin after intravenous administration to rats was investigated. An HPLC method with an ODS column (250 mm x 4.6 mm, i.d.) and a mobile phase of acetonitrile-water-acetic acid (23:77:1) was used for the determination of spinosin in the plasma and tissues of rats. Vanillin was used as an internal standard, and spinosin was detected at 334 nm. The calibration curve of spinosin in plasma showed good linearity over the concentration range of 1-300 microg/ml, and the quantitation of limit of plasma was 1 microg/ml. The linear range of concentrations of spinosin in the heart, spleen, stomach, lung, testis, brain, and intestine was 0.1-40 microg/ml and the quantitation limit was 0.1 microg/ml. The linear range of concentrations of spinosin in the liver and kidney was 1-150 microg/ml, and the quantitation limit was 1 microg/ml. The correlation coefficients of all calibration curves were between 0.9939 and 0.9980. The intra and interrun precision for all samples was less than < or =11.0%. The time-concentration curve of spinosin after the intravenous administration of a single dose of 20 mg/kg to rats corresponded to the two-compartment model. The main pharmacokinetic parameters T(0.5alpha), T(0.5beta), CLs, AUC(0-T), and V(c) were 6.66 min, 51.5 min, 1.42 l.min(-1), 2.83 mg.min.ml(-1), and 14.0 l.kg(-1), respectively. At 20 min, a concentration peak occurred in liver and brain tissues. The highest level of spinosin occurred in the liver, followed by the spleen and kidney. The lowest level of spinosin appeared in the testis, followed by the brain. Spinosin was not detected in smooth and skeletal muscle. After intravenous administration, the drug was distributed extensively and transferred quickly in rats in vivo. PMID

  17. Development of a population pharmacokinetic model characterizing the tissue distribution of azithromycin in healthy subjects.

    PubMed

    Zheng, Songmao; Matzneller, Peter; Zeitlinger, Markus; Schmidt, Stephan

    2014-11-01

    Recent clinical trials indicate that the use of azithromycin is associated with the emergence of macrolide resistance. The objective of our study was to simultaneously characterize free target site concentrations and correlate them with the MIC90s of clinically relevant pathogens. Azithromycin (500 mg once daily [QD]) was administered orally to 6 healthy male volunteers for 3 days. The free concentrations in the interstitial space fluid (ISF) of muscle and subcutaneous fat tissue as well as the total concentrations in plasma and polymorphonuclear leukocytes (PMLs) were determined on days 1, 3, 5, and 10. All concentrations were modeled simultaneously in NONMEM 7.2 using a tissue distribution model that accounts for nonlinear protein binding and ionization state at physiological pH. The model performance and parameter estimates were evaluated via goodness-of-fit plots and nonparametric bootstrap analysis. The model we developed described the concentrations at all sampling sites reasonably well and showed that the overall pharmacokinetics of azithromycin is driven by the release of the drug from acidic cell/tissue compartments. The model-predicted unionized azithromycin (AZM) concentrations in the cytosol of PMLs (6.0 ± 1.2 ng/ml) were comparable to the measured ISF concentrations in the muscle (8.7 ± 2.9 ng/ml) and subcutis (4.1 ± 2.4 ng/ml) on day 10, whereas the total PML concentrations were >1,000-fold higher (14,217 ± 2,810 ng/ml). The total plasma and free ISF concentrations were insufficient to exceed the MIC90s of the skin pathogens at all times. Our results indicate that the slow release of azithromycin from low pH tissue/cell compartments is responsible for the long terminal half-life of the drug and thus the extended period of time during which free concentrations reside at subinhibitory concentrations. PMID:25155592

  18. In vivo pharmacokinetics, tissue distribution and underlying mechanisms of various PEI(-PEG)/siRNA complexes

    SciTech Connect

    Malek, Anastasia; Merkel, Olivia; Fink, Ludger; Czubayko, Frank; Kissel, Thomas; Aigner, Achim

    2009-04-01

    Background: RNA interference (RNAi) represents a novel therapeutic strategy allowing the knockdown of any pathologically relevant target gene. Since it relies on the action of small interfering RNAs (siRNAs), the in vivo delivery of siRNAs is instrumental. Polyethylenimines (PEIs) and PEGylated PEIs have been shown previously to complex siRNAs, thus mediating siRNA protection against nucleolytic degradation, cellular uptake and intracellular release. Purpose: The present study determines in vivo pharmacokinetics, tissue distribution/efficacy of siRNA delivery and adverse effects of a broad panel of PEI(-PEG)-based siRNA complexes. The aim is to systematically evaluate the effects of different degrees and patterns of PEGylation in PEI-PEG copolymers on the in vivo behavior of PEI(-PEG)/siRNA complexes in mice. Results: Upon i.v. injection of radioactively labeled, PEI(-PEG) complexed siRNAs, marked differences in the pharmacokinetics and biodistribution of the complexes are observed, with the fate of the PEI(-PEG)/siRNA complexes being mainly dependent on the degree of uptake in liver, spleen, lung and kidney. Thus, the role of these tissues is investigated in greater detail using representative PEI(-PEG)/siRNA complexes. The induction of erythrocyte aggregation and hemorrhage is dependent on the degree and pattern of PEGylation as well as on the PEI/siRNA (N/P) ratio, and represents one important effect in the lung. Furthermore, siRNA uptake in liver and spleen, but not in lung or kidney, is mediated by macrophage and is dependent on macrophage activity. In the kidney PEI(-PEG)/siRNA uptake is mostly passive and reflects the total stability of the complexes. Conclusion: Liver, lung, spleen and kidney are the major players determining the in vivo biodistribution of PEI(-PEG)/siRNA complexes. Beyond their physicochemical and in vitro bioactivity characteristics, PEI(-PEG)/siRNA complexes show marked differences in vivo which can be explained by distinct effects in

  19. Pharmacokinetics, tissue distribution, and excretion of nomegestrol acetate in female rats.

    PubMed

    Huang, Qingbiao; Chen, Xiaoke; Zhu, Yan; Cao, Lin; Riviere, Jim E

    2015-12-01

    Nomegestrol acetate (NOMAC), a synthetic progestogen derived from 19-norprogesterone, is an orally active drug with a strong affinity for the progesterone receptor. NOMAC inhibits ovulation and is devoid of undesirable androgenic and estrogenic activities. The aim of this study was to evaluate the pharmacokinetics, tissue distribution, and excretion of NOMAC in female rats. Sprague-Dawley female rats were orally administered a single dose of NOMAC (10, 20 or 40 mg/kg) and drug plasma concentrations at different times were determined by RP-HPLC. Tissue distribution at 1, 2, and 4 h and excretion of NOMAC into bile, urine, and feces after dosing were investigated. The results showed that NOMAC was rapidly absorbed after oral administration, with [Formula: see text] of 1-2 h. The plasma concentration-time curves were fitted in a two-compartment model. The exposure to NOMAC ([Formula: see text] and [Formula: see text]) increased dose proportionally from 10 to 40 mg/kg. The average CL and [Formula: see text] were 5.58 L/(h·kg) and 10.8 h, respectively. The highest concentrations of NOMAC in ovary, liver, kidney, lung, heart, brain, spleen, muscle, and uterus were observed at 2 h, whereas the highest concentrations in stomach, pituitary, and hypothalamus appeared at 1 h. The total cumulative excretion of NOMAC in feces (0-72 h), urine (0-72 h), and bile (0-48 h) was ~1.06, 0.03, and 0.08 % of the oral administered dose, respectively. This study indicated that NOMAC had a widespread distribution in tissues, including ovary, pituitary, and hypothalamus, which are main target tissues where NOMAC inhibits ovulation. NOMAC was excreted via both feces and urine with few unchanged NOMAC excreted. Enterohepatic circulation was found in the drug elimination; however, it did not significantly affect [Formula: see text]. PMID:25168884

  20. Noninvasive assessment of tissue distribution and tumor pharmacokinetics of Pc 181, a silicon phthalocyanine analogue, in mice

    NASA Astrophysics Data System (ADS)

    Bai, Lihua; Guo, Jianxia; Clausen, Dana M.; Eiseman, Julie L.

    2010-02-01

    Objective: In in vitro photodynamic therapy, the LD50 of Pc 181 has been reported to be 7 to 8 times less than that of silicon phthalocyanine 4 (Pc 4). The Optical Pharmacokinetic System (OPS) can measure photosensitizer concentrations in accessible tissues non-invasively. We used OPS to evaluate the tumor pharmacokinetics of Pc 181 and Pc 4 and the tissue drug distribution in SCID mice bearing either human breast cancer MDA-MB-231 or human head and neck squamous cell carcinoma SCC-15 xenografts. Methods: Following iv administration of 2.5 mg/kg Pc 181 or 2 mg/kg Pc 4 to SCID mice, OPS measurements were taken on tumor and normal tissues between 5 and 4320 min in vivo or in situ. Results: Large variations in tumor Pc 181 concentrations were observed among mice. In MDA-MB-231 tumors, the Pc 181 concentration peaked at 240 min, and was retained in the tumor. Tumor Pc 181 concentrations were much less than the tumor Pc 4 concentrations at an equimolar dose. Pc 181 concentrations were the highest in liver, followed by spleen, and kidney. In mice bearing SCC-15 xenografts, skin and underlying tissue Pc 181 concentrations were higher than tumor concentrations at all time points examined. Conclusions: This first Pc 181 pharmacokinetics study described a tissue Pc 181 distribution similar to that of Pc 4. However, tumor Pc 181 concentrations were lower than those of Pc 4 at equimolar doses.

  1. Tissue Distribution and Pharmacokinetics of Stable Polyacrylamide Nanoparticles Following Intravenous Injection in the Rat

    PubMed Central

    WENGER, Yvan; SCHNEIDER, Randal J.; REDDY, G. Ramachandra; KOPELMAN, Raoul; JOLLIET, Olivier; PHILBERT, Martin A.

    2011-01-01

    A variety of polymer nanoparticles (NP) are under development for imaging and therapeutic use. However, little is known about their behavior. This study examined pharmacokinetics, distribution and elimination of stable polyacrylamide (PAA) nanoparticles (~31 nm average diameter). PAA-NPs and polyethylene glycol-coated PAA-NPs were injected into the tail veins of healthy male rats. Blood, tissues and excreta were collected at times ranging from 5 minutes to 120 hours and their radioactive content was quantified. A mathematical model was then applied to analyze the distribution dynamics of both NPs. Elimination from the blood could be accounted for by a quick but finite relocation to the major organs (about 20%, 0.6 to 1.3h half-lives), and a slower distribution to the carcass (about 70%, 35 to 43h half-lives). Excreted urinary levels correlated with blood concentrations. Combined cumulative urinary and fecal output accounted for less than 6% of the dose at 120h. Compared to five other polymeric nanoparticles, the studied particles are at the highest half-lives and Area Under the Curve (4000 to 5000 %-h). These two parameters decrease by three orders of magnitude when nanoparticle size increases from the 30 nm range up to 250 nm. For similar sizes, pegylated nanoparticles are more persistent in the blood than non pegylated ones, but this difference is much smaller in the 30 nm and relatively high dose range than above 100 nm. Persistence of PAA NPs is not associated with acute toxicity signs as measured by typical serum markers of inflammation and cellular damage. PMID:21134391

  2. Tissue distribution and pharmacokinetics of stable polyacrylamide nanoparticles following intravenous injection in the rat

    SciTech Connect

    Wenger, Yvan; Schneider, Randal J.; Reddy, G. Ramachandra; Kopelman, Raoul; Jolliet, Olivier; Philbert, Martin A.

    2011-03-15

    A variety of polymer nanoparticles (NP) are under development for imaging and therapeutic use. However, little is known about their behavior. This study examined pharmacokinetics, distribution and elimination of stable polyacrylamide (PAA) nanoparticles ({approx} 31 nm average diameter). PAA NPs and polyethylene glycol-coated PAA NPs were injected into the tail veins of healthy male rats. Blood, tissues and excreta were collected at times ranging from 5 min to 120 h and their radioactive content was quantified. A mathematical model was then applied to analyze the distribution dynamics of both NPs. Elimination from the blood could be accounted for by a quick but finite relocation to the major organs (about 20%, 0.6 to 1.3 h half-lives), and a slower distribution to the carcass (about 70%, 35 to 43 h half-lives). Excreted urinary levels correlated with blood concentrations. Combined cumulative urinary and fecal output accounted for less than 6% of the dose at 120 h. Compared to five other polymeric nanoparticles, the studied particles are at the highest half-lives and Area Under the Curve (4000 to 5000%-h). These two parameters decrease by three orders of magnitude when nanoparticle size increases from the 30 nm range up to 250 nm. For similar sizes, pegylated nanoparticles are more persistent in the blood than non-pegylated ones, but this difference is much smaller in the 30 nm and relatively high dose range than above 100 nm. Persistence of PAA NPs is not associated with acute toxicity signs as measured by typical serum markers of inflammation and cellular damage.

  3. Study on pharmacokinetics and tissue distribution of the isocorydine derivative (AICD) in rats by HPLC-DAD method

    PubMed Central

    Chen, Yali; Yan, Qian; Zhong, Mei; Zhao, Quanyi; Liu, Junxi; Di, Duolong; Liu, Jinxia

    2015-01-01

    A simple and effective high-performance liquid chromatography with diode-array detection method coupled with a liquid-liquid extraction pretreatment has been developed for determining the pharmacokinetics and tissue distribution of a novel structurally modified derivative (8-acetamino-isocorydine) of isocorydine. According to the in vivo experiments data calculations by DAS 2.0 software, a two-compartment metabolic model was suitable for describing the pharmacokinetic of 8-acetamino-isocorydine in rats. 8-Acetamino-isocorydine was absorbed well after oral administration, and the absolute bioavailability was 76.5%. The half-life of 8-acetamino-isocorydine after intravenous and oral administration was 2.2 h and 2.0 h, respectively. In vivo, 8-acetamino-isocorydine was highly distributed in the lungs, kidney and liver; however, relatively little entered the brain, suggesting that 8-acetamino-isocorydine could not easily pass through the blood brain barrier. Our work describes the first characterization of the pharmacokinetic parameters and tissue distribution of 8-acetamino-isocorydine. The acquired data will provide useful information for the in vivo pharmacology of 8-acetamino-isocorydine, and can be applied to new drug research. PMID:26579452

  4. Pharmacokinetics and tissue distribution of intraperitoneal 5-fluorouracil with a novel carrier solution in rats

    PubMed Central

    Wei, Zhi-Gang; Li, Guo-Xin; Huang, Xiang-Cheng; Zhen, Li; Yu, Jiang; Deng, Hai-Jun; Qing, Shan-Hua; Zhang, Ce

    2008-01-01

    AIM: To compare the pharmacokinetics and tissue distribution of 5-fluorouracil administered intraperitoneally with two isotonic carrier solutions: HAES-steri (neotype 6% hydroxyethyl starch), a novel carrier solution with middle molecular weight and physiologic saline (0.9% sodium chloride solution), a traditional carrier solution for intraperitoneal chemotherapy, in rats. METHODS: A total of 60 Sprague Dawley rats were randomized into groups according to the carrier solution administered. Each group was further randomized according to the intraperitoneal dwell period (1, 3, 6, 12, 18 and 24 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and quantitated. Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high-performance liquid chromatography. RESULTS: The mean volumes remaining in the peritoneal cavity were significantly higher with HAES-steri than those with physiologic saline at 1, 6, 12, 18, and 24 h (P = 0.047, 0.009, 0.005, 0.005 and 0.005 respectively, the percentages of remaining peritoneal fluid volume were 89.9 ± 5.6 vs 83.4 ± 4.9, 79.9 ± 2.8 vs 56.2 ± 15.7, 46.8 ± 5.5 vs 24.7 ± 9.7, 23.0 ± 2.8 vs 0.0 ± 0.0 and 4.2 ± 1.7 vs 0.0 ± 0.0 respectively). Mean concentrations in peritoneal fluid were significantly higher with HAES-steri than those with physiologic saline at 3, 12 and 18 h (P = 0.009, 0.009 and 0.005 respectively, the concentrations were 139.2768 ± 28.2317 mg/L vs mg/L, 11.5427 ± 3.0976 mg/L vs 0.0000 ± 0.0000 mg/L and 4.7724 ± 1.0936 mg/L vs 0.0000 ± 0.0000 mg/L respectively). Mean plasma 5-fluorouracil concentrations in portal vein were significantly higher with HAES-steri at 3, 12, 18 and 24 h (P = 0.009, 0.034, 0.005 and 0.019 respectively, the concentrations were 3.3572 ± 0.8128 mg/L vs 0.8794 ± 0.2394 mg/L, 0.6203 ± 0.9935 mg/L vs 0.0112 ± 0.0250 mg/L, 0.3725 ± 0.3871 mg/L vs 0.0000 ± 0.0000 mg/L, and 0.2469 ± 0.1457 mg/L vs 0.0000 ± 0

  5. 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

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

    PubMed

    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

  7. Differential effects of ketoconazole and primaquine on the pharmacokinetics and tissue distribution of imatinib in mice.

    PubMed

    Soo, Gian Wan; Law, Jason H K; Kan, Elaine; Tan, Shin Yee; Lim, Wei Yin; Chay, Grace; Bukhari, Nadeem I; Segarra, Ignacio

    2010-08-01

    Imatinib, a selective inhibitor of c-KIT and Bcr-Abl tyrosine kinases, approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors, shows further therapeutic potential for gliomas, glioblastoma, renal cell carcinoma, autoimmune nephritis and other neoplasms. It is metabolized by CYP3A4, is highly bound to alpha-1-acid glycoprotein and is a P-glycoprotein substrate limiting its brain distribution. We assess imatinib's protein binding interaction with primaquine, which also binds to alpha-1-acid glycoprotein, and its metabolic interaction with ketoconazole, which is a CYP3A4 inhibitor, on its pharmacokinetics and biodistribution. Male ICR mice, 9-12 weeks old were given imatinib PO (50 mg/kg) alone or co-administered with primaquine (12.5 mg/kg), ketoconazole (50 mg/kg) or both, and imatinib concentration in the plasma, kidney, liver and brain was measured at prescheduled time points by HPLC. Noncompartmental pharmacokinetic parameters were estimated. Primaquine increased 1.6-fold plasma AUC(0)--> infinity, C(Max) decreased 24%, T(Max) halved and t(1/2) and mean residence time were longer. Ketoconazole increased plasma AUC(0)-->infinity 64% and doubled the C(Max), but this dose did not affect t(1/2) or mean residence time. When ketoconazole and primaquine were co-administered, imatinib AUC(0)-->infinity and C(Max) increased 32 and 35%, respectively. Ketoconazole did not change imatinib's distribution efficiency in the liver and kidney, primaquine increased it two-fold and it was larger when both the drugs were co-administered with imatinib. Ketoconazole did not change brain penetration but primaquine increased it approximately three-fold. Ketoconazole and primaquine affect imatinib clearance, bioavailability and distribution pattern, which could improve the treatment of renal and brain tumors, but also increase toxicity. This would warrant hepatic and renal functions monitoring. PMID:20629201

  8. Multiple-dose pharmacokinetics and distribution in tissue of terbinafine and metabolites.

    PubMed Central

    Kovarik, J M; Mueller, E A; Zehender, H; Denouël, J; Caplain, H; Millerioux, L

    1995-01-01

    The pharmacokinetics of terbinafine and its inactive metabolites SDZ 86-621 (the N-demethyl form), SDZ 280-027 (the carboxybutyl form), and SDZ 280-047 (N-demethyl- carboxybutyl form) in plasma were characterized for 10 healthy male subjects receiving 250 mg of terbinafine orally once a day for 4 weeks and in the subsequent 8-week washout phase. Terbinafine concentrations were also measured in sebum, hair, nail, and stratum corneum samples. Concentrations of the parent compound and metabolites were determined by validated high-performance liquid chromatography methods. Terbinafine was rapidly absorbed, with peak concentrations in plasma of 1.70 +/- 0.77 micrograms/ml occurring 1.2 +/- 0.3 h postdose. Concentrations subsequently exhibited a triphasic decline, with a terminal deposition half-life of 16.5 +/- 2.8 days. Terbinafine accumulated approximately twofold over the 4-week dosing phase. The predominant metabolite in plasma samples was SDZ 280-027; specifically, the ratios of metabolite area under the curve to terbinafine area under the curve following the last dose were 1.25, 1.38, and 1.08 for metabolites SDZ 86-621, SDZ 280-027, and SDZ 280-047. Measurable concentrations of terbinafine were achieved in sebum and hair samples within the first week of administration and by week 3 in stratum corneum and nail samples. Fungicidal concentrations persisted in plasma and peripheral tissue samples for prolonged periods (weeks to months) after administration of the last dose. These pharmacokinetic properties are likely an underlying factor in the shorter treatment times and good clinical cure rates which have been reported for terbinafine in the therapy of onychomycoses and dermatomycoses. PMID:8593011

  9. Tissue distribution model and pharmacokinetics of nuciferine based on UPLC-MS/MS and BP-ANN

    PubMed Central

    Xu, Yanyan; Bao, Shihui; Tian, Weiqiang; Wen, Congcong; Hu, Lufeng; Lin, Chongliang

    2015-01-01

    Nuciferine has shown remarkable biological activities and been considered as a promising drug. In this study, a sensitive and selective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determination of nuciferine in tissue and plasma. An electrospray ionization source was applied and operated in positive ion mode; multiple reactions monitoring (MRM) mode was used for quantification using target fragment ions m/z 296.0→265.1 for nuciferine, and m/z 322.0→307.0 for berberrubine internal standard (IS). Based on the UPLC-MS/MS method, the tissue distribution profile of nuciferine in mice and plasma pharmacokinetics in rat were studied. The results showed nuciferine was absorbed through intestinal tract and distributed into tissues rapidly. The bioavailability of nuciferine was identified at 17.9%. It can across through blood brain barrier, the concentrations in liver and kidney are highest, then followed by spleen, lung heart and brain. Nuciferine is eliminated quickly in the tissues and plasma, the t1/2 within 5 hour. The concentrations in these tissues are correlated to each other, and can be predicted by a back-propagation artificial neural network model. PMID:26770351

  10. Quantitative determination of periplocymarin in rat plasma and tissue by LC-MS/MS: application to pharmacokinetic and tissue distribution study.

    PubMed

    Yan, Kaijing; Wang, Xiangyang; Jia, Yumeng; Chu, Yang; Guan, Xiufeng; Ma, Xiaohui; Li, Wei; Pan, Guixiang; Zhou, Shuiping; Sun, He; Liu, Changxiao

    2016-08-01

    A simple, rapid and sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for the determination of periplocymarin in biological samples was developed and successfully applied to the pharmacokinetic and tissue distribution study of periplocymarin after oral administration of periplocin. Biological samples were processed with ethyl acetate by liquid-liquid extraction, and diazepam was used as the internal standard. Periplocymarin was analyzed on a C18 column with isocratic eluted mobile phase composed of methanol and water (containing 0.1% formic acid) at a flow rate of 0.2 mL/min (73:27, v/v). Detection was performed on a triple-quadrupole tandem mass spectrometer using positive-ion mode electrospray ionization in the selected reaction monitoring mode. The MS/MS ion transitions monitored were m/z 535.3→355.1 and 285.1→193.0 for periplocymarin and diazepam, respectively. Good linearity was observed over the concentration ranges. The lower limit of quantification was 0.5 ng/mL in plasma and tested tissues. The intra-and inter-day precisions (relative standard deviation) were <10.2 and 10.5%, respectively, and accuracies (relative error) were between -6.8 and 8.9%. Recoveries in plasma and tissue were >90%. The validated method was successfully applied to the pharmacokinetic and tissue distribution studies of periplocymarin in rats. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26663385

  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. PMID:26048667

  12. Pharmacokinetics in rats and tissue distribution in mouse of magnoflorine by ultra performance liquid chromatography-tandem mass spectrometry

    PubMed Central

    Bao, Shihui; Geng, Peiwu; Wang, Shuanghu; Zhou, Yunfang; Hu, Lufeng; Yang, Xuezhi

    2015-01-01

    Magnoflorine is one of the most widespread aporphine alkaloids. In this work, a sensitive and selective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of magnoflorine in rat plasma and mouse tissue have been developed and validated. After addition of nuciferine as an internal standard (IS), protein precipitation by acetonitrile-methanol (9:1, v/v) was used for samples treatment. Chromatographic separation was achieved on a UPLC BEH C18 column (2.1 mm×100 mm, 1.7 μm) with 0.1% formic acid and acetonitrile as the mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; multiple reactions monitoring (MRM) mode was used for quantification using target fragment ions m/z 342.8→298.2 for magnoflorine and m/z 296.0→265.1 for IS. Calibration plots were linear throughout the range 2-2000 ng/mL for magnoflorine in rat plasma and tissue. Mean recoveries of magnoflorine in rat plasma were better than 83.0%. RSD of intra-day and inter-day precision were both less than 9%. The accuracy of the method was between 95.5% and 107.5%. The method was successfully applied to pharmacokinetics and tissue distribution study of magnoflorine. The absolute bioavailability of magnoflorine was reported as 22.6%. The magnoflorine underwent a rapid and wide distribution to tissues; the level of magnoflorine in liver is highest, then followed by heart, spleen and lung. Based on tissue distribution data, a back-propagation artificial neural network (BP-ANN) method was developed and it could be used to predict the concentrations of magnoflorine in tissues. PMID:26884929

  13. 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. PMID:25853479

  14. Pharmacokinetics, tissue distribution and excretion of peimisine in rats assessed by liquid chromatography-tandem mass spectrometry.

    PubMed

    Chen, Lihua; Li, Dongxun; Zhang, Guosong; Zhang, Wei; Zhang, Lihua; Guan, Yongmei; Zhu, Weifeng; Liu, Hongning

    2015-06-01

    Peimisine, the common ingredient of "zhebeimu" groups and "chuanbeimu" groups, is responsible for the expectorant and cough relieving effects. The aim of this study was to investigate the pharmacokinetics, tissue distribution and excretion of peimisine in male and female SD (Sprague-Dawley) rats by a rapid and sensitive LC-MS/MS (liquid chromatography-tandem mass spectrometry) method used carbamazepine as the internal standard after oral administration, carbamazepine was stated as an IS. The results showed that peimisine was slowly distributed, and eliminated from rat plasma and manifested linear dynamics in a dose range of 0.26-6.5 mg/kg. Tested by ANOVA, there were gender differences in the pharmacokinetic parameters of AUC(0-t), AUC(0-∞) among a single dose of 0.26, 1.3, 6.5 mg/kg (P < 0.05). Drug blood and tissue levels in male rats were significantly higher than the female counterparts after oral administration, while both the males and the females showed high drug levels in spleen, kidney, lung, liver and heart. On the other hand, the peimisine levels that can be reached in uterus, ovary, testis and brain is low. The excretion study showed that little administered peimisine (<0.7%) was recovered in the male and female bile. Approximately 13.46 and 15.05% were recovered in female urine and feces, while 43.07 and 7.49% were recovered in male urine and feces, respectively, which indicated that the major elimination route of male rats was urine excretion. In addition, there was significant differences in total cumulative excretive ratio of peimisine in feces (P < 0.05) and no significant differences in the urine (P > 0.05) at a dose of 1.3 mg/kg. PMID:25001900

  15. Quantitative analysis of tenuifolin concentrations in rat plasma and tissue using LC⬜MS/MS: application to pharmacokinetic and tissue distribution study.

    PubMed

    Ma, Bo; Li, Xiaotian; Li, Jing; Zhang, Qi; Liu, Yinhui; Yang, Xiaojing; Sun, Jingjing; Yao, Di; Liu, Lei; Liu, Xiaoxin; Ying, Hanjie

    2014-01-01

    A sensitive, reliable and accurate reversed-phased liquid chromatography with tandem mass spectrometry (LC⬜MS/MS) in negative ion mode was developed and validated for the quantification of tenuifolin in rat plasma and tissue. A single step protein precipitation by methanol was used to prepare plasma and tissue homogenate samples. Tenuifolin and polydatin (internal standard, IS) were separated by HPLC using a C18 column and an isocratic mobile phase consisted of acetonitrile and water containing 0.05% formic acid (42:58, v/v) running at a flow rate of 0.2 ml/min for 6 min. Detection and quantification were performed using a mass spectrometer by the multiple reaction monitoring (MRM) in negative electrospray ionization mode. The transition monitored were m/z [M↙H](↙) 679.4 ⠙ 455.4 for tenuifolin and m/z [M↙H](↙) 389.0 ⠙ 227.2 for IS, respectively. Calibration curves were recovered over a concentration range of 0.5⬜1000 ng/ml for plasma, heart, liver, lung and kidney, 0.5⬜200 ng/ml for spleen, and 0.5⬜50 ng/ml for brain, respectively. The lower limit of quantification was 0.5 ng/ml for plasma and tissue homogenates. The inter-day precision (R.S.D.) was less than 12.9% and intra-day precision R.S.D. was less than 13.4%, while the inter-day accuracy (R.E.) was ranged from ↙7.20 to 6.87% and intra-day accuracy (R.E.) was ranged from ↙6.20 to 8.04% in plasma and tissue homogenates. This method was successfully applied to the pharmacokinetic and tissue distribution study of pure tenuifolin in rat. The pharmacokinetic study indicated that poor absorption into systemic circulation was observed after rat was administered orally tenuifolin, and the absolute bioavailability was low (0.83 ± 0.28%). The results of tissue distribution showed the higher tenuifolin concentrations were found in liver, kidney and heart, and the small amount of drug was distributed quickly into the brain tissue at 5 min after the intravenous injection of tenuifolin

  16. High-performance liquid chromatographic analysis of amphotericin B in plasma, blood, urine and tissues for pharmacokinetic and tissue distribution studies.

    PubMed

    Wang, L H; Smith, P C; Anderson, K L; Fielding, R M

    1992-09-01

    A sensitive and reproducible high-performance liquid chromatographic method was developed to assay ampherotericin B in plasma, blood, urine and various tissue samples. Amphotericin B was isolated from each sample matrix by solid-phase extraction (Bond-Elut). The eluate from Bond-Elut containing amphotericin B was injected onto a reversed-phase C18 column (Waters, mu Bondpak, 10 microns, 300 mm x 3.9 mm I.D.) with a mobile phase of 45% acetonitrile in 2.5 mM Na2EDTA at 1 ml/min. Detection of amphotericin B was by ultraviolet absorption at 382 nm. Blood and tissues were homogenized and extracted with methanol prior to Bond-Elut extraction. The extraction efficiencies of amphotericin B from plasma, blood and tissues were approximately 90, 70 and 75%, respectively. The sensitivity of the assay was less than or equal to 5 ng/ml for plasma, less than or equal to 25 ng/ml for blood, 2.5 ng/ml for urine and 50 ng/g for tissues. The linearity of the assay method was up to 2.5 micrograms/ml for plasma, 5 micrograms/ml for blood, 500 ng/ml for urine and 500 micrograms/g for tissues. The assay was reproducible with an intra-day coefficient of variation (C.V., n = 3) of less than 5% in general for plasma, blood and tissues. The inter-day C.V. of the assay was less than 5% for plasma (n = 5), less than 10% for blood (n = 4) and less than 5% for tissues (n = 3). The overall variability in the urine assay was generally less than 10%. This method has demonstrated significant improvement in the sensitivity and reproducibility in assaying amphotericin B in plasma and especially in blood, urine and tissues. We have employed this assay to compare the pharmacokinetic and tissue distribution profiles of amphotericin B in rats and dogs following administration of Fungizone and ABCD (amphotericin B-cholesteryl sulfate colloidal dispersion), a lipid-based dosage form. In addition, the assay method for plasma and urine samples can also be applied to pharmacokinetics studies of amphotericin B

  17. Pharmacokinetics, tissue distribution and excretion study of a furostanol glycoside-based standardized fenugreek seed extract in rats.

    PubMed

    Kandhare, Amit D; Bodhankar, Subhash L; Mohan, V; Thakurdesai, Prasad A

    2015-08-01

    The furostanol glycoside isolated from the seed of fenugreek (SFSE-G) has an array of pharmacological activities. To date, no validated high-performance liquid chromatography (HPLC) method has been reported for quantification of SFSE-G in biological samples. Hence, the aim of the present study was to study the pharmacokinetics, tissue distribution and excretion profiles of SFSE-G after oral administration in rats. A rapid, sensitive, selective, robust and reproducible HPLC method has been developed for determination of SFSE-G in the rat biological samples. The chromatographic separation was accomplished on a reversed-phase C18 column using formic acid and acetonitrile (80:20) as mobile phase at a flow rate of 1.0 mL/min and 274 nm as a detection wavelength. The assay was linear for SFSE-G with the correlation coefficients (R(2)) >0.996. The analytes were stable during samples storage and handling, and no matrix effects were observed. After oral dosing of SFSE-G at a dose of 200 mg/kg, the elimination half-life was app. 40.10 h. It showed relatively slowly distribution and eliminated in urine and feces after 24 h, and could be detected until 108 h post-dosing. Following oral single dose (200 mg/kg), SFSE-G was detected in lung and brain which indicated that it could cross the blood-brain barrier. It is a major route of elimination is excretion through urine and feces. In conclusion, oral administration of SFSE-G showed slow distribution to tissues, such as lung and brain, but showed fast renal elimination. PMID:26104039

  18. Development of a liquid chromatography with mass spectrometry method for the determination of gelsemine in rat plasma and tissue: Application to a pharmacokinetic and tissue distribution study.

    PubMed

    Zhang, Shuangshuang; Hu, Shuping; Yang, Xiangxiang; Shen, Jiaqi; Zheng, Xiaoyong; Huang, Kexin; Xiang, Zheng

    2015-03-01

    Gelsemine from Gelsemium elegans Benth is a potential anesthetic and analgesic agent with no physical dependence and opiate addiction. This study was aimed at developing an ultrafast liquid chromatography coupled to tandem mass spectrometry method to quantify gelsemine in rat plasma and tissues. Plasma and tissues were processed with acetonitrile precipitation, and dendrobine was chosen as the internal standard. Sample separation was performed on an ACQUITY HSS T3 column. The mobile phase consisted of acetonitrile and 0.1% formic acid aqueous solution. Multiple reactions monitoring mode was utilized to detect the compounds of interest. The mass spectrometer was operated in the positive ion mode for detection. The MS/MS ion transitions monitored were m/z 323.2→70.5 for gelsemine and 264.2→108.05 for dendrobine, respectively. The calibration curves were linear over the range of 1-500 ng/mL in all biological matrices. The lower limit of quantification for rats plasma and tissues was 1.0 ng/mL. The values for inter- and intraday precision and accuracy were well within the ranges acceptable (< 15%). It was successfully applied to the pharmacokinetic and tissue distribution studies of gelsemine after intravenous doses of 5, 2, and 0.5 mg/kg in rats. These data of gelsemine would be useful for clinical application and further development. PMID:25580713

  19. 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

  20. Prediction of the pharmacokinetics and tissue distribution of levofloxacin in humans based on an extrapolated PBPK model.

    PubMed

    Zhu, Liqin; Zhang, Yuan; Yang, Jianwei; Wang, Yongming; Zhang, Jianlei; Zhao, Yuanyuan; Dong, Weilin

    2016-08-01

    This study developed a physiologically based pharmacokinetic (PBPK) model in intraabdominally infected rats and extrapolated it to humans to predict the levofloxacin pharmacokinetics and penetration into tissues. Twelve male rats with intraabdominal infections induced by Escherichia coli received a single dose of 50 mg/kg body weight of levofloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480 and 1440 min after injection, respectively. A PBPK model was developed in rats and extrapolated to humans using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration-versus-time profile of levofloxacin in rats, C max was 23.570 μg/ml at 5 min after intravenous injection, and t1/2 was 2.38 h. The plasma concentration and kinetics in humans were predicted and validated by the observed data. Levofloxacin penetrated and accumulated with high concentrations in the heart, liver, kidney, spleen, muscle and skin tissues in humans. The predicted tissue-to-plasma concentration ratios in abdominal viscera were between 1.9 and 2.3. When rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict the drug pharmacokinetics and penetration in humans. Levofloxacin had good penetration into the liver, kidney and spleen as well as other tissues in humans. This pathological model extrapolation may provide a reference for the study of antiinfective PK/PD. In our study, levofloxacin penetrated well into abdominal organs. Also ADR monitoring should be implemented when using levofloxacin. PMID:25753830

  1. Preclinical pharmacokinetics, tissue distribution and excretion studies of a potential analgesics - corydaline using an ultra performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Wang, Jianfeng; Liang, Lishuang; Zhang, Qiongyu; Li, Xingang; Fu, Zhijian

    2013-12-30

    A rapid resolution ultra performance liquid chromatography (UPLC) coupled with electrospray ionization (ESI) mass spectrometry method was developed and validated for the quantitative analysis of corydaline in rats' plasma and various tissues for pharmacokinetic, tissue distribution and excretion studies of corydaline. The analytes were separated on an Acquity UPLC BEH C18 column (2.1mm×100mm, 1.7μm) 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 370.0→192.0 for corydaline and 354.1→188.0 for IS, respectively. Calibration curves (1/x(2) weighted) offered satisfactory linearity (r(2)>0.9984) within 1-1000ng/mL. The accuracy and precision ranged from -7.4% to 8.5% and 3.4% to 12.8%, respectively. The absolute matrix effect (94.2-119.2%), relative matrix effect (1.7-9.6%) and recoveries (81.4-93.7%) were satisfactory in all the biological matrices examined. The assay was successfully applied to the plasma pharmacokinetics, tissue distribution and excretion studies of corydaline in rats. The pharmacokinetic parameters such as half-life (t1/2), mean residence time (MRT) and maximum concentration (Cmax) were determined. These preclinical data of corydaline would be useful for the clinical reference. PMID:24216274

  2. 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

    2014-12-01

    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. PMID:25375210

  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 Central

    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. PMID:27588003

  4. 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. PMID:27588003

  5. 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. PMID:27287046

  6. In vivo pharmacokinetics of and tissue distribution study of physalin B after intravenous administration in rats by liquid chromatography with tandem mass spectrometry.

    PubMed

    Zheng, Yunliang; Chen, Jing; Liu, Lin; Liang, Xingguang; Hong, Dongsheng

    2016-08-01

    A rapid and sensitive liquid chromatography tandem mass spectrometry quantitative analysis method was established for the pharmacokinetics and tissue distribution study of physalin B in rat. Physalin B and physalin H (internal standard, IS) were separated on an Agilent Eclips XDB C8 column. MS detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction monitoring mode with a positive eletrospray ionization source. The assay was validated in the concentration ranges of 22.6-22600 ng/mL for heart and lung and 4.52-4520 ng/mL for other tissues. The intra- and inter-day precisions (RSD) were ≤9.23 and ≤12.51%, respectively, with accuracy (%) in the range of 88.07-113.2%. A pharmacokinetic study showed that physalin B has a long dwell time with a half-life of 321.2 ± 29.5 min and clearance of 175.4 ± 25.7 mL/min/kg after intravenous administration. Additionally, physalin B showed a wide tissue distribution with a special higher penetration in lung. The data presented in this study could provide useful information for the further study of physalin B. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26714262

  7. Determination of tissue distribution of potent antitumor agent ureidomustin (BO-1055) by HPLC and its pharmacokinetic application in rats.

    PubMed

    Chien, Shin-I; Yen, Jiin-Cherng; Kakadiya, Rajesh; Chen, Ching-Huang; Lee, Te-Chang; Su, Tsann-Long; Tsai, Tung-Hu

    2013-02-15

    Ureidomustin hydrochloride (BO-1055) was designed as a water-soluble nitrogen-mustard, which exhibited potent anticancer activity and was selected as a candidate for preclinical studies. However, up to date, there is rarely an easy and economic method to quantize ureidomustin in the biological samples. The aim of this study is to develop a simple yet valid quantization method to tackle this challenge. Here we present a combined high-performance liquid chromatography with photodiode array (HPLC-PDA) method in quantizing the ureidomustin in the plasma and various organs of Sprague-Dawley rats. The method was validated in terms of precision, accuracy, and extraction recovery. Furthermore, the established method was applied to study pharmacokinetics of ureidomustin in the rat's plasma and verified via a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Calibration curves of the plasma and organ samples were falling at the range between 0.5-50μg/mL and 0.1-50μg/mL (r(2)≥0.999 and CV≤±15%), respectively. The limits of detection (LOD) were 0.1μg/mL for plasma samples and 0.05μg/mL for organ samples, while the detection limits of quantification (LOQ) were 0.5μg/mL for plasma samples and 0.1μg/mL for organ samples. The average recovery of ureidomustin was about 83%. These results demonstrated a linear pharmacokinetic pattern at dosages of 10 and 30mg/kg. The pharmacokinetic data revealed that ureidomustin was best fitted to a two-compartment model with a rapid distribution phase and a slow elimination phase. Besides, after a short intravenous administration time at the dose of 10mg/kg, ureidomustin was found to be quickly distributed to all organs in rats, accumulated mainly in the kidney, and only a limited amount was detected in the brain. PMID:23353940

  8. 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. PMID:27232980

  9. Determination of xanthotoxin using a liquid chromatography-mass spectrometry and its application to pharmacokinetics and tissue distribution model in rat

    PubMed Central

    Tian, Weiqiang; Cai, Jinzhang; Xu, Yanyan; Luo, Xinhua; Zhang, Jin; Zhang, Zixue; Zhang, Qingwei; Wang, Xianqin; Hu, Lufeng; Lin, Guanyang

    2015-01-01

    A simple and selective liquid chromatography mass spectrometry method for determination of xanthotoxin in rat plasma and various tissues for pharmacokinetic was developed. Chromatographic separation was achieved on a C18 (2.1 mm × 150 mm, 5 μm) column with acetonitrile-0.1% formic acid in water as mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring (SIM) mode was used for quantification using target fragment ions m/z 217 for xanthotoxin and m/z 326 for the internal standard. The resulting calibration curves offered satisfactory linearity (R2 > 0.99) within the test range. Mean recoveries of xanthotoxin in rat plasma were in the range of 79.9%-84.6%. RSD of intra-day and inter-day precision were both < 14%. The accuracy of the method ranged from 87.5% to 109.8%. The assay was successfully applied to the pharmacokinetics and tissue distribution model studies of xanthotoxin in rats. The oral bioavailability of xanthotoxin was 73.2% in rats. PMID:26629000

  10. Pharmacokinetics and tissue distribution of novel platinum containing anticancer agent BP‐C1 studied in rabbits using sector field inductively coupled plasma mass spectrometry

    PubMed Central

    Navolotskii, Denis V.; Ivanenko, Natalya B.; Fedoros, Elena I.; Panchenko, Andrey V.

    2015-01-01

    A method of platinum quantification in whole blood samples after microwave digestion using sector field inductively coupled plasma mass spectrometry has been developed. The following analytical figures of merit have been established: limit of detection 1.1 µg/L for blood samples, dynamic range 3.6–200 µg/L, intra‐day precision (relative standard deviation, n = 9) did not exceed 5%. Spiked samples were analyzed for method validation. The method was used for pharmacokinetics studies of a novel anti‐cancer drug BP‐С1, a complex of cis‐configured platinum and benzene‐poly‐carboxylic acids. Main pharmacokinetic parameters (area under curve, maximum concentration, clearance, half‐life times for α‐ and β‐phase) were estimated for two dosage forms of BP‐C1 0.05 and 0.125 mass %. Pharmacokinetic curves were assessed for single and course administration. Studies were performed using rabbits (n = 6) as a model. BP‐C1 was injected intramuscularly. The study established dose proportionality of the tested dosage forms and suggested clinical dosing schedule: 5 days of injections followed by 2 days’ break. Platinum tissue distribution was studied in tissue samples collected 20 days after the last injection. Predominant platinum accumulation was observed in kidneys, liver, and muscles near injection site. ‘Slow’ phase of platinum excretion kinetics may be related to the muscles at the injection site. © 2015 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd. PMID:26061351

  11. Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution.

    PubMed

    Girard, A E; Girard, D; English, A R; Gootz, T D; Cimochowski, C R; Faiella, J A; Haskell, S L; Retsema, J A

    1987-12-01

    Azithromycin (CP-62,993), a new acid-stable 15-membered-ring macrolide, was well absorbed following oral administration in mice, rats, dogs, and cynomolgus monkeys. This compound exhibited a uniformly long elimination half-life and was distributed exceptionally well into all tissues. This extravascular penetration of azithromycin was demonstrated by tissue/plasma area-under-the-curve ratios ranging from 13.6 to 137 compared with ratios for erythromycin of 3.1 to 11.6. The significance of these pharmacokinetic advantages of azithromycin over erythromycin was shown through efficacy in a series of animal infection models. Azithromycin was orally effective in treating middle ear infections induced in gerbils by transbulla challenges with amoxicillin-resistant Haemophilus influenzae or susceptible Streptococcus pneumoniae; erythromycin failed and cefaclor was only marginally active against the H. influenzae challenge. Azithromycin was equivalent to cefaclor and erythromycin against Streptococcus pneumoniae. In mouse models, the new macrolide was 10-fold more potent than erythromycin and four other antibiotics against an anaerobic infection produced by Fusobacterium necrophorum. Similarly, azithromycin was effective against established tissue infections induced by Salmonella enteritidis (liver and spleen) and Staphylococcus aureus (thigh muscle); erythromycin failed against both infections. The oral and subcutaneous activities of azithromycin, erythromycin, and cefaclor were similar against acute systemic infections produced by Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, or S. aureus, whereas azithromycin was more potent than erythromycin and cefaclor against the intracellular pathogen Listeria monocytogenes. The pharmacokinetic advantage of azithromycin over erythromycin in half-life was clearly demonstrated in prophylactic treatment of an acute mouse model of S. aureus infection. These properties of azithromycin strongly support the

  12. Plasma pharmacokinetics and tissue distribution of arctiin and its main metabolite in rats by HPLC-UV and LC-MS.

    PubMed

    He, Fan; Fan, He; Dou, De-Qiang; De-Qiang, Dou; Sun, Yu; Yu, Sun; Zhu, Lin; Lin, Zhu; Xiao, Hong-Bin; Hong-Bin, Xiao; Kang, Ting-Guo; Ting-Guo, Kang

    2012-05-01

    The pharmacokinetic profile of arctiin, the major active lignan in fruits of Arctium lappa L., was investigated. Its main meta"bolite arctigenin was identified by an LC-MS method, and an HPLC-UV technique was developed for the simultaneous quantification of the metabolite and arctiin in plasma and organs. Chromatographic separation was performed on an Agilent™ C₁₈ HPLC column with acetonitrile and water by linear gradient elution. Arctiin and arctigenin were identified on-line by LC-MS. The pharmacokinetics and tissue distribution of arctiin and arctigenin were determined for the first time by using a simple, selective, and accurate HPLC method. The AUC0-t values of arctigenin were larger compared with arctiin after oral administration of arctiin. The concentration of the metabolite was significantly higher than the concentration of arctiin in the stomach and small intestine in rats after oral administration of arctiin, indicating that the stomach and small intestine were the major organs of arctiin metabolism. These findings could provide support for the clinical studies conducted with Fructus Arctii. PMID:22499560

  13. Preclinical Development of an anti-5T4 Antibody-Drug Conjugate: Pharmacokinetics in Mice, Rats, and NHP and Tumor/Tissue Distribution in Mice.

    PubMed

    Leal, Mauricio; Wentland, JoAnn; Han, Xiaogang; Zhang, Yanhua; Rago, Brian; Duriga, Nicole; Spriggs, Franklin; Kadar, Eugene; Song, Wei; McNally, James; Shakey, Quazi; Lorello, Leslie; Lucas, Judy; Sapra, Puja

    2015-11-18

    The pharmacokinetics of an antibody (huA1)-drug (auristatin microtubule disrupting MMAF) conjugate, targeting 5T4-expressing cells, were characterized during the discovery and development phases in female nu/nu mice and cynomolgus monkeys after a single dose and in S-D rats and cynomolgus monkeys from multidose toxicity studies. Plasma/serum samples were analyzed using an ELISA-based method for antibody and conjugate (ADC) as well as for the released payload using an LC-MS/MS method. In addition, the distribution of the Ab, ADC, and released payload (cys-mcMMAF) was determined in a number of tissues (tumor, lung, liver, kidney, and heart) in two tumor mouse models (H1975 and MDA-MB-361-DYT2 models) using similar LBA and LC-MS/MS methods. Tissue distribution studies revealed preferential tumor distribution of cys-mcMMAF and its relative specificity to the 5T4 target containing tissue (tumor). Single dose studies suggests lower CL values at the higher doses in mice, although a linear relationship was seen in cynomolgus monkeys at doses from 0.3 to 10 mg/kg with no evidence of TMDD. Evaluation of DAR (drug-antibody ratio) in cynomolgus monkeys (at 3 mg/kg) indicated that at least half of the payload was still on the ADC 1 to 2 weeks after IV dosing. After multiple doses, the huA1 and conjugate data in rats and monkeys indicate that exposure (AUC) increases with increasing dose in a linear fashion. Systemic exposure (as assessed by Cmax and AUC) of the released payload increased with increasing dose, although exposure was very low and its pharmacokinetics appeared to be formation rate limited. The incidence of ADA was generally low in rats and monkeys. We will discuss cross species comparison, relationships between the Ab, ADC, and released payload exposure after multiple dosing, and insights into the distribution of this ADC with a focus on experimental design as a way to address or bypass apparent obstacles and its integration into predictive models. PMID:26180901

  14. Pharmacokinetics and tissue distribution of ginkgolide A, ginkgolide B, and ginkgolide K after intravenous infusion of ginkgo diterpene lactones in a rat model.

    PubMed

    Wang, Shuyao; Ouyang, Bingchen; Aa, Jiye; Geng, Jianliang; Fei, Fei; Wang, Pei; Wang, Jiankun; Peng, Ying; Geng, Ting; Li, Yanjing; Huang, Wenzhe; Wang, Zhenzhong; Xiao, Wei; Wang, Guangji

    2016-07-15

    Ginkgo diterpene lactones are compounds that are extracted from the Ginkgo biloba leaf and possess pharmacologic activities with neuroprotective effects. To address the poor bioavailability of ginkgo diterpene lactones, ginkgo diterpene lactone meglumine injection (GDLI) was formulated and is commercially available. In this study, a simple, sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for assessing the total amount and the amount of the prototype forms of ginkgolides A (GA), B (GB) and K (GK) in rat plasma and tissues. This method was used to calculate the concentrations of the hydrolysed carboxylic forms and assess the pharmacokinetics of the ginkgolides after intravenous (i.v.) GDLI administration in rats. Generally, all three ginkgolide forms showed dose-dependent plasma concentrations, and no obvious differences in pharmacokinetic parameters, i.e., area under the curve (AUC) of plasma concentration versus time and half-life, were observed after GDLI administration on 7 consecutive days. These ginkgolides primarily existed in the carboxylic form in the plasma, and the systemic concentrations of the carboxylic forms of GA and GB were 11- to 17- and 3- to 4-fold higher than those of their prototype forms, respectively. In contrast, dramatically increased levels of the GA and GB prototype lactones were detected in the liver and heart. GA, GB, and GK were extensively distributed in various organs/tissues; the highest levels were found in the kidneys, liver, and intestine, and the lowest levels were found in the brain. These data suggest that ginkgolides have difficulty crossing the blood-brain barrier and that their targets for protecting against cerebral ischaemia are located outside the central system. PMID:27182682

  15. Development and Validation of a Rapid and Simple UPLC-ESI-MS Method for Pharmacokinetics and Tissue Distribution of Astragaloside III in Rats.

    PubMed

    Liu, Xiao-Hua; Guo, Long; Yang, Ying-Lai; Hu, Fang; Chen, Xin-Yue; Feng, Shi-Lan

    2016-05-01

    A rapid and simple ultra-performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-ESI-MS) method for the determination of astragaloside III was developed and used in a pharmacokinetic and tissue distribution study in rats following the oral administration 95% ethanol extraction of Zhenqi Fuzheng capsules. Although astragaloside III and astragaloside IV have the same molecular weight and very similar structures, they were successfully separated using this method. Quantification was performed using low-energy collision tandem mass spectrometry (CID-MS-MS) with the multiple reaction monitoring scan mode of the following precursor ion → product ion atm/z807.61→335.22 for astragaloside III and atm/z633.18→331.18 for the internal standard (hesperidin). Both astragaloside III and astragaloside IV in rat plasma were best fit to a two-compartment model. The tissue distribution study showed the overall trend of disposition of astragaloside III were Cthymus> Cspleen> Cstomach> Cliver> Cheart> Ckidney> Clung> Ctesticle The high levels of astragaloside III in thymus and spleen indicated an accumulation in organs involved in immune responses and showed that these organs are major target sitesin vivo The results in the article will provide valuable information for use in clinical applications of astragaloside III. PMID:26931734

  16. Pharmacokinetics, tissue distribution, excretion, and metabolite profiling of PEGylated rFIX (nonacog beta pegol, N9-GP) in rats.

    PubMed

    Sternebring, Ola; Christensen, Jesper Kammersgaard; Bjørnsdottir, Inga

    2016-09-20

    Nonacog beta pegol (N9-GP) is a novel recombinant factor IX conjugated with a 40-kDa branched polyethylene glycol (PEG) to extend plasma half-life (t½) compared with native FIX, developed for the treatment of haemophilia B. This is the first time distribution, metabolism, and excretion data of N9-GP have been presented. ADME studies were performed using single i.v. doses of radiolabelled N9-GP administered to rats, focussing on the biological fate of the 40-kDa PEG. Results indicated that N9-GP-related radioactivity was distributed throughout the body, being most abundant in highly vascularised tissues, and with lowest levels seen in the central nervous system. N9-GP was cleared from plasma within 1week after dosing, while total radioactivity was eliminated more slowly, in a more pronounced biphasic manner. N9-GP seems to be cleared via receptor-mediated uptake (e.g., in the liver) or via the reticuloendothelial system with subsequent proteolysis. PEG is thereafter either cleared alongside the protein or released back into circulation. Furthermore, N9-GP-related radioactivity was excreted in both faeces and urine as 40kDa PEG and degradation products. Some PEG-related radioactivity (not in any particular organ) was present in the carcass 12weeks postdose, consistent with the long terminal elimination t½ of plasma radioactivity. As shown here for N9-GP, and previously for other protein-PEG conjugate products, disposition kinetics of conjugates and individual constituents appears to be compound specific. In addition to the size/structure of the PEG and protein moieties, protein-specific clearance pathways may contribute to the disposition of intact conjugate and PEG moiety. PMID:27378188

  17. Pharmacokinetics and Tissue Distribution of Folate-Decorated Human Serum Albumin Loaded With Nano-Hydroxycamptothecin for Tumor Targeting.

    PubMed

    Wang, Wenchao; Liang, Hui; Sun, Baihe; Xu, Jialin; Zeng, Zhen; Zhao, Xiaojun; Li, Qingyong

    2016-06-01

    The goal of this work is to develop the method of preparing folate (FA)-decorated human serum albumin (HSA) loaded with nano-hydroxycamptothecin (nHCPT) nanoparticles (NPs) (FA-HSA-nHCPT-NPs) and to explore its antitumor activity in vivo and in vitro. FA-HSA-nHCPT-NPs were obtained by preparing nHCPT by a high-pressure homogenization technique followed with an anti-solvent method. The drug-loading efficiency of the FA-HSA-nHCPT-NPs was 7.8%. We adopted the human breast cancer cells (FA receptor-expressing MCF-7 cells) and BALB/c mice inoculated with human MCF-7 cells to determine the antitumor activity of FA-HSA-nHCPT-NPs in vitro and in vivo, respectively. The antitumor activity of FA-HSA-nHCPT-NPs was stronger than that of the raw HCPT in both conditions. Tissue distribution analysis showed that the FA-HSA-nHCPT-NPs carried more HCPT to tumors than the raw HCPT. The tumor inhibitory rate of FA-HSA-nHCPT-NPs was much higher compared with the raw HCPT. Th7us, the FA-HSA-nHCPT-NPs could serve as a viable delivery system with an obvious target effect on tumor. PMID:27129905

  18. Pharmacokinetics, tissue distribution and excretion of 40kDa PEG and PEGylated rFVIII (N8-GP) in rats.

    PubMed

    Bjørnsdottir, Inga; Sternebring, Ola; Kappers, Wendela A; Selvig, Helle; Kornø, Hanne T; Kristensen, Jesper B; Bagger, Morten A

    2016-05-25

    The biologic fate of the [(3)H]PEG-moiety incorporated into N8-GP was evaluated based on single i.v. bolus doses to rats. Furthermore, the 40kDa [(3)H]PEG-moiety was given separately to rats by single i.v. bolus doses, to investigate if the pharmacokinetics were dose-dependent. For both compounds, plasma pharmacokinetics, distribution and excretion pathways were investigated, based on total radioactivity measurements ([(3)H]N8-GP: 0.17-4.1mg/kg;~1300-30,000U/kg, PEG load of ~0.03-0.7mg/kg); ([(3)H]PEG: 0.6, 1, 12, 100 and 200mg/kg). The plasma concentration of the intact N8-GP conjugate was also measured by ELISA. After single i.v. administration to rats, both [(3)H]N8-GP and [(3)H]PEG were shown to be widely distributed, mainly in highly vascularized tissues, with the lowest levels of radioactivity found in the CNS. Though a slow elimination of radioactivity was observed over the 12-week study period, approximately half of the radioactive dose of either compound was removed from the body 1week post-dose. The radioactivity was eliminated mainly via the kidney into urine but also via the liver into feces, with a larger fraction found in the feces for [(3)H]N8-GP. Elimination of the 40kDa PEG-moiety was shown to be dose-dependent with faster elimination at lower dose levels. The clinical dose of N8-GP provides a substantially lower PEG exposure (50-75U/kg; PEG load of <0.002mg/kg) when compared to the PEG doses investigated in this paper (0.03-200mg/kg). This may imply an even faster clearance of the PEG-moiety after N8-GP administration of clinically relevant doses. PMID:26517963

  19. A HPLC-MS/MS method for determination of 6'''-feruloylspinosin in rat plasma and tissues: Pharmacokinetics and tissue distribution study.

    PubMed

    Qiao, Longdong; Liu, Yan; Chen, Xiaoyan; Xie, Junbo; Zhang, Yanqing; Yang, Ke; Zhou, Hongjian; Duan, Yayun; Zheng, Wei; Xie, Wenlin

    2016-03-20

    A sensitive, reliable and accurate HPLC-MS/MS method was developed and validated for the quantification of 6'''-feruloylspinosin in rat plasma and tissues with puerarin as the internal standard. The separation was performed on a Proshell 120 EC-C18 column (4.6×150 mm, 2.7 μm) with a mobile phase consisting of acetonitrile and 0.1% formic acid (20:80, v/v) at 0.3 mL/min. The quantification was performed by MRM with m/z [M-H](-) 783.3→427.2 for 6'''-feruloylspinosin and m/z [M-H](-) 415.4→295.4 for the internal standard, respectively. The calibration curves covered over a concentration range of 20-2000 ng/mL in plasma and various tissues samples (heart, liver, spleen, lung, kidney, stomach, intestine, muscle, cerebrum and cerebellum) with good linearity (r(2)≥0.9914). Both the intra- and inter-day precisions were less than 14.70%, and the accuracy (RE%) ranged from -5.80% to 4.93%. The extraction recoveries were within 75.21-92.96%, and the matrix effect ranged from 87.21% to 113.44%. Compared with spinosin, 6'''-feruloylspinosin was distributed in rats faster whereas more slowly eliminated from the plasma. 6'''-Feruloylspinosin could be distributed rapidly and widely in various tissues, and transfer across the blood-brain barrier. In addition, both 6'''-feruloylspinosin and spinosin could enhance the expression of GABAAα1, GABAAα5, GABABR1 mRNA in rat hippocampal neurons significantly, indicating the bioactivity mechanism of 6'''-feruloylspinosin was involved in the GABA receptors. PMID:26780157

  20. 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

    SciTech Connect

    Lin, Zhoumeng; Fisher, Jeffrey W.; Wang, Ran; Ross, Matthew K.; Filipov, Nikolay M.

    2013-11-15

    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) at 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 data.

  1. Pharmacokinetics of ractopamine and its organ distribution in rats.

    PubMed

    Ho, Jing-Kai; Huo, Teh-Ia; Lin, Lie-Chwen; Tsai, Tung-Hu

    2014-09-24

    Ractopamine, a β-agonist, is used to increase the proportion of lean meat in livestock. However, due to potential cardiovascular risks, ractopamine has been banned for use in food-producing animals in many countries. Nevertheless, pharmacokinetic studies of ractopamine have not been completed. The aim of this study was to develop a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the determination of ractopamine. This validated method was used to investigate the pharmacokinetics and organ distribution of ractopamine in rats. The validation results complied with the U.S. Food and Drug Administration's standards. The oral bioavailability of ractopamine was 2.99%. After intravenous administration, ractopamine concentrations varied as follows: kidney > lung > spleen > heart > liver > muscle > plasma > brain. Nonlinear pharmacokinetics and strong partitioning into tissues were observed after intravenous administration of ractopamine. These effects may be due to nonlinear elimination via the kidney. PMID:25207456

  2. In vivo toxicity, pharmacokinetic features and tissue distribution of N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-236), a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase.

    PubMed

    Chen, C L; Venkatachalam, T K; Waurzyniak, B; Chelstrom, L; Uckun, F M

    2001-01-01

    N-[2-(2,5-Dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-236, CAS 233271-65-3) possesses potent anti-viral activity against zidovudine-sensitive as well as multidrug-resistant HIV-1 (human immunodeficiency virus) strains. The purpose of the present study was to examine in vivo toxicity, pharmacokinetic features and tissue distribution of HI-236 in mice. HI-236 had an elimination half-life of 85.8 min after i.v. administration and 86.6 min after i.p. administration. The systemic clearance of HI-236 was 4337 ml/h/kg after i.v. administration and 10,130 ml/h/kg after i.p. administration. Following i.v. injection, HI-236 rapidly distributed to and accumulated in multiple tissues with particularly high accumulation in lung, adipose tissue, skin, urinary bladder, adrenal gland and uterus + ovary. The concentration of HI-236 in brain tissue was comparable to that in the plasma, indicating that HI-236 easily crosses the blood-brain barrier. Following i.p. injection, HI-236 was rapidly absorbed with a tmax values of 5.6 min and showed linear pharmacokinetics within the dose range of 10-80 mg/kg. Following oral administration, HI-236 was absorbed with a tmax of 5.8 min. The intraperitoneal bioavailability was estimated at 42.9%, while the oral bioavailability was only 2.2%. The pharmacokinetic study described herein provides the basis for advanced pharmacodynamic study of HI-236. PMID:11505789

  3. A rapid and sensitive LC-MS/MS method for the determination of linarin in small-volume rat plasma and tissue samples and its application to pharmacokinetic and tissue distribution study.

    PubMed

    Feng, Xinchi; Liu, Youping; Wang, Xin; Di, Xin

    2016-04-01

    A rapid and sensitive LC-MS/MS method was developed for the determination of linarin in small-volume rat plasma and tissue sample. Sample preparation was employed by the combination of protein precipitation (PPT) and liquid-liquid extraction (LLE) to allow measurement over a 5-order-of-magnitude concentration range. Fast chromatographic separation was achieved on a Hypersil Gold column (100 × 2.1 mm i.d., 5 µm). Mass spectrometric detection was achieved using a triple-quadrupole mass spectrometer equipped with an electrospray ionization interface operating in positive ionization mode. Quantification was performed using selected reaction monitoring of precursor-product ion transitions at m/z 593 → 285 for linarin and m/z 447 → 271 for baicalin (internal standard). The total run time was only 2.8 min per sample. The calibration curves were linear over the concentration range of 0.4-200 µg/mL for PPT and 0.001-1.0 µg/mL for LLE. A lower limit of quantification of 1.0 ng/mL was achieved using only 20 μL of plasma or tissue homogenate. The intra- and inter-day precisions in all samples were ≤14.7%, while the accuracy was within ±5.2% of nominal values. The validated method has been successfully applied to pharmacokinetic and tissue distribution study of linarin. PMID:26385597

  4. Plasma pharmacokinetics, bioavailability and tissue distribution of agnuside following peroral and intravenous administration in mice using liquid chromatography tandem mass spectrometry.

    PubMed

    Ramakrishna, Rachumallu; Bhateria, Manisha; Singh, Rajbir; Puttrevu, Santosh Kumar; Bhatta, Rabi Sankar

    2016-06-01

    Agnuside (AGN), an iridoid glycoside, is the chemotaxonomic marker of the genus Vitex which has gained enormous attention by virtue of its potential health benefits. Regardless of claiming many therapeutic applications reports demonstrating its pharmacokinetics or quantification in biomatrices are lacking. This is the first report which presents a sensitive liquid chromatography coupled to a tandem mass spectrometry (LC-MS/MS) method for the quantification of AGN in mice plasma and various tissues (including liver, intestine, spleen, kidney, heart, lungs and brain). AGN was extracted from the biological samples using protein precipitation followed by liquid-liquid extraction and the separation was achieved on C18 reversed phase column with a mobile phase consisted of 0.1% formic acid in acetonitrile-0.1% formic acid in triple distilled water (92:8, v/v) at a flow rate of 0.7mL/min. The MS/MS detection was performed by electrospray ionization (ESI) using multiple reaction monitoring (MRM) in negative scan mode. The bioanalytical method was found linear over the concentration range of 1-4000ng/mL for plasma and tissue homogenates (r(2)≥0.990). The lower limit of quantitation (LLOQ) for all matrices was 1ng/mL. Intra-day and inter-day variance and accuracy ranged from 90 to 110% and 1-10%, respectively. Matrix effect and recoveries were well within the satisfactory limits. The validated method was applied successfully to measure AGN concentrations in plasma and tissues following intravenous (i.v.) and peroral (p.o.) administration to mice. Maximal AGN concentrations in plasma and tissues were reached within 30-45min. The mean absolute bioavailability (%F) of AGN was∼0.7%. After oral administration, AGN was most abundant in intestine, followed by kidney, liver, spleen, brain, lungs and heart. The identified target tissues of AGN may help in understanding its pharmacological action in vivo. PMID:27018507

  5. New insight into the clinical pharmacokinetics of cefaclor: tissue penetration.

    PubMed

    Mazzei, T; Novelli, A; Esposito, S; Periti, P

    2000-02-01

    The serum pharmacokinetic data presented are generally in agreement with those obtained by other authors with both the cefaclor IR (immediate release) and AF (advanced formulation) or MR (modified release) formulations. With the new sustained-release formulation, the time of peak (Tmax) and mean residence time (MRT) values are significantly longer than those observed with the standard cefaclor IR. For the first time the penetration of the MR formulation of cefaclor was determined both in suction blister fluid (SBF) and alveolar epithelial lining fluid (ELF). Cefaclor demonstrated a high tissue distribution, with a high penetration index (PI) into blister fluid, which is at least representative of a relatively large volume of fluid-filled spaces and in part of highly vascularized tissues. SBF and ELF concentrations were higher than blood levels starting at the 4th-6th hour after dose, with longer elimination half-lives from the extravascular compartment than from serum. Cefaclor has a favorable pharmacokinetic profile, especially the new sustained-release formulation, which maintains effective concentrations for a longer time than the IR preparation. The MR formulation improves the kinetic properties of the cefaclor molecule with a prolonged MRT which allows a daily dosage of 750 mg every 12 h. PMID:10768516

  6. Determination of Meserine, a new candidate for Alzheimer's disease in mice brain by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic and tissue distribution study.

    PubMed

    Zheng, Zhaoxi; Tang, Yabin; Lv, Haoyu; Xu, Jianrong; Zhao, Hengyi; Xie, Qiong; Qiu, Zhuibai; Chen, Hongzhuan; Wang, Hao

    2014-05-01

    A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of Meserine ((-)-meptazinol phenylcarbamate), a novel potent inhibitor of acetylcholinesterase (AChE), was developed, validated, and applied to a pharmacokinetic study in mice brain. The lower limit of quantification (LLOQ) was 1 ng mL(-1) and the linear range was 1-1,000 ng mL(-1). The analyte was eluted on a Zorbax SB-Aq column (2.1 × 100 mm, 3.5 μm) with the mobile phase composed of methanol and water (70:30, v/v, aqueous phase contained 10 mM ammonium formate and 0.3% formic acid) using isocratic elution, and monitored by positive electrospray ionization in multiple reaction monitoring (MRM) mode. The flow rate was 0.25 mL min(-1). The injection volume was 5 μL and total run time was 4 min. The relative standard deviation (RSD) of intraday and interday variation was 2.49-7.81 and 3.01-7.67%, respectively. All analytes were stable after 4 h at room temperature and 6 h in autosampler. The extraction recoveries of Meserine in brain homogenate were over 90%. The main brain pharmacokinetic parameters obtained after intranasal administration were T max = 0.05 h, C max = 462.0 ± 39.7 ng g(-1), T 1/2 = 0.4 h, and AUC(0-∞) = 283.1 ± 9.1 ng h g(-1). Moreover, Meserine was distributed rapidly and widely into brain, heart, liver, spleen, lung, and kidney tissue. The method is validated and could be applied to the pharmacokinetic and tissue distribution study of Meserine in mice. PMID:24756818

  7. Development and validation of an UPLC-MS/MS method for the quantification of ethoxzolamide in blood, brain tissue, and bioequivalent buffers: applications to absorption, brain distribution, and pharmacokinetic studies.

    PubMed

    Gao, Song; Zhao, Jing; Yin, Taijun; Ma, Yong; Xu, Beibei; Moore, Anthony N; Dash, Pramod K; Hu, Ming

    2015-04-01

    The purpose of this study is to develop and validate an UPLC-MS/MS method to quantify ethoxzolamide in plasma (EZ) and apply the method to absorption, brain distribution, as well as pharmacokinetic studies. A C₁₈ column was used with 0.1% of formic acid in acetonitrile and 0.1% of formic acid in water as the mobile phases to resolve EZ. The mass analysis was performed in a triple quadrupole mass spectrometer using multiple reaction monitoring (MRM) with positive scan mode. The results show that the linear range of EZ is 4.88-10,000.00 nM. The intra-day variance is less than 12.43% and the accuracy is between 88.88 and 108.00%. The inter-day variance is less than 12.87% and accuracy is between 89.27 and 115.89%. Protein precipitation was performed using methanol to extract EZ from plasma and brain tissues. Only 40 μL of plasma is needed for analysis due to the high sensitivity of this method, which could be completed in less than three minutes. This method was used to study the pharmacokinetics of EZ in SD rats, and the transport of EZ in Caco-2 and MDCK-MDR1 overexpressing cell culture models. Our data show that EZ is not a substrate for p-glycoprotein (P-gp) and its entry into the brain may not limited by the blood-brain barrier. PMID:25706567

  8. Preclinical pharmacokinetics, tissue distribution and excretion studies of a novel anti-candidal agent-thiosemicarbazide derivative of isoniazid (TSC-INH) by validated UPLC-MS/MS assay.

    PubMed

    Iqbal, Muzaffar; Ezzeldin, Essam; Bhat, Mashooq A; Raish, Mohammad; Al-Rashood, Khalid A

    2016-01-01

    A simple and sensitive UPLC-MS/MS assay was developed and validated for rapid determination of thiosemicarbazide derivative of isoniazid (TSC-INH), a potent anti-candidal agent in rat plasma, tissues, urine and feces. All biological samples were prepared by protein precipitation method using celecoxib as an internal standard (IS). Chromatographic separation was achieved on Acquity BEH™ C18 (50×2.1 mm, 1.7 μm) column using gradient mobile phase of acetonitrile and water (containing 0.1% formic acid) at flow rate of 0.3 mL/min. The MRM transitions were monitored at m/z 305.00→135.89 for TSC-INH and m/z 380.08→316.03 for IS in ESI negative mode. All validation parameter results were within the acceptable range described in guideline for bioanalytical method validation. The pharmacokinetic study showed that the compound TSC-INH was orally active with 66% absolute bioavailability in rats. It was rapidly absorbed with peak plasma concentration of 1985.92 ng/mL achieved within 1 h after single oral dose (10 mg/kg) administration. TSC-INH exhibited rapid distribution across the body with highest levels in liver and lungs. Penetration in brain tissues suggests that TSC-INH crossed the blood brain barrier. Only 5.23% of the orally administered drug was excreted as unconverted form in urine and feces implying that TSC-INH was metabolized extensively before excretion. With the preliminary knowledge of in vivo pharmacokinetics and disposition properties, this study will be beneficial for further development of compound TSC-INH in future studies. PMID:26355768

  9. Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT)

    PubMed Central

    Madden, Andrew J.; Rawal, Sumit; Sandison, Katie; Schell, Ryan; Schorzman, Allison; Deal, Allison; Feng, Lan; Ma, Ping; Mumper, Russell; DeSimone, Joseph; Zamboni, William C.

    2015-01-01

    The pharmacokinetics (PK) of carrier-mediated agents (CMA) is dependent upon the carrier system. As a result, CMA PK differs greatly from the PK of small molecule (SM) drugs. Advantages of CMAs over SMs include prolonged circulation time in plasma, increased delivery to tumors, increased antitumor response, and decreased toxicity. In theory, CMAs provide greater tumor drug delivery than SMs due to their prolonged plasma circulation time. We sought to create a novel PK metric to evaluate the efficiency of tumor and tissue delivery of CMAs and SMs. We conducted a study evaluating the plasma, tumor, liver, and spleen PK of CMAs and SMs in mice bearing subcutaneous flank tumors using standard PK parameters and a novel PK metric entitled relative distribution over time (RDI-OT), which measures efficiency of delivery. RDI-OT is defined as the ratio of tissue drug concentration to plasma drug concentration at each time point. The standard concentration versus time area under the curve values (AUC) of CMAs were higher in all tissues and plasma compared with SMs. However, 8 of 17 SMs had greater tumor RDI-OT AUC0–last values than their CMA comparators and all SMs had greater tumor RDI-OT AUC0–6 h values than their CMA comparators. Our results indicate that in mice bearing flank tumor xenografts, SMs distribute into tumor more efficiently than CMAs. Further research in additional tumor models that may more closely resemble tumors seen in patients is needed to determine if our results are consistent in different model systems. PMID:26392803

  10. Systemic exposure to parabens: pharmacokinetics, tissue distribution, excretion balance and plasma metabolites of [14C]-methyl-, propyl- and butylparaben in rats after oral, topical or subcutaneous administration.

    PubMed

    Aubert, Nicolas; Ameller, Thibault; Legrand, Jean-Jacques

    2012-03-01

    Parabens (PB) are preservatives used in food, drugs and personal care products preventing microbial and fungal contamination. We investigated ADME profiles of [14C]-methyl-, propyl- or butylparaben (MP, PP, BP) following single oral, dermal or subcutaneous (BP) doses at 100 mg/kg to Sprague-Dawley rats. Plasma Cmax and AUC values after oral or subcutaneous doses were 4- to 10-fold higher relative to respective values after dermal administration. tmax ranged from 0.5, 2 or 8 h after oral, subcutaneous or dermal administration, respectively. MP produced higher blood Cmax and AUC levels relative to those after PP or BP. Following oral or subcutaneous administration, urinary excretion was predominant (>70%, mainly during the first 24 h), less than 4% were eliminated in the feces, 2% were retained in the tissues and carcasses. Following dermal application, >50% of the dose was unabsorbed, 14-27% or <2% were respectively excreted in the urine or feces, respectively. Overall, parabens were well absorbed after oral and subcutaneous, and partially absorbed after dermal administration. All administration routes produced a single peak in the plasma, corresponding to that of para-hydroxybenzoic acid (PHBA) suggesting that PB produce no significant systemic exposure of mammalian organisms after oral, topical or subcutaneous administration. PMID:22265941

  11. 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. PMID:27227502

  12. Pharmacokinetic Behaviors of Intravenously Administered siRNA in Glandular Tissues.

    PubMed

    Huang, Yuanyu; Cheng, Qiang; Ji, Jia-Li; Zheng, Shuquan; Du, Lili; Meng, Lingwei; Wu, Yidi; Zhao, Deyao; Wang, Xiaoxia; Lai, Li; Cao, Huiqing; Xiao, Kai; Gao, Shan; Liang, Zicai

    2016-01-01

    The pharmacokinetics of small interfering RNAs (siRNAs) is a pivotal issue for siRNA-based drug development. In this study, we comprehensively investigated the behavior of siRNAs in vivo in various tissues and demonstrated that intravenously-injected naked siRNA accumulated remarkably in the submandibular gland, bulbourethral gland, and pancreas, with a respective half-life of ~22.7, ~45.6, and ~30.3 h. This was further confirmed by gel separation of tissue homogenates and/or supernatants. In vivo imaging and cryosectioning suggested that delivery carriers significantly influence the distribution and elimination profiles of siRNA. Gene-silencing assays revealed that neither naked nor liposome-formulated siRNA resulted in gene knockdown in the submandibular and bulbourethral glands after systemic administration, suggesting that these glands function as drug reservoirs that enable slow siRNA release into the circulation. But robust gene-silencing was achieved by local injection of liposome-encapsulated siRNA into the submandibular gland. Our results enhance understanding of the pharmacokinetic properties of siRNAs and we believe that they will facilitate the development of siRNA therapy, especially for the submandibular gland. PMID:27446488

  13. Pharmacokinetic Behaviors of Intravenously Administered siRNA in Glandular Tissues

    PubMed Central

    Huang, Yuanyu; Cheng, Qiang; Ji, Jia-Li; Zheng, Shuquan; Du, Lili; Meng, Lingwei; Wu, Yidi; Zhao, Deyao; Wang, Xiaoxia; Lai, Li; Cao, Huiqing; Xiao, Kai; Gao, Shan; Liang, Zicai

    2016-01-01

    The pharmacokinetics of small interfering RNAs (siRNAs) is a pivotal issue for siRNA-based drug development. In this study, we comprehensively investigated the behavior of siRNAs in vivo in various tissues and demonstrated that intravenously-injected naked siRNA accumulated remarkably in the submandibular gland, bulbourethral gland, and pancreas, with a respective half-life of ~22.7, ~45.6, and ~30.3 h. This was further confirmed by gel separation of tissue homogenates and/or supernatants. In vivo imaging and cryosectioning suggested that delivery carriers significantly influence the distribution and elimination profiles of siRNA. Gene-silencing assays revealed that neither naked nor liposome-formulated siRNA resulted in gene knockdown in the submandibular and bulbourethral glands after systemic administration, suggesting that these glands function as drug reservoirs that enable slow siRNA release into the circulation. But robust gene-silencing was achieved by local injection of liposome-encapsulated siRNA into the submandibular gland. Our results enhance understanding of the pharmacokinetic properties of siRNAs and we believe that they will facilitate the development of siRNA therapy, especially for the submandibular gland. PMID:27446488

  14. [The pharmacokinetics of antibiotics: parenteral and oral administration, distribution in the organism, elimination].

    PubMed

    Segre, G; Urso, R

    1994-03-01

    The efficacy of antimicrobial therapy is largely dependent on the pharmacokinetics of the drug. Pharmacokinetics is the study of the kinetics, that is of the movements of drugs in the body fluids and tissue cells. Often, despite the complexity of mammalian organism, relatively simple compartmental systems are capable to describe the kinetics of many drugs and to provide a rationale in interpreting the experimental results. As most bacterial infections are localized in tissues, the pharmacokinetic modelling of antimicrobial agents should mainly be devoted to clarify the relationship between plasma and tissue drug levels, the former being easily accessible to sampling and the latter more closely related to therapeutic efficacy. In this paper an introduction to pharmacokinetic modelling is presented and the pharmacokinetics of many antimicrobial drugs is discussed. PMID:8011272

  15. 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

  16. DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR PERCHLOROETHYLENE USING TISSUE CONCENTRATION-TIME DATA

    EPA Science Inventory

    The tissue disposition of perchloroethylene (PCE) was characterized experimentally in rats in order to: 1) btain input parameters from in vivo data for the development of a physiologically-based pharmacokinetic (PBPK) model; and 2) use the PBPK model to predict the deposition of ...

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

    SciTech Connect

    Vuillemenot, Brian R.; Kennedy, Derek; Reed, Randall P.; Boyd, Robert B.; Butt, Mark T.; Musson, Donald G.; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O'Neill, Charles A.

    2014-05-15

    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 mild 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 administered

  18. Modeling pharmacokinetic data using heavy-tailed multivariate distributions.

    PubMed

    Lindsey, J K; Jones, B

    2000-08-01

    Pharmacokinetic studies of drug and metabolite concentrations in the blood are usually conducted as crossover trials, especially in Phases I and II. A longitudinal series of measurements is collected on each subject within each period. Dependence among such observations, within and between periods, will generally be fairly complex, requiring two levels of variance components, for the subjects and for the periods within subjects, and an autocorrelation within periods as well as a time-varying variance. Until now, the standard way in which this has been modeled is using a multivariate normal distribution. Here, we introduce procedures for simultaneously handling these various types of dependence in a wider class of distributions called the multivariate power exponential and Student t families. They can have the heavy tails required for handling the extreme observations that may occur in such contexts. We also consider various forms of serial dependence among the observations and find that they provide more improvement to our models than do the variance components. An integrated Ornstein-Uhlenbeck (IOU) stochastic process fits much better to our data set than the conventional continuous first-order autoregression, CAR(1). We apply these models to a Phase I study of the drug, flosequinan, and its metabolite. PMID:10959917

  19. Pharmacokinetics of orbifloxacin and its concentration in body fluids and in endometrial tissues of mares.

    PubMed

    Haines, G R; Brown, M P; Gronwall, R R; Merritt, K A; Baltzley, L K

    2001-07-01

    Pharmacokinetics and distribution of orbifloxacin into body fluids and endometrium was studied in 6 mares after intragastric (IG) administration at a single dose rate of 7.5 mg/kg body weight. Orbifloxacin concentrations were serially measured in serum, synovial fluid, peritoneal fluid, urine, cerebrospinal fluid, and endometrial tissues over 24 hours. Minimum inhibitory concentrations of orbifloxacin were determined for 120 equine pathogens over an 11-month period. The mean peak serum concentration (Cmax) was 2.41+/-0.30 microg/mL at 1.5 hours after administration and decreased to 0.17+/-0.01 microg/mL (Cmin) at 24 hours. The mean elimination half-life (t1/2) was 9.06+/-1.33 hours and area under the serum concentration vs time curve (AUC) was 20.54+/-1.70 mg h/L. Highest mean peritoneal fluid concentration was 2.15+/-0.49 microg/mL at 2 hours. Highest mean synovial fluid concentration was 1.17+/-0.28 microg/mL at 4 hours. Highest mean urine concentration was 536.67+/-244.79 microg/mL at 2 hours. Highest mean endometrial concentration was 0.72+/-0.23 microg/g at 1.5 hours. Mean CSF concentration was 0.46+/-0.55 microg/mL at 3 hours. The minimum inhibitory concentration of orbifloxacin required to inhibit 90% of isolates (MIC90) ranged from < or = 0.12 to > 8.0 microg/mL, with gram-negative organisms being more sensitive than gram-positive organisms. Orbifloxacin was uniformly absorbed in the 6 mares and was well distributed into body fluids and endometrial tissue. At a dosage of 7.5 mg/kg once a day, many gram-negative pathogens, such as Actinobacillus equuli, Escherichia coli, Pasteurella spp., and Salmonella spp. would be expected to be susceptible to orbifloxacin. PMID:11480524

  20. Pharmacokinetics of orbifloxacin and its concentration in body fluids and in endometrial tissues of mares.

    PubMed Central

    Haines, G R; Brown, M P; Gronwall, R R; Merritt, K A; Baltzley, L K

    2001-01-01

    Pharmacokinetics and distribution of orbifloxacin into body fluids and endometrium was studied in 6 mares after intragastric (IG) administration at a single dose rate of 7.5 mg/kg body weight. Orbifloxacin concentrations were serially measured in serum, synovial fluid, peritoneal fluid, urine, cerebrospinal fluid, and endometrial tissues over 24 hours. Minimum inhibitory concentrations of orbifloxacin were determined for 120 equine pathogens over an 11-month period. The mean peak serum concentration (Cmax) was 2.41+/-0.30 microg/mL at 1.5 hours after administration and decreased to 0.17+/-0.01 microg/mL (Cmin) at 24 hours. The mean elimination half-life (t1/2) was 9.06+/-1.33 hours and area under the serum concentration vs time curve (AUC) was 20.54+/-1.70 mg h/L. Highest mean peritoneal fluid concentration was 2.15+/-0.49 microg/mL at 2 hours. Highest mean synovial fluid concentration was 1.17+/-0.28 microg/mL at 4 hours. Highest mean urine concentration was 536.67+/-244.79 microg/mL at 2 hours. Highest mean endometrial concentration was 0.72+/-0.23 microg/g at 1.5 hours. Mean CSF concentration was 0.46+/-0.55 microg/mL at 3 hours. The minimum inhibitory concentration of orbifloxacin required to inhibit 90% of isolates (MIC90) ranged from < or = 0.12 to > 8.0 microg/mL, with gram-negative organisms being more sensitive than gram-positive organisms. Orbifloxacin was uniformly absorbed in the 6 mares and was well distributed into body fluids and endometrial tissue. At a dosage of 7.5 mg/kg once a day, many gram-negative pathogens, such as Actinobacillus equuli, Escherichia coli, Pasteurella spp., and Salmonella spp. would be expected to be susceptible to orbifloxacin. PMID:11480524

  1. Oral ciprofloxacin in the treatment of serious soft tissue and bone infections. Efficacy, safety, and pharmacokinetics.

    PubMed

    Nix, D E; Cumbo, T J; Kuritzky, P; DeVito, J M; Schentag, J J

    1987-04-27

    Forty-eight patients were enrolled in a clinical study of oral ciprofloxacin for the treatment of soft tissue or bone infections. Patients received 500 to 750 mg of ciprofloxacin every 12 hours. In the predominantly older population studied, there were 13 patients with osteomyelitis, 24 diabetic patients with soft tissue infection and probable osteomyelitis, and 11 patients with other soft tissue infections. Infecting pathogens included Pseudomonas aeruginosa in 25 patients, Serratia species in nine patients, Staphylococcus aureus in 13 patients, and other aerobic gram-negative rods in 21 patients. Clinical response (defined as resolution or improvement) was noted in 84 percent of patients with non-diabetic osteomyelitis, in 79 percent of patients with diabetic infections, and in 91 percent of patients with soft tissue infections. Microbiologic outcome was very favorable in 75 percent of cases, and Pseudomonas responded as well as any other pathogen. Pharmacokinetic properties of ciprofloxacin were evaluated in 12 patients, and the data were analyzed using both compartmental and non-compartmental analyses. Mean values for compartmental rate constants (hours-1) were as follows: absorption rate constant = 1.15; intercompartmental rate constants, k12 = 0.48, and k21 = 0.58; elimination rate constant = 0.46; distribution rate constant = 1.31; and terminal elimination rate constant = 0.19. The apparent volume of distribution at steady state/bioavailability was 196 liters and total body clearance/bioavailability was 45.9 liters/hour. The mean time to peak concentration was 1.3 hours. The mean peak concentration as determined by compartmental fitting (2.4 micrograms/ml) underestimated the observed peak (3.2 micrograms/ml) by 24.8 percent. Clearance of ciprofloxacin was similar regardless of the method used to fit the data, whereas the volume of distribution was significantly different when the two analysis techniques were compared. Ciprofloxacin was well tolerated, with

  2. Pharmacokinetics and tissue concentrations of tylosin in selected avian species

    USGS Publications Warehouse

    Locke, D.; Bush, M.; Carpenter, J.W.

    1982-01-01

    Tissue and plasma concentrations and the biological half-life of tylosin in avian species of a variety of body sizes and metabolic rates were studied. The species chosen were eastern bobwhite quail (Colinus virginianus virginianus), pigeons (Columba livia), greater sandhill cranes (Grus canadensis tabida), and emus (Dromaius novaehollandiae). In the 1st phase of this study, tylosin was administered IM to quail, pigeons, and emus at a dosage rate of 25 mg/kg of body weight and to cranes at a dosage rate of 15 mg/kg. The average peak plasma concentrations of tylosin in quail, pigeons, cranes, and emus were 4.31, 5.63, 3.62, and 3.26 microgram/ml, respectively. These peak concentrations occurred at 0.5 to 1.5 hours after administration. The biological half-life of tylosin averaged 1.2 hours in quail, pigeons, and cranes, and was 4.7 hours in emus. In the 2nd phase of this study, tylosin concentrations in the tissues of quail, pigeons, and cranes were markedly higher than were plasma concentrations at corresponding sampling times. Six hours after antibiotic administration, tissue concentrations of tylosin in all species remained within the minimum inhibitory concentration for most pathogenic organisms. Dosage regimens of 25 mg of tylosin/kg 4 times daily for quail and pigeons, 15 mg/kg 3 times daily for cranes, and 25 mg/kg 3 times daily for emus would be needed to establish and maintain therapeutic tissue concentrations.

  3. 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. PMID:26927982

  4. A Rapid and Sensitive HPLC Method for Quantitation of Paclitaxel in Biological Samples using Liquid-Liquid Extraction and UV Detection: Application to Pharmacokinetics and Tissues Distribution Study of Paclitaxel Loaded Targeted Polymeric Micelles in Tumor Bearing Mice.

    PubMed

    Rezazadeh, Mahboubeh; Emami, Jaber; Mostafavi, Abolfazl; Rostami, Mahboubeh; Hassanzadeh, Farshid; Sadeghi, Hojjat; Minaiyan, Mohsen; Lavasanifar, Afsaneh

    2015-01-01

    A simple, rapid, and sensitive reversed-phase HPLC method was developed and validated for determination of paclitaxel (PTX) in plasma, various organs and tumor tissues of tumor-bearing mice. Tissue specimens of liver, kidneys, spleen, lungs, heart and tumor were separately homogenized in normal saline. Plasma or tissue homogenate (250 µl) containing PTX and internal standard (diazepam) were extracted by diethyl ether (6 ml). The separation was achieved on a µ-Bondapak C18 HPLC column using sodium acetate buffer solution (0.01 M)/acetonitrile (58/42 v/v) at pH 5 ± 0.1 and flow rate of 1.9 mL/min. The effluent was monitored at 227 nm and column temperature was adjusted at 58ºC. The internal standard and PTX were eluted at 4.2 and 5.2 min, respectively and no interfering peaks were observed. Calibration curves were linear over the concentration range of 0.25-10 µg/ml of PTX in plasma and 0.3-20 µg/ml PTX in tissue homogenates with acceptable precision and accuracy (<15%). The mean recoveries of the drug after plasma extraction was 87.4% ± 3.6 while those of tissue homogenates ranged from 62.1± 4.5 to 75.5± 3.2 depending on the type of tissues studied. PTX was stable in samples with no evidence of degradation during 3 freeze-thaw cycles and 3 months storage at -70 °C. The developed HPLC method was applied to quantify PTX in the mouse plasma and tissues after intravenous administration of 10 mg equivalent PTX/Kg dose of PTX-loaded tocopherol succinate-chitosan-polyethylene glycol-folate (TS-CS-PEG-FA) micelles formulation or Anzatax® (Cremophor® EL- based formulation of PTX) to female Balb/c mice. PMID:26670364

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

    SciTech Connect

    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 the 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.

  6. Pharmacokinetic Modeling of Non-Linear Brain Distribution of Fluvoxamine in the Rat

    PubMed Central

    Geldof, Marian; Freijer, Jan; van Beijsterveldt, Ludy

    2007-01-01

    Introduction A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine. Materials and methods Rats with arterial and venous cannulas and a microdialysis probe in the frontal cortex received intravenous infusions of 1, 3.7 or 7.3 mg.kg−1 of fluvoxamine. Analysis With increasing dose a disproportional increase in brain concentrations was observed. The kinetics of brain distribution was estimated by simultaneous analysis of plasma, free brain ECF and total brain tissue concentrations. The PK model consists of three compartments for fluvoxamine concentrations in plasma in combination with a catenary two compartment model for distribution into the brain. In this catenary model, the mass exchange between a shallow perfusion-limited and a deep brain compartment is described by a passive diffusion term and a saturable active efflux term. Results The model resulted in precise estimates of the parameters describing passive influx into (kin) of 0.16 min−1 and efflux from the shallow brain compartment (kout) of 0.019 min−1 and the fluvoxamine concentration at which 50% of the maximum active efflux (C50) is reached of 710 ng.ml−1. The proposed brain distribution model constitutes a basis for precise characterization of the PK–PD correlation of fluvoxamine by taking into account the non-linearity in brain distribution. PMID:17710515

  7. Reversed-phase high-performance liquid chromatography method for the determination of bemegride in serum and brain tissue: pharmacokinetics and brain distribution of an intraperitoneal subconvulsive dose in rats.

    PubMed

    Soto-Otero, R; Mendez-Alvarez, E; Sierra-Paredes, G; Galan-Valiente, J; Aguilar-Veiga, E; Sierra-Marcuño, G

    1991-01-01

    A simple and rapid HPLC method has been developed for the quantification of bemegride in serum and brain tissue, using p-methylphenobarbital as an internal standard. Serum and brain tissue homogenate samples were extracted with ethyl acetate and the evaporated and redissolved extracts injected into a reversed-phase column. The compounds were eluted with an acetonitrile-phosphate buffer mixture and monitored at 200 nm. A linear response was obtained in the range 1-40 micrograms ml-1 for serum and 1-40 micrograms g-1 for brain tissue. Within-day and between-day precisions were less than 5% and the analytical recovery greater than 76.4%. This method has been used to investigate the kinetic profiles of the drug in serum and discrete areas of rat brain after intraperitoneal administration of a subconvulsive dose of bemegride (10 mg kg-1). Peak concentrations occurred in the brain and serum at the same time (30 min), followed by a biphasic decay. The results also indicated the accumulation of the drug in the brain, with no significant differences (p greater than 0.05) in the impregnation of the different brain areas investigated. PMID:1873309

  8. Pharmacokinetics of tulathromycin in edible tissues of healthy and experimentally infected pigs with Actinobacillus pleuropneumoniae.

    PubMed

    Bladek, Tomasz; Posyniak, Andrzej; Jablonski, Artur; Gajda, Anna

    2015-01-01

    The aim of this study was the comparison of the tissue pharmacokinetics of tulathromycin in healthy pigs and pigs experimentally infected with Actinobacillus pleuropneumoniae (App). Tulathromycin was given to 24 healthy and 24 infected pigs by intramuscular injection at a single dosage of 2.5 mg kg(-1) body weight (b.w.). Pigs were euthanised at each group and then samples of liver, kidney, muscle, injection site and skin with fat were taken at scheduled time points. Drug concentrations were determined by LC-MS/MS. In this study, higher values of the area under the concentration-time curves (AUC) were calculated in all tissue samples taken from infected than healthy pigs. In pigs with App the AUCs of liver, kidney, muscle, skin with fat and injection site were 1111, 1973, 235, 181 and 2931 mg kg(-1) h, while in pigs without inflammation they were 509, 1295, 151, 111 and 1587 mg kg(-1) h, respectively. Maximum drug tissue concentrations (Cmax) in infected animals were 2370, 6650, 2016, 666 and 83,870 µg kg(-1), while in healthy pigs they were 1483, 6677, 1733, 509 and 55,006 µg kg(-1), respectively. The eliminations half-times (T1/2) were respectively longer in all tissue samples taken from infected animals (from 157.3 to 187.3 h) than in healthy ones (from 138.6 to 161.2 h). The tulathromycin tissue concentrations were significantly higher (p < 0.05) in all tissue samples of the infected pigs compared with the healthy animals at 360 h (from 0.0014 to 0.0280) and at 792 h (from 0.0007 to 0.0242) after drug administration. The results suggest that the tissue pharmacokinetic properties and residue depletion of tulathromycin can be influenced by the disease state of animals. PMID:26247868

  9. Ivermectin Pharmacokinetics, Metabolism, and Tissue/Egg Residue Profiles in Laying Hens.

    PubMed

    Moreno, Laura; Dominguez, Paula; Farias, Cristina; Canton, Lucila; Virkel, Guillermo; Maté, Laura; Ceballos, Laura; Lanusse, Carlos; Alvarez, Luis

    2015-12-01

    The goals were to determine the ivermectin (IVM) plasma pharmacokinetics, tissue and egg residue profiles, and in vitro metabolism in laying hens. Experiments conducted were (1) 8 hens were intravenously treated with IVM and blood samples taken; (2) 88 hens were treated with IVM administered daily in water (5 days) (40 were kept and their daily eggs collected; 48 were sacrificed in groups (n = 8) at different times and tissue samples taken and analyzed); (3) IVM biotransformation was studied in liver microsomes. Pharmacokinetic parameters were AUC = 85.1 ng·day/mL, Vdss = 4.43 L/kg, and T1/2el = 1.73 days. Low IVM tissue residues were quantified with the highest measured in liver and skin+fat. IVM residues were not found in egg white, but significant amounts were quantified in yolk. Residues measured in eggs were greater than some MRL values, suggesting that a withdrawal period would be necessary for eggs after IVM use in laying hens. PMID:26553292

  10. Design, synthesis, and pharmacokinetic evaluation of a chemical delivery system for drug targeting to lung tissue.

    PubMed

    Saah, M; Wu, W M; Eberst, K; Marvanyos, E; Bodor, N

    1996-05-01

    We espouse the application of a novel chemical delivery system (CDS) approach to a delivery mechanism for drug targeting to lung tissue using the 1,2-dithiolane-3-pentyl moiety of lipoic acid as the "targetor moiety". The synthesis and the physicochemical and pharmacokinetic evaluation of a CDS modeling the lipoyl and other ester derivatives of chlorambucil (an antineoplastic agent) and cromolyn (a bischromone used in antiasthma prophylaxis) as compared with their respective parent drugs are described. The chlorambucil CDS was synthesized by esterifying the alcohol derivative of lipoic acid with chlorambucil using dicyclohexylcarbodiimide as the coupling agent. The cromolyn CDS was prepared by a multistep synthetic procedure culminating in the reaction of the alkyl bromide derivative of lipoic acid with the disodium salt of the bischromone compound. All the esters were highly lipophilic unlike the parent compounds. The in-vitro kinetic and in-vivo pharmacokinetic studies showed that the respective CDSs were sufficiently stable in buffer and biological media, hydrolyzed rapidly into the respective active parent drugs, and significantly enhanced delivery and retention of the active compound to lung tissue in comparison with the underivatized parent compounds used in conventional therapy. PMID:8742941

  11. Pharmacokinetics and tissue residues of moroxydine hydrochloride in gibel carp, Carassius gibelio after oral administration.

    PubMed

    Liu, W; Xu, J; Zhou, Y; Chen, J; Ma, J; Zeng, L

    2016-08-01

    The pharmacokinetics and tissue residues of moroxydine hydrochloride were studied in gibel carp at water temperature of 15 and 25 °C. Samples (blood, skin, muscle, liver, and kidney) were collected over 10 days after the treatment and analyzed by high-performance liquid chromatography with an ultraviolet detector. The results indicated that the influence of water temperature on the metabolism of the drug was significant. The plasma concentration-time data of moroxydine hydrochloride conformed to single-compartment open model at the two water temperatures. There were higher absorption rate (t1/2ka ) and longer elimination half-lives (t1/2ke ) at 15 °C (4.29 and 15.87 h, respectively) compared with those at 25 °C (3.02 and 4.22 h, respectively). The maximum plasma concentration (Cmax ) and the time-point of maximum plasma concentration (Tp ) were 2.98 μg/mL and 10.35 h at 15 °C and 3.12 μg/mL and 4.03 h at 25 °C, respectively. The distribution volume (Vd /F) of moroxydine hydrochloride was estimated to be 4.55 L/kg at 15 °C and 2.89 L/kg at 25 °C. The total body clearance (CLb ) of moroxydine hydrochloride was determined to be 0.25 and 0.49 L/(h·kg) at 15 °C and 25 °C, respectively; the areas under the concentration-time curve were 75.89 μg·h/mL at 15 °C and 42.33 μg·h/mL at 25 °C. The depletion of moroxydine hydrochloride in gibel carp was slower with a longer half-life period, especially at lower water temperature that was tested. PMID:26763124

  12. Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs.

    PubMed

    Kuttler, Andreas; Dimke, Thomas; Kern, Steven; Helmlinger, Gabriel; Stanski, Donald; Finelli, Luca A

    2010-12-01

    We introduce how biophysical modeling in pharmaceutical research and development, combining physiological observations at the tissue, organ and system level with selected drug physiochemical properties, may contribute to a greater and non-intuitive understanding of drug pharmacokinetics and therapeutic design. Based on rich first-principle knowledge combined with experimental data at both conception and calibration stages, and leveraging our insights on disease processes and drug pharmacology, biophysical modeling may provide a novel and unique opportunity to interactively characterize detailed drug transport, distribution, and subsequent therapeutic effects. This innovative approach is exemplified through a three-dimensional (3D) computational fluid dynamics model of the spinal canal motivated by questions arising during pharmaceutical development of one molecular therapy for spinal cord injury. The model was based on actual geometry reconstructed from magnetic resonance imaging data subsequently transformed in a parametric 3D geometry and a corresponding finite-volume representation. With dynamics controlled by transient Navier-Stokes equations, the model was implemented in a commercial multi-physics software environment established in the automotive and aerospace industries. While predictions were performed in silico, the underlying biophysical models relied on multiple sources of experimental data and knowledge from scientific literature. The results have provided insights into the primary factors that can influence the intrathecal distribution of drug after lumbar administration. This example illustrates how the approach connects the causal chain underlying drug distribution, starting with the technical aspect of drug delivery systems, through physiology-driven drug transport, then eventually linking to tissue penetration, binding, residence, and ultimately clearance. Currently supporting our drug development projects with an improved understanding of systems

  13. Absorption, tissue distribution, tissue metabolism and safety of α-mangostin in mangosteen extract using mouse models.

    PubMed

    Choi, Young Hee; Han, Seung Yon; Kim, You-Jin; Kim, Young-Mi; Chin, Young-Won

    2014-04-01

    The commercially available herbal products as the form of extract were usually mixtures containing various compounds. In spite of the purported efficacy in each active constituent, the coexisting constituents in the herbal extract might interfere with the efficacy and safety and affect the pharmacokinetic properties of active constituents. To compare for the pharmacokinetic properties of α-mangostin, a major bioactive compound, in mangosteen extract and pure α-mangostin, the pharmacokinetics as well as tissue distribution, in vitro metabolism, plasma protein binding and safety evaluation were conducted in mice because a mouse model is required a small amount of compounds and useful to develop disease models. The absorption of α-mangostin was increased and hepatic metabolism of α-mangostin was decreased in mice treated with mangosteen extract. However, the intestinal metabolism α-mangostin is comparable and still extensive in mice treated with α-mangostin and mangosteen extract. Intraperitorial LC50 of α-mangostin and mangosteen extract was 150 and 231 mg/kg, respectively. These findings may be valuable to explain the different pharmacokinetics and safety of α-mangostin and mangosteen extract. Furthermore, these findings are useful to design the efficacy and safety investigation of α-mangostin or mangosteen extract in mice with disease models or combination therapies to extrapolate into the clinical levels. PMID:24472368

  14. PET measurement of C-11-methylphenidate pharmacokinetics and distribution in the human brain

    SciTech Connect

    Ding, Y.S.; Fowler, J.S.; Wang, G.J.

    1994-05-01

    Methylphenidate (MP), a psychostimulant drug which binds to the dopamine transporter (DAT), is the most commonly prescribed psychotropic medication for children in the USA yet little is known about its pharmacokinetics and distribution in the human brain. PET was used to measure the pharmacokinetics of d,l-threo-[{sup 11}C]methylphenidate (MP*) the labelled form of the prescribed drug (ritalin) in eight normal male subjects (age range 20-74 years). Four subjects had 2 repeated scans to assess test/retest reproducibility and 4 had one wan as baseline and the second 10 minutes after administration of 0.5 mg/kg MP to assess specific to nonspecific binding. Dynamic scans were started immediately after injection of MP*(5-10 mCi) for 90 min on the CTI-931 (6 x 6 x 6.5 mm FWHM). Time activity curves for tissue concentration and for unchanged tracer in plasma were used to calculate the distribution volume (DV) in basal ganglia (BG), cerebellum (CB) and global (GL) regions using graphical analysis. Binding of MP* was highest in the BG (0.008% dose/cc) uptake in CB corresponded to (0.006) and in GL to (0.005). Kinetic analysis revealed fast uptake of MP* with peak uptake in BG occurring 5-20 min PI, and in CB and GL at 5-13 min PI. Half time clearance for MP* occurred 90 min PI for BG and 60 min for CB and GL. Test/retest variability was <10% (range -0.5 to +7.0% for the DV ratio (BG/CB)). Pretreatment with MP selectively reduced uptake in BG wherein it did not affect uptake in CB or GL. The ratio of the DV in BG to that in CB changed from 2.12{plus_minus}0.1 to 1.35{plus_minus}0.04. The lack of an effect of MP in CB an area with a high density of norepinephrine (NE) transporters suggests that MP* is not binding to the NE transporter.

  15. Sunitinib tissue distribution changes after coadministration with ketoconazole in mice.

    PubMed

    Chee, Evelyn Li-Ching; Lim, Adeline Yi Ling; Modamio, Pilar; Fernandez-Lastra, Cecilia; Segarra, Ignacio

    2016-06-01

    Sunitinib is a multitargeted tyrosine kinase inhibitor approved for gastrointestinal stromal tumor (GIST), advanced renal cell carcinoma (RCC) and pancreatic neuroendocrine tumors. It is metabolized via CYP3A4 and has low brain penetration due to efflux transporters ABCB1B and ABCG2. We studied the interaction with ketoconazole (50 mg/kg), antifungal drug which shares metabolic pathways and efflux transporters, in ICR female mice after oral coadministration (30 min apart) of 60 mg/kg sunitinib (study group) versus sunitinib alone (control group). Plasma, liver, kidney and brain sunitinib concentrations were measured by HPLC at 2, 5, 10, 20, 40 min, 1, 2, 4, 6, 12 h post-sunitinib administration, and non-compartmental pharmacokinetic parameters estimated. In plasma, ketoconazole coadministration increased plasma maximum concentration (C MAX) 60 %, delayed time to C MAX (T MAX); 1.6-fold greater area under the curve AUC0→∞ (p < 0.001); lower apparent steady-state volume of distribution (V SS/F) and oral clearance (Cl/F) 40 and 61 %, respectively; and shorter elimination half-life (t 1/2). Sunitinib exhibited extensive tissue distribution which increased after ketoconazole coadministration: total area under the curve (AUC0→∞) increased 1.8-, 2.8- and 1.2-fold in kidney, liver and brain, respectively (all p < 0.001). Sunitinib presented high tissue-to-plasma AUC0→∞ ratio in liver (17.8 ± 1.2), kidney (14.6 ± 1.52) and brain (2.25 ± 0.18) which was modified after coadministration: AUC0→∞ ratio increased in liver (31.4 ± 4.7; p < 0.001), kidney (17.1 ± 2.2; p > 0.05) and decreased in brain (1.70 ± 0.23, p > 0.05). The results showed a significant ketoconazole-sunitinib interaction that affected plasma, tissue pharmacokinetics and tissue uptake mechanisms. The study portrays the risk to increase toxicity and potential clinical translatability to treat tumors in tissues. PMID:25656737

  16. Determination of tissue penetration and pharmacokinetics of linezolid in patients with diabetic foot infections using in vivo microdialysis.

    PubMed

    Wiskirchen, Dora E; Shepard, Ashley; Kuti, Joseph L; Nicolau, David P

    2011-09-01

    Staphylococcus aureus and other Gram-positive organisms, including methicillin-resistant S. aureus, continue to be the predominant pathogens associated with diabetic foot infections. Consequently, linezolid is often used to treat these infections. The purpose of the current study was to describe the pharmacokinetic profile and determine the level of penetration of linezolid into healthy thigh tissue and infected wound tissue of the same extremity in 9 diabetic patients with chronic lower limb infections by use of in vivo microdialysis. Hourly plasma and dialysate samples were obtained over a 12-h dosing interval following 3 to 4 doses of linezolid (600 mg intravenously every 12 h). Plasma protein binding was also assessed at 1, 6, and 12 h postdose. The means ± standard deviations (SD) for the maximum concentration in serum (C(max)), the volume of distribution at terminal phase (V(z)), and the half-life (t(1/2)) for linezolid in plasma were 11.99 ± 3.67 μg/ml, 0.71 ± 0.25 liters/kg of body weight, and 4.71 ± 1.23 h, respectively. Mean protein binding was 14.78% (range, 3.85 to 32.03%). The mean areas under the concentration-time curves from 0 to 12 h for the free, unbound fraction of linezolid (fAUC(0-12) values) ± SD for plasma, wound tissue, and thigh tissue were 51.24 ± 12.72, 82.76 ± 59.01, and 92.52 ± 60.44 μg · h/ml, respectively. Tissue penetration ratios (tissue fAUC to plasma fAUC) were similar for thigh (1.42; range, 1.08 to 2.23) and wound (1.27; range, 0.86 to 2.26) tissues (P = 0.648). With the currently approved dosing regimen, linezolid penetrated well into both healthy thigh tissue and infected wound tissue in these diabetic patients. PMID:21709078

  17. Determination of Tissue Penetration and Pharmacokinetics of Linezolid in Patients with Diabetic Foot Infections Using In Vivo Microdialysis▿

    PubMed Central

    Wiskirchen, Dora E.; Shepard, Ashley; Kuti, Joseph L.; Nicolau, David P.

    2011-01-01

    Staphylococcus aureus and other Gram-positive organisms, including methicillin-resistant S. aureus, continue to be the predominant pathogens associated with diabetic foot infections. Consequently, linezolid is often used to treat these infections. The purpose of the current study was to describe the pharmacokinetic profile and determine the level of penetration of linezolid into healthy thigh tissue and infected wound tissue of the same extremity in 9 diabetic patients with chronic lower limb infections by use of in vivo microdialysis. Hourly plasma and dialysate samples were obtained over a 12-h dosing interval following 3 to 4 doses of linezolid (600 mg intravenously every 12 h). Plasma protein binding was also assessed at 1, 6, and 12 h postdose. The means ± standard deviations (SD) for the maximum concentration in serum (Cmax), the volume of distribution at terminal phase (Vz), and the half-life (t1/2) for linezolid in plasma were 11.99 ± 3.67 μg/ml, 0.71 ± 0.25 liters/kg of body weight, and 4.71 ± 1.23 h, respectively. Mean protein binding was 14.78% (range, 3.85 to 32.03%). The mean areas under the concentration-time curves from 0 to 12 h for the free, unbound fraction of linezolid (fAUC0–12 values) ± SD for plasma, wound tissue, and thigh tissue were 51.24 ± 12.72, 82.76 ± 59.01, and 92.52 ± 60.44 μg · h/ml, respectively. Tissue penetration ratios (tissue fAUC to plasma fAUC) were similar for thigh (1.42; range, 1.08 to 2.23) and wound (1.27; range, 0.86 to 2.26) tissues (P = 0.648). With the currently approved dosing regimen, linezolid penetrated well into both healthy thigh tissue and infected wound tissue in these diabetic patients. PMID:21709078

  18. Plasma Pharmacokinetics and Tissue Disposition of Novel Dextran- Methylprednisolone Conjugates with Peptide Linkers in Rats

    PubMed Central

    Penugonda, Suman; Agarwal, Hitesh K.; Parang, Keykavous; Mehvar, Reza

    2012-01-01

    The plasma and tissue disposition of two novel dextran prodrugs of methylprednisolone (MP) containing one (DMP-1) or five (DMP-5) amino acids as linkers were studied in rats. Single 5-mg/kg doses (MP equivalent) of each prodrug or MP were administered intravenously, and blood and tissue samples were collected. Prodrug and drug concentrations were quantitated using HPLC, and non-compartmental pharmacokinetic parameters were estimated. Whereas conjugation of MP with dextran in both prodrugs substantially decreased the clearance of the drug by ~200 fold, the accumulations of the drug in the liver, spleen, and kidneys were significantly increased by conjugation. However, the extent of accumulation of DMP-1 in these tissues was substantially greater than that for DMP-5. Substantial amounts of MP were regenerated from both prodrugs in the liver and spleen, with the rate of release from DMP-5 being twice as fast as that from DMP-1. However, the AUCs of MP regenerated from DMP-1 in the liver and spleen were substantially higher than those after DMP-5. In contrast, in the kidneys, the AUC of MP regenerated from DMP-5 was higher than that after DMP-1 administration. These data suggest that DMP-1 may be more suitable than DMP-5 for targeting immunosuppression to the liver and spleen. PMID:19780131

  19. Pharmacokinetics of macrolides in foals.

    PubMed

    Villarino, N; Martín-Jiménez, T

    2013-02-01

    Macrolides are used for treatment of pneumonia and extrapulmonary conditions caused by Rhodococcus equi. In foals, macrolides have an extraordinary capacity to accumulate in different lung tissue compartments. These drugs show unique pharmacokinetic features such as rapid and extensive distribution and long persistence in pulmonary epithelial lining fluid (PELF) and bronchoalveolar lavage (BAL) cells from foals. This article reviews the pharmacokinetic characteristics of erythromycin, azithromycin, clarithromycin, tulathromycin, telithromycin, gamithromycin, and tilmicosin in foals, with emphasis on PELF and BAL cell concentrations. PMID:23082900

  20. In Vivo Tissue Pharmacokinetics of Carbon-11-Labeled Clozapine in Healthy Volunteers: A Positron Emission Tomography Study

    PubMed Central

    Park, HS; Kim, E; Moon, BS; Lim, NH; Lee, BC; Kim, SE

    2015-01-01

    We investigated clozapine (CLZ) tissue pharmacokinetics in vivo by using carbon-11-labeled CLZ (11C-CLZ) and positron emission tomography (PET). Eight healthy volunteers underwent 11C-CLZ studies wherein computed tomography image acquisition was followed by PET scans (whole-body, four; brain, four). After bolus intravenous 11C-CLZ injection, PET images were acquired at various timepoints for 2–3 hours. Tissue 11C-CLZ signals were plotted over time, and pharmacokinetic parameters were determined. High 11C-CLZ radioactivity was detected in the liver and brain, implying CLZ hepatic metabolism and efficient blood–brain barrier penetration. The urinary and hepatobiliary tracts were involved in 11C-CLZ excretion. Moderate to high radioactivity was observed in the dopaminergic and serotonergic receptor-rich brain regions, indicating CLZ binding to multiple receptor types. To our knowledge, this is the first study to report the determination of 11C-CLZ tissue pharmacokinetics in humans. PET using radiolabeled drugs can provide valuable information that could complement plasma pharmacokinetic data. PMID:26225256

  1. Differential pharmacokinetics and the brain distribution of morphine and ephedrine constitutional isomers in rats after oral administration with Keke capsule using rapid-resolution LC-MS/MS.

    PubMed

    Song, Yonggui; Su, Dan; Lu, Tulin; Mao, Chunqin; Ji, De; Liu, Yali; Wei, Binbin; Fan, Ronghua

    2014-02-01

    Opioid and ephedra alkaloids known as the active ingredients for Keke capsule, which is used to treat coughs and bronchial asthma, could have potential adverse effects on the central nervous system. Therefore, an efficient, sensitive rapid-resolution LC-MS/MS method for the simultaneous determination of morphine, ephedrine, and pseudoephedrine in rat plasma and brain tissue homogenate has been developed. The method was validated in the plasma and brain tissue samples, showed good linearity over a wide concentration range (r(2) > 0.99). The intra- and interday assay variability was less than 15% for all analytes, and the accuracy was between -8.8 and 5.7%. The study provided the pharmacokinetics profiles and the brain regional distribution of the three active alkaloids after oral administration of Keke capsule. The results also indicated that significant difference in pharmacokinetics parameters of the epimers was observed between ephedrine and pseudoephedrine. PMID:24318005

  2. Evaluation of Oral and IntravenousRoute Pharmacokinetics, Plasma Protein Binding and Uterine Tissue Dose Metrics of Bisphenol A: A Physiologically Based Pharmacokinetic Approach

    SciTech Connect

    Teeguarden, Justin G.; Waechter, John M.; Clewell, III, H. J.; Covington, Tammie R.; Barton, H. A.

    2005-06-01

    Bisphenol A (BPA) is a weakly estrogenic monomer used in the production of polycarbonate plastic and epoxy resins, both of which are used in food contact and other applications. A physiologically based pharmacokinetic (PBPK) model of BPA pharmacokinetics in rats and humans was developed to provide a physiological context in which the processes controlling BPA pharmacokinetics (e.g. plasma protein binding, enterohepatic recirculation of the glucuronide (BPAG)) could be incorporated. A uterine tissue compartment was included to allow the correlation of simulated ER binding of BPA with increases in uterine wet weight (UWW) in rats. Intravenous and oral-route blood kinetics of BPA in rats and oral-route plasma and urinary elimination kinetics in humans were well described by the model. Simulations of rat oral-route BPAG pharmacokinetics were less exact, most likely the result of oversimplification of the GI tract compartment. Comparison of metabolic clearance rates derived from fitting rat i.v. and oral-route data implied that intestinal glucuronidation of BPA is significant. In rats but not humans, terminal elimination rates were strongly influenced by enterohepatic recirculation. In the absence of BPA binding to plasma proteins, simulations showed high ER occupancy at doses without uterine effects. Restricting free BPA to the measured unbound amount demonstrated the importance of including plasma binding in BPA kinetic models: the modeled relationship between ER occupancy and UWW increases was consistent with expectations for a receptor mediated response with low ER occupancy at doses with no response and increasing occupancy with larger increases in UWW.

  3. Plasma and tissue pharmacokinetics of marbofloxacin in experimentally infected chickens with Mycoplasma gallisepticum and Escherichia coli.

    PubMed

    Ding, H; Wang, L; Shen, X; Gu, X; Zeng, D; Zeng, Z

    2013-10-01

    The plasma and tissue pharmacokinetics of marbofloxacin in chickens experimentally infected with Mycoplasma gallisepticum and Escherichia coli were studied. Marbofloxacin was given to 66 infected chickens by oral administration at a dosage of 5 mg/kg b.w., once a day for three days. Plasma, brain, kidney, liver, lung, muscle and trachea were collected and marbofloxacin concentrations were analyzed by a high performance liquid chromatography method. In the infected chickens, maximal marbofloxacin concentrations in plasma, brain, kidney, liver, lung, muscle and trachea were 1.84, 1.33, 7.35, 5.61, 3.12, 2.98, and 4.51 g/mL (g); the elimination half-lives of marbofloxacin were 6.8, 2.74, 9.31, 8.45, 9.55, 11.53 and 5.46 h for plasma, brain, kidney, liver, lung, muscle and trachea, respectively. AUC were calculated to be 9.68, 8.04, 45.1, 27.03, 20.56, 19.47, and 32.68 μg/mL (g) for plasma, brain, kidney, liver, lung, muscle and trachea, respectively. Marbofloxacin concentration in tissues except for brain exceeded marbofloxacin concentration in plasma, with AUC(tissue) /AUC(plasma) ranging from 2.01 to 4.66 and Peak(tissue) /Peak(plasma) ranging from 1.62 to 3.99. The results showed that a marbofloxacin dosage of 5 mg/kg administered orally at 24 h intervals may provide successful treatment of chicken with MG and E. coli infection. PMID:23550715

  4. Pharmacokinetics and tissue disposition of meloxicam in beef calves after repeated oral administration.

    PubMed

    Coetzee, J F; Mosher, R A; Griffith, G R; Gehring, R; Anderson, D E; KuKanich, B; Miesner, M

    2015-12-01

    The objective of this study was to investigate the pharmacokinetics and tissue disposition of meloxicam after repeated oral administration in calves. Thirteen male British × Continental beef calves aged 4 to 6 months and weighing 297-392 kg received 0.5 mg/kg meloxicam per os once daily for 4 days. Plasma meloxicam concentrations were determined in 8 calves over 6 days after first treatment. Calves were randomly assigned to be euthanized at 5, 10, 15 (n = 3/timepoint), and 19 days (n = 4) after final administration. Meloxicam concentrations were determined in plasma (LOQ= 0.025 μg/mL) and muscle, liver, kidney, and fat samples (LOQ = 2 ng/g) after extraction using validated LC-MS-MS methods. The mean (± SD) Cmax , Cmin , and Caverage plasma meloxicam concentrations were 4.52 ± 0.87 μg/mL, 2.95 ± 0.77 μg/mL, and 3.84 ± 0.81 μg/mL, respectively. Mean (± SD) tissue meloxicam concentrations were highest in liver (226.67 ± 118.16 ng/g) and kidney samples (52.73 ± 39.01 ng/g) at 5 days after final treatment. Meloxicam concentrations were below the LOQ in all tissues at 15 days after treatment. These findings suggest that tissue from meloxicam-treated calves will have low residue concentrations by 21 days after repeated oral administration. PMID:25708937

  5. Oxygen distributions within tissue by phosphorescence quenching

    NASA Astrophysics Data System (ADS)

    Wilson, David F.; Grosul, Pavel; Rozhkov, Vladimir; Dugan, Benjamin W.; Reitveld, Ivo; Vinogradov, Sergei A.

    2002-06-01

    Oxygen dependent quenching of phosphorescence is a powerful method for measuring oxygen. Phosphors are now available that absorb and emit in the near IR region of the spectrum, are nontoxic, and remain in the blood, allowing rapid measure of oxygen through out selected tissue volumes. In vivo measurements are non-invasive except for the need to inject phosphor into the blood, and phosphorescence lifetimes can be measured without interference by tissue pigments that absorb or fluorescence at the measurement wavelengths. Phosphorescence quenching is uniquely useful for: (1) imaging oxygen in optically clear media or in the surface layer of the tissue, such as in the retina of the eye; (2) determining the distribution of oxygen in media, such as tissue, which have heterogeneous distributions by deconvoluting phosphorescence decay dat. These can be used to calculate the corresponding oxygen histograms. Measurement in 2D grids can b used to construct contour maps of the fraction of the sampled tissue volume with any selected range of oxygen pressures. These maps accurately show the location and size of any regions of hypoxia within the sampled tissue.

  6. Pharmacokinetics and distributions of bevacizumab by intravitreal injection of bevacizumab-PLGA microspheres in rabbits

    PubMed Central

    Ye, Zhuo; Ji, Yan-Li; Ma, Xiang; Wen, Jian-Guo; Wei, Wei; Huang, Shu-Man

    2015-01-01

    AIM To investigate the pharmacokinetics and distributions of bevacizumab by intravitreal injection of prepared bevacizumab-poly (L-lactic-co-glycolic acid) (PLGA) microspheres in rabbits, to provide evidence for clinical application of this kind of bevacizumab sustained release dosage form. METHODS Bevacizumab was encapsulated into PLGA microsphere via the solid-in-oil-in-hydrophilic oil (S/O/hO) method. Fifteen healthy New Zealand albino-rabbits were used in experiments. The eyes of each rabbit received an intravitreal injection. The left eyes were injected with prepared bevacizumab-PLGA microspheres and the right eyes were injected with bevacizumab solution. After intravitreal injection, rabbits were randomly selected at days 3, 7, 14, 28 and 42 respectively, three animals each day. Then we used immunofluorescence staining to observe the distribution and duration of bevacizumab in rabbit eye tissues, and used the sandwich ELISA to quantify the concentration of free bevacizumab from the rabbit aqueous humor and vitreous after intravitreal injection. RESULTS The results show that the concentration of bevacizumab in vitreous and aqueous humor after administration of PLGA formulation was higher than that of bevacizumab solution. The T1/2 of intravitreal injection of bevacizumab-PLGA microspheres is 9.6d in vitreous and 10.2d in aqueous humor, and the T1/2 of intravitreal injection of soluble bevacizumab is 3.91d in vitreous and 4.1d in aqueous humor. There were statistical significant difference for comparison the results of the bevacizumab in vitreous and aqueous humor between the left and right eyes (P<0.05). The AUC0-t of the sustained release dosage form was 1-fold higher than that of the soluble form. The relative bioavailability was raised significantly. The immunofluorescence staining of PLGA-encapsulated bevacizumab (b-PLGA) in rabbit eye tissues was still observed up to 42d. It was longer than that of the soluble form. CONCLUSION The result of this study

  7. Tissue distribution and ontogeny of sulfotransferase enzymes in mice.

    PubMed

    Alnouti, Yazen; Klaassen, Curtis D

    2006-10-01

    Sulfotransferases (Sults) are phase-II conjugation enzymes that catalyze the transfer of a sulfonate group from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to target endo and xenobiotics. PAPS is formed from inorganic sulfate by the action of the enzyme PAPS synthase (PAPSs). In the present study, the tissue distribution and developmental changes in the mRNA expression of 11 Sult isozymes and 2 PAPSs isoforms in mice were quantified. Sult1a1, 1b1, 1c1, 1c2, 1d1, 1e1, 2a1/2, 2b1, 3a1, 4a1, 5a1, PAPSs1, and PAPSs2 mRNA expression was quantified in 14 tissues from male and female mice using the branched DNA signal amplification assay. Sult2a1/2 and 3a1 expression were highest in liver; Sult1b1, 2b1, and PAPSs2 in small intestine; Sult1a1 in large intestine; Sult1c2 in stomach; Sult1d1 in kidney; Sult1e1 in placenta; and Sult4a1 in brain. Sult1c1, 5a1, and PAPSs1 were ubiquitously expressed in most tissues. These enzymes demonstrated three different ontogenic expression patterns in liver. Sult1a1, 1c2, 1d1, 2a1/2, and PAPSs2 hepatic expression gradually increased from birth until about 3 weeks of age and then declined somewhat thereafter, Sult1c1 expression was highest before birth and declined after that, and Sult3a1 mRNA expression was very low in fetal livers and remained low until 30 days of age, when expression in females dramatically increased, whereas it never increased in males. The organ-specific distribution of Sults as well as the different expression of the Sults in young animals may affect the pharmacokinetic behavior and organ-specific toxicity of xenobiotics. PMID:16807285

  8. Pharmacokinetic and Tumor Distribution Characteristics of Temsirolimus in Patients with Recurrent Malignant Glioma

    PubMed Central

    Kuhn, John G.; Chang, Susan M.; Wen, Patrick Y.; Cloughesy, Timothy F.; Greenberg, Harry; Schiff, David; Conrad, Charles; Fink, Karen L.; Robins, H. Ian; Mehta, Minesh; DeAngelis, Lisa; Raizer, Jeffrey; Hess, Kenneth; Lamborn, Kathleen R.; Dancey, Janet; Prados, Michael D.

    2016-01-01

    Purpose To characterize the pharmacokinetics of temsirolimus and its major metabolite, sirolimus, in patients receiving enzyme-inducing antiepileptic drugs (EIAED) compared with patients receiving non-EIAEDs. An additional objective was to determine whether concentrations of temsirolimus or sirolimus were achieved in brain tumor tissue. Experimental Design Patients with recurrent malignant gliomas not receiving EIAEDs initially received temsirolimus weekly at a dose of 250 mg i.v. The dose was subsequently reduced to 170 mg due to intolerable side effects. For patients taking EIAEDs, the starting dose of temsirolimus was 250 mg with standard dose escalation until the maximal tolerated dose was established. Ten whole blood samples were obtained over a period of 24 h after administration of temsirolimus for pharmacokinetic assessments. Patients eligible for cytoreductive surgery received temsirolimus before tumor resection. Whole blood and tumor tissue were obtained for analysis. Results Significant differences in the pharmacokinetic variables for temsirolimus and sirolimus were observed between the two patient groups at a comparable dose level of 250 mg. For patients receiving EIAEDs, the systemic exposure to temsirolimus was lower by 1.5-fold. Likewise, peak concentrations and exposure to sirolimus were lower by 2-fold. Measurable concentrations of temsirolimus and sirolimus were observed in brain tumor specimens. The average tissue to whole blood ratio for temsirolimus was 1.43 and 0.84 for sirolimus. Conclusions Drugs that induce cytochrome P450 3A4, such as EIAEDs, significantly affect the pharmacokinetics of temsirolimus and its active metabolite, sirolimus. Total exposure to temsirolimus and sirolimus was lower in the EIAED group at the maximum tolerated dose of 250 mg compared with the non-EIAED group at the maximum tolerated dose of 170 mg. However, brain tumor tissue concentrations of temsirolimus and sirolimus were relatively comparable in both groups of

  9. 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

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

    PubMed

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

    1989-07-01

    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

  11. Oritavancin Pharmacokinetics and Bone Penetration in Rabbits

    PubMed Central

    Ostiguy, Valerie; Cadieux, Cordelia; Malouin, Mireille; Belanger, Odette; Far, Adel Rafai; Parr, Thomas R.

    2015-01-01

    The pharmacokinetics and bone concentrations of oritavancin were investigated after a single intravenous dose was administered to rabbits. The pharmacokinetic profile of oritavancin in rabbits showed that it is rapidly distributed to bone tissues, with concentrations remaining stable for up to 168 h, the last measured time point. Based on these findings, further evaluation of oritavancin for the treatment of infections in bone tissues is warranted. PMID:26239977

  12. 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

  13. Iterative multiple reference tissue method for estimating pharmacokinetic parameters on prostate DCE MRI

    NASA Astrophysics Data System (ADS)

    Ginsburg, Shoshana B.; Bloch, B. Nicolas; Rofsky, Neil M.; Genega, Elizabeth M.; Lenkinski, Robert E.; Madabhushi, Anant

    2013-02-01

    Pharmacokinetic (PK) parameters are probes of tissue status that can be assessed by analysis of dynamic contrast-enhanced (DCE) MRI and are useful for prostate cancer (CaP) detection and grading. Traditionally, PK analysis requires knowledge of the time-resolved concentration of the contrast agent in the blood plasma, the arterial input function (AIF), which is typically estimated in an artery in the field-of-view (FOV). In cases when no suitable artery is present in the FOV, the multiple reference tissue method (MRTM) enables the estimation of PK parameters without the AIF by leveraging PK parameter values from the literature for a reference tissue in the FOV. Nevertheless, PK parameters estimated in the prostate vary significantly between patients. Consequently, population-based values obtained from the literature may introduce error into PK parameter estimation via MRTM. The objectives of this paper are two-fold. First we present a novel scheme, iterative MRTM (IMRTM), to estimate PK parameter values in the absence of the AIF without making assumptions about the PK constants associated with a reference tissue. Then, using IMRTM we investigate differences in PK constants between CaP in the peripheral zone (PZ) and CaP in the central gland (CG), as CG and PZ CaP have previously been shown to differ significantly in terms of both texture and prognosis. We apply IMRTM to 15 patients with CaP in either the CG or the PZ who were scheduled for a radical prostatectomy and a pre-operative MRI. Values for the PK parameters Ktrans and ve estimated via IMRTM average 0.29 and 0.60 for normal central gland (CG), 0.29 and 0.64 for normal peripheral zone (PZ), and 0.30 and 0.53 for CaP. It is noteworthy that PK constants estimated in PZ CaP are significantly higher than those estimated in CG CaP (p < 0:05). While both MRTM and IMRTM provide PK parameter values that are biologically feasible, IMRTM has the advantage that it invokes patient-specific information rather than

  14. Pharmacokinetics of difloxacin and its concentration in body fluids and endometrial tissues of mares after repeated intragastric administration.

    PubMed

    Adams, Aric R; Haines, Gregory R; Brown, Murray P; Gronwall, Ronald; Merritt, Kelly

    2005-07-01

    Pharmacokinetics of difloxacin and its distribution within the body fluids and endometrium of 6 mares were studied after intragastric (IG) administration of 5 individual doses. Difloxacin concentrations were serially measured in serum, urine, peritoneal fluid, synovial fluid, cerebrospinal fluid, and endometrium over 120 h. Bacterial susceptibility to difloxacin was determined for 174 equine pathogens over a 7-month period. Maximum serum concentration (Cmax) was 2.25 +/- 0.70 microg/mL at 3.12 +/- 2.63 h and Cmax after the 5th dose was 2.41 +/- 0.86 microg/mL at 97.86 +/- 1.45 h. The mean elimination half-life (t(1/2)) was 8.75 +/- 2.77 h and area under the serum concentration versus time curve (AUC) was 25.13 +/- 8.79 microg h/mL. Highest mean synovial fluid concentration was 1.26 +/- 0.49 microg/mL at 100 h. Highest mean peritoneal fluid concentration was 1.50 +/- 0.56 microg/mL at 98 h. Highest mean endometrial concentration was 0.78 +/- 0.48 microg/g at 97.5 h. Mean cerebrospinal fluid concentration was 0.87 +/- 0.52 microg/mL at 99 h. Highest mean urine concentration was 92.05 +/- 30.35 microg/mL at 104 h. All isolates of Salmonella spp. and Pasteurella spp. were susceptible. In general, gram-negative organisms were more susceptible than gram-positives. Difloxacin appears to be safe, adequately absorbed, and well distributed to body fluids and endometrial tissues of mares and may be useful in the treatment of susceptible bacterial infections in adult horses. PMID:16187554

  15. Pharmacokinetics of difloxacin and its concentration in body fluids and endometrial tissues of mares after repeated intragastric administration

    PubMed Central

    2005-01-01

    Abstract Pharmacokinetics of difloxacin and its distribution within the body fluids and endometrium of 6 mares were studied after intragastric (IG) administration of 5 individual doses. Difloxacin concentrations were serially measured in serum, urine, peritoneal fluid, synovial fluid, cerebrospinal fluid, and endometrium over 120 h. Bacterial susceptibility to difloxacin was determined for 174 equine pathogens over a 7-month period. Maximum serum concentration (Cmax) was 2.25 ± 0.70 μg/mL at 3.12 ± 2.63 h and Cmax after the 5th dose was 2.41 ± 0.86 μg/mL at 97.86 ± 1.45 h. The mean elimination half-life (t1/2) was 8.75 ± 2.77 h and area under the serum concentration versus time curve (AUC) was 25.13 ± 8.79 μg h/mL. Highest mean synovial fluid concentration was 1.26 ± 0.49 μg/mL at 100 h. Highest mean peritoneal fluid concentration was 1.50 ± 0.56 μg/mL at 98 h. Highest mean endometrial concentration was 0.78 ± 0.48 μg/g at 97.5 h. Mean cerebrospinal fluid concentration was 0.87 ± 0.52 μg/mL at 99 h. Highest mean urine concentration was 92.05 ± 30.35 μg/mL at 104 h. All isolates of Salmonella spp. and Pasteurella spp. were susceptible. In general, gram-negative organisms were more susceptible than gram-positives. Difloxacin appears to be safe, adequately absorbed, and well distributed to body fluids and endometrial tissues of mares and may be useful in the treatment of susceptible bacterial infections in adult horses. PMID:16187554

  16. Tissue and subcellular distribution of CLIC1

    PubMed Central

    Ulmasov, Barbara; Bruno, Jonathan; Woost, Philip G; Edwards, John C

    2007-01-01

    Background CLIC1 is a chloride channel whose cellular role remains uncertain. The distribution of CLIC1 in normal tissues is largely unknown and conflicting data have been reported regarding the cellular membrane fraction in which CLIC1 resides. Results New antisera to CLIC1 were generated and were found to be sensitive and specific for detecting this protein. These antisera were used to investigate the distribution of CLIC1 in mouse tissue sections and three cultured cell lines. We find CLIC1 is expressed in the apical domains of several simple columnar epithelia including glandular stomach, small intestine, colon, bile ducts, pancreatic ducts, airway, and the tail of the epididymis, in addition to the previously reported renal proximal tubule. CLIC1 is expressed in a non-polarized distribution in the basal epithelial cell layer of the stratified squamous epithelium of the upper gastrointesitinal tract and the basal cells of the epididymis, and is present diffusely in skeletal muscle. Distribution of CLIC1 was examined in Panc1 cells, a relatively undifferentiated, non-polarized human cell line derived from pancreatic cancer, and T84 cells, a human colon cancer cell line which can form a polarized epithelium that is capable of regulated chloride transport. Digitonin extraction was used to distinguish membrane-inserted CLIC1 from the soluble cytoplasmic form of the protein. We find that digitonin-resistant CLIC1 is primarily present in the plasma membrane of Panc1 cells. In T84 cells, we find digitonin-resistant CLIC1 is present in an intracellular compartment which is concentrated immediately below the apical plasma membrane and the extent of apical polarization is enhanced with forskolin, which activates transepithelial chloride transport and apical membrane traffic in these cells. The sub-apical CLIC1 compartment was further characterized in a well-differentiated mouse renal proximal tubule cell line. The distribution of CLIC1 was found to overlap that of

  17. Pharmacokinetic studies of phellodendrine in rat plasma and tissues after intravenous administration using ultra-high performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Li, Yi; Liu, Xin-Guang; Wang, Hui-Ying; Dong, Xin; Gao, Wen; Xu, Xiao-Jun; Li, Ping; Yang, Hua

    2016-09-01

    Phellodendrine, a quaternary ammonium alkaloid extracted from the dried bark of Phellodendrom chinensis Schneid and Phellodendrom amurense Rupr, has the effect of suppressing cellular immune response, reducing blood pressure and antinephritis. However, few investigations have been conducted for the pharmacokinetic study of phellodendrine. Thus, a rapid, simple and reliable ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry (UHPLC-QQQ MS/MS) method has been established for quantification of phellodendrine in rat plasma and tissues by using magnoflorine as internal standard. The chromatographic separation was achieved on an Agilent ZORBAX SB-C18 column (4.6mm×50mm, 1.8μm) by gradient elution using 0.1% aqueous formic acid (A) and methanol (B). Triple quadrupole mass detection with multiple reaction monitoring mode was used to monitor the ion transitions, at m/z 342.20→192.20 for phellodendrine and m/z 342.20→58.20 for internal standard, respectively. The developed method was fully validated and successfully applied to the pharmacokinetics and tissue distribution study of phellodendrine after intravenous administration. The lower limits of quantification were 0.5ng/mL for plasma samples, 2.5ng/g for brain and 1ng/g for other tested tissues. Precisions and accuracy values were within the Food and Drug Administration acceptance criteria, the recovery and matrix effects were between 87.8-113.5%. The area under the curve (AUC0-t) ranged from 15.58 to 57.41mg/L min and Cmax were between 1.63-4.93mg/L. The results showed that phellodendrine was eliminated in 120min in plasma and most of tissues and the highest concentrations of phellodendrine were found in the kidney. This study may provide a basis for the further study of phellodendrine. PMID:27428451

  18. Distribution of prosaposin in rat lymphatic tissues.

    PubMed

    Shimokawa, Tetsuya; Nabeka, Hiroaki; Yamamiya, Kimiko; Wakisaka, Hiroyuki; Takeuchi, Takashi; Kobayashi, Naoto; Matsuda, Seiji

    2013-06-01

    Prosaposin (PSAP) is as a trophic factor and an activator protein for sphingolipid hydrolase in lysosomes. We generated a specific antibody to PSAP and examined the spatiotemporal distribution of PSAP-immunoreactive (PSAP-IR) cells in the lymphatic tissues of Wistar rats. Immunoblots of tissue homogenates separated electrophoretically showed a single band for PSAP in brain but two bands in spleen. PSAP-IR cells were distributed in both the red and white pulp of the spleen, in both the cortex and medulla of the thymus and in mesenteric lymph nodes. Many PSAP-IR cells were found in the dome portion of Peyer's patches and the number of PSAP-IR cells increased with the age of the rat. To identify the PSAP-IR cells, double- and triple-immunostainings were performed with antibodies against PSAP, CD68 and CD1d. The large number of double- and triple-positive cells suggested that antigen-presenting cells contained much PSAP in these lymphatic tissues. Intense expression of PSAP mRNA, examined by in situ hybridisation, was observed in the red pulp and corona of the spleen. In rats, the PSAP gene generates two alternative splicing forms of mRNA: Pro+9 containing a 9-base insertion and Pro+0 without the insertion. We examined the expression patterns of the alternative splicing forms of PSAP mRNA in the spleen. The presence of both types of mRNA (Pro+9 and Pro+0) indicated that the spleen contains various types of prosaposin-producing and/or secreting cells. These findings suggest diverse functions for PSAP in the immune system. PMID:23420452

  19. Physiologically-based pharmacokinetic modelling of distribution, bioaccumulation and excretion of POPs in Greenland sledge dogs (Canis familiaris).

    PubMed

    Sonne, Christian; Gustavson, Kim; Letcher, Robert J; Dietz, Rune

    2015-10-01

    We used PBPK (physiologically-based pharmacokinetic) modelling to investigate distribution, bioaccumulation and excretion of the seven POPs (persistent organic pollutants) CB-99, CB-153, HCB, oxychlordane, p,p'-DDE, BDE-47 and BDE-99 in 4 adult captive Greenland sledge dog (Canis familiaris) bitches fed minke whale (Balaenoptera acuterostrata) blubber for 500-635 days. The PBPK modelled POP concentrations in adipose tissue, liver, kidney and plasma were mostly within a factor 2 of actual measured tissue levels even for those at the lower concentration end. The excretion route for oxychlordane and CB-153 was modelled to be via faeces while lung alveolar excretion dominated for BDE-47, BDE-99, HCB, p,p'-DDE and CB-99. Furthermore the model suggested the retained mass of POPs after 500 and 635 days of exposure, respectively, to be relatively low despite these POPs being highly recalcitrant. The retention increased in the following order (% of total intake); p,p'-DDE (1%)

  20. Radiometric assay of ghrelin hydrolase activity and 3H-ghrelin distribution into mouse tissues.

    PubMed

    Chen, Vicky Ping; Gao, Yang; Geng, Liyi; Brimijoin, Stephen

    2015-12-15

    A high-throughput radiometric assay was developed to characterize enzymatic hydrolysis of ghrelin and to track the peptide's fate in vivo. The assay is based on solvent partitioning of [(3)H]-octanoic acid liberated from [(3)H]-octanoyl ghrelin during enzymatic hydrolysis. This simple and cost-effective method facilitates kinetic analysis of ghrelin hydrolase activity of native and mutated butyrylcholinesterases or carboxylesterases from multiple species. In addition, the assay's high sensitivity facilitates ready evaluation of ghrelin's pharmacokinetics and tissue distribution in mice after i.v. bolus administration of radiolabeled peptide. PMID:26514871

  1. Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis.

    PubMed

    Veselinovic, Milena; Yang, Kuo-Hsiung; Sykes, Craig; Remling-Mulder, Leila; Kashuba, Angela D M; Akkina, Ramesh

    2016-02-01

    Orally administered anti-retroviral drugs show considerable promise for HIV/AIDS pre-exposure prophylaxis (PrEP). For the success of these strategies, pharmacokinetic (PK) data defining the optimal concentration of the drug needed for protection in relevant mucosal exposure sites is essential. Here we employed a humanized mouse model to derive comprehensive PK data on the HIV integrase inhibitor raltegravir (RAL), a leading PrEP drug candidate. Under steady state conditions following oral dosing, plasma and multiple mucosal tissues were sampled simultaneously. RAL exhibited higher drug exposure in mucosal tissues relative to that in plasma with one log higher exposure in vaginal and rectal tissue and two logs higher exposure in intestinal mucosa reflecting the trends seen in the human studies. These data demonstrate the suitability of RAL for HIV PrEP and validate the utility of humanized mouse models for deriving important preclinical PK-PD data. PMID:26771889

  2. 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...

  3. Pharmacokinetic study on pradofloxacin in the dog – Comparison of serum analysis, ultrafiltration and tissue sampling after oral administration

    PubMed Central

    2013-01-01

    Background Pradofloxacin, a newly developed 8-cyano-fluoroquinolone, show enhanced activity against Gram-positive organisms and anaerobes to treat canine and feline bacterial infections. The purpose of this cross-over study was to measure the unbound drug concentration of pradofloxacin in the interstitial fluid (ISF) using ultrafiltration and to compare the kinetics of pradofloxacin in serum, ISF and tissue using enrofloxacin as reference. Results After oral administration of enrofloxacin (5 mg/kg) and pradofloxacin (3 mg/kg and 6 mg/kg, respectively), serum collection and ultrafiltration in regular intervals over a period of 24 h were performed, followed by tissue sampling at the end of the third dosing protocol (pradofloxacin 6 mg/kg). Peak concentrations of pradofloxacin (3 mg/kg) were 1.55±0.31 μg/ml in the ISF and 1.85±0.23 μg/ml in serum and for pradofloxacin (6 mg/kg) 2.71±0.81 μg/kg in the ISF and 2.77±0.64 μg/kg in serum; both without a statistical difference between ISF and serum. Comparison between all sampling approaches showed no consistent pattern of statistical differences. Conclusions Despite some technical shortcomings the ultrafiltration approach appears to be the most sensitive sampling technique to estimate pharmacokinetic values of pradofloxacin at the infection site. Pharmacokinetics – Pradofloxacin – Ultrafiltration – Dog – Oral Administration. PMID:23410255

  4. 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. PMID:26875641

  5. A sensitive LC-MS/MS method for quantifying capsaicin and dihydrocapsaicin in rabbit plasma and tissue: application to a pharmacokinetic study.

    PubMed

    Wang, Dimin; Meng, Fanhua; Yu, Lin; Sun, Lu; Sun, Lili; Guo, Jifen

    2015-04-01

    Prescription and nonprescription products for topical management of pain, including cream, lotion and patch forms, contain capsaicin (CAP) and dihydrocapsaicin (DHC). There are few in vivo studies on absorption, bioavailability and disposition of CAP and DHC. We established a sensitive and rapid LC-MS/MS assay to determine CAP and DHC levels in rabbit plasma and tissue. Bio-samples prepared by liquid-liquid extraction using n-hexane-dichloromethane-isopropanol (100: 50: 5, v/v/v) mixture were separated by isocratic chromatography with an Extend C18 column. The mobile phase was acetonitrile-water-formic acid (70: 30: 0.1, v/v/v). The method was linear from 0.125 to 50 ng/mL for a 100 μL bio-sample, and the lower quantification limit was 0.125 ng/mL. Total run time to analyze each sample was 3.5 min. We used this validated method to study pharmacokinetics and tissue distribution of CAP gel administered topically to rabbits. A very small amount of CAP and DHC was absorbed into the systemic circulation. The highest plasma concentration was 2.39 ng/mL, and the mean peak plasma concentration value after 12 h of CAP gel application was 1.68 ng/mL. Drug concentration in treated skin was relatively high, with low concentration in other tissues. Thus, topical CAP gel had strong local effects and weaker systemic effects. PMID:25088519

  6. Tissue distribution of berberine and its metabolites after oral administration in rats.

    PubMed

    Tan, Xiang-Shan; Ma, Jing-Yi; Feng, Ru; Ma, Chao; Chen, Wen-Jing; Sun, Yu-Peng; Fu, Jie; Huang, Min; He, Chi-Yu; Shou, Jia-Wen; He, Wen-Yi; Wang, Yan; Jiang, Jian-Dong

    2013-01-01

    Berberine (BBR) has been confirmed to have multiple bioactivities in clinic, such as cholesterol-lowering, anti-diabetes, cardiovascular protection and anti- inflammation. However, BBR's plasma level is very low; it cannot explain its pharmacological effects in patients. We consider that the in vivo distribution of BBR as well as of its bioactive metabolites might provide part of the explanation for this question. In this study, liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LC/MS(n)-IT-TOF) as well as liquid chromatography that coupled with tandem mass spectrometry (LC-MS/MS) was used for the study of tissue distribution and pharmacokinetics of BBR in rats after oral administration (200 mg/kg). The results indicated that BBR was quickly distributed in the liver, kidneys, muscle, lungs, brain, heart, pancreas and fat in a descending order of its amount. The pharmacokinetic profile indicated that BBR's level in most of studied tissues was higher (or much higher) than that in plasma 4 h after administration. BBR remained relatively stable in the tissues like liver, heart, brain, muscle, pancreas etc. Organ distribution of BBR's metabolites was also investigated paralleled with that of BBR. Thalifendine (M1), berberrubine (M2) and jatrorrhizine (M4), which the metabolites with moderate bioactivity, were easily detected in organs like the liver and kidney. For instance, M1, M2 and M4 were the major metabolites in the liver, among which the percentage of M2 was up to 65.1%; the level of AUC (0-t) (area under the concentration-time curve) for BBR or the metabolites in the liver was 10-fold or 30-fold higher than that in plasma, respectively. In summary, the organ concentration of BBR (as well as its bioactive metabolites) was higher than its concentration in the blood after oral administration. It might explain BBR's pharmacological effects on human diseases in clinic. PMID:24205048

  7. The effect of renal and hepatic impairment on the pharmacokinetics of ospemifene, a tissue-selective estrogen agonist/antagonist.

    PubMed

    Preston, Richard A; Marbury, Thomas C; Wajima, Toshihiro; Graham, Shelli

    2015-01-01

    Ospemifene is a nonestrogen tissue-selective estrogen agonist/antagonist approved to treat moderate to severe dyspareunia due to vulvar and vaginal atrophy in postmenopausal women. Three single-dose, open-label, parallel-group pharmacokinetic studies examined the pharmacokinetics of ospemifene in postmenopausal women with (1) mild hepatic impairment (n = 7), (2) moderate hepatic impairment (n = 8), and (3) severe renal impairment (n = 8) compared with a similar number of matched healthy controls. The study durations ranged from 8 to 12 days. Study participants received a single oral dose of ospemifene 60 mg on day 1 and blood samples were collected serially. The geometric mean ratios (hepatic or renal impairment/healthy) and 90% confidence intervals (CIs) for area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) and maximum concentration (Cmax), respectively, of ospemifene were 90.86% (90% CI, 65.95%-125.19%) and 79.48% (90% CI, 65.95%-95.79%) in the mild hepatic impairment study; 128.62% (90% CI, 87.13%-189.88%) and 101.12% (90% CI, 66.17%-154.52%) in the moderate hepatic impairment study, and 119.63% (90% CI, 81.37%-175.88%) and 79.30% (90% CI, 52.85%-118.99%) in the severe renal impairment study. Overall, there was no clinically important effect of hepatic or renal impairment on the pharmacokinetics of ospemifene, indicating that dosing does not need to be adjusted in postmenopausal women with mild or moderate hepatic impairment or in subjects with severe renal impairment. PMID:24413373

  8. Evaluation of tissue optical properties from light distribution images

    NASA Astrophysics Data System (ADS)

    Tsai, Cheng-Lun; Chang, Ming; Hsieh, Jui-Hsiang; Yang, Yi-Fong; Chou, Yi-Sheong

    2000-06-01

    Images of light distribution in biological soft tissue we used to study the optical characteristics of tissue. The light distribution image was taken under a microscope with light injected through a pinhole close to the edge of the top surface. Images taken on skin, fat, and muscle tissues were compared to study the effect of cellular structure and temperature on the light intensity distribution. Monte Carlo simulation with the same conditions was also performed to simulate the light intensity distribution in tissue for comparison. The anisotropy scattering of light in tissue is affected by the tissue microscopic structure, such as the direction of muscle tissue fibers. The change in optical properties of fat and muscle tissue with temperature was observed. The two-dimensional light distribution images offer more information than general reflectance and transmission measurements. By matching the simulated light intensity distribution with the light distribution image, the optical properties of biological tissue could be estimated. This method might be applied in tissue engineering as an economic way for evaluating the microscopic structure of tissue.

  9. Pharmacokinetic/pharmacodynamic relationship of marbofloxacin against Pasteurella multocida in a tissue-cage model in yellow cattle.

    PubMed

    Shan, Q; Wang, J; Yang, F; Ding, H; Liang, C; Lv, Z; Li, Z; Zeng, Z

    2014-06-01

    The fluoroquinolone antimicrobial drug marbofloxacin was administered to yellow cattle intravenously and intramuscularly at a dose of 2 mg/kg of body weight in a two-period crossover study. The pharmacokinetic properties of marbofloxacin in serum, inflamed tissue-cage fluid (exudate), and noninflamed tissue-cage fluid (transudate) were studied by using a tissue-cage model. The in vitro and ex vivo activities of marbofloxacin in serum, exudate, and transudate against a pathogenic strain of Pasteurella multocida (P. multocida) were determined. 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 155.75, 153.00, and 138.88, respectively, after intravenous dosing and 160.50, 151.00, and 137.63, respectively, after intramuscular dosing. After intramuscular dosing, the maximum concentration/MIC ratios for serum, exudate, and transudate were 21.13, 9.13, and 8.38, respectively. The ex vivo growth inhibition data after intramuscular 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 17.25, 31.29, and 109.62, and slightly lower values were obtained for transudate and exudate. It is proposed that these findings might be used with MIC50 or MIC90 data to provide a rational approach to the design of dosage schedules which optimize efficacy in respect of bacteriological as well as clinical cures. PMID:24033339

  10. 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.

  11. Radiosensitizing activity and pharmacokinetics of multiple dose administered KU-2285 in peripheral nerve tissue in mice

    SciTech Connect

    Iwai, Hiroyuki; Matsuno, Etsuko ); Sasai, Keisuke; Abe, Mitsuyuki; Shibamoto, Yuta )

    1994-06-15

    In a clinical trial in which a 2-nitroimidazole radiosensitizer was administered repeatedly, the dose-limiting toxicity was found to be peripheral neuropathy. In the present study, the in vivo radiosensitizing activity of KU-2285 in combination with radiation dose fractionation, and the pharmacokinetics of cumulative dosing of KU-2285 in the peripheral nerves were examined. The ability of three nitroimidazoles, misonidazole (MISO), etanidazole (SR-2508) and KU-2285, to sensitize SCCVII tumors to radiation treatment has been compared for drug doses in the range 0-200 mg/kg. Single radiation doses or two different fractionation schedules (6 Gy/fractions [times] three fractions/48 h or 5 Gy/fractions [times] five fractions/48 h) were used; the tumor cell survival was determined using an in vivo/in vitro colony assay. The pharmacokinetics in the sciatic nerves were undertaken, when KU-2285 or etanidazole were injected at a dose of 200 mg/kg intravenously one, two, three, or four times at 2-h intervals. At less than 100 mg/kg, KU-2285 sensitized SCCVII tumors more than MISO and SR-2508 by fractionated irradiation. Evaluation of pharmacokinetics in the peripheral nerves showed that the apparent biological half-life of SR-2508 increased with the increases in the number of administrations, whereas that of KU-2285 became shorter. Since most clinical radiotherapy is given in small multiple fractions, KU-2285 appears to be a hypoxic cell radiosensitizer that could be useful in such regimens, and that poses no risk of chronic peripheral neurotoxicity. 12 refs., 5 figs., 1 tab.

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

    SciTech Connect

    Poulin, Patrick; Ekins, Sean; Theil, Frank-Peter

    2011-01-15

    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. This 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.

  13. Extended-Duration Dosing and Distribution of Dalbavancin into Bone and Articular Tissue

    PubMed Central

    Puttagunta, Sailaja; Sprenger, Craig R.; Rubino, Chris; Van Wart, Scott; Baldassarre, James

    2015-01-01

    Dalbavancin is an intravenous lipoglycopeptide with activity against Gram-positive pathogens and an MIC90 for Staphylococcus aureus of 0.06 μg/ml. With a terminal half-life of >14 days, dosing regimens with infrequent parenteral administration become available to treat infectious diseases such as osteomyelitis and endocarditis that otherwise require daily dosing for many weeks. In order to support a rationale for these novel regimens, the pharmacokinetics over an extended dosing interval and the distribution of dalbavancin into bone and articular tissue were studied in two phase I trials and pharmacokinetic modeling was performed. Intravenous administration of 1,000 mg of dalbavancin on day 1 followed by 500 mg weekly for seven additional weeks was well tolerated and did not demonstrate evidence of drug accumulation. In a separate study, dalbavancin concentrations in cortical bone 12 h after infusion of a single 1,000-mg intravenous infusion were 6.3 μg/g and 2 weeks later were 4.1 μg/g. A two-dose, once-weekly regimen that would provide tissue exposure over the dalbavancin MIC for Staphylococcus aureus for 8 weeks, maximizing the initial exposure to treatment while minimizing the frequency of intravenous therapy, is proposed. PMID:25561338

  14. Pharmacokinetics and distribution of dietary tributyltin and methylmercury in the snow crab (Chionoecetes opilio)

    SciTech Connect

    Rouleau, C.; Gobeil, C.; Tjaelve, H.

    1999-10-01

    The pharmacokinetics and distribution of a single 5-{micro}g dietary dose of radiolabeled [{sup 113}Sn]tributyltin (TBT) and [{sup 203}Hg]methylmercury (MeHg) were studied over 154 days in the snow crab, using in vivo gamma counting and whole-body autoradiography. Experiment was done under conditions typical of those encountered in the cold natural habitat of this crustacean. Retention efficiency was high for both compounds, and two kinetic pools could be distinguished. Elimination of the first pool proceeded within 20--80 days, but it accounted for 27--62% of the assimilated TBT, compared to 8--11% for MeHg. Biological half-life of the second pool was 33--187 days for TBT and 520--650 days for MeHg. Autoradiographic and dissection data revealed a less homogeneous distribution of the radiolabel and much higher radioactivity in gut lumen for TBT compared to MeHg. This suggests that the larger size of the first pool in the case of TBT resulted from metabolization in the hepatopancreas and fecal elimination of the metabolites. The whole-body biomagnification factor (BMF) that would result from the long-term chronic exposure of snow crab to TBT-contaminated food was estimated as 0.1--0.6. Although these BMF values were an order of magnitude lower than those estimated for MeHg, they are not negligible and indicate that uptake of TBT via food may be an important accumulation route.

  15. Tissue optics, light distribution, and spectroscopy

    NASA Astrophysics Data System (ADS)

    Tuchin, Valery V.; Utz, Sergei R.; Yaroslavsky, Ilya V.

    1994-10-01

    A model of multilayered tissue is considered. The Monte Carlo simulation technique is used to study laser beam transport through tissues with varying optical properties for each layer (absorption, scattering, scattering anisotropy factor, and refractive index). Calculations are performed for some models of the human skin and adjacent tissues for visible and UV wavelength ranges. New technology for human epidermis optical parameters determination is presented. This technology includes epidermis upper layers glue stripping; in vitro measurements of total transmission, diffuse reflection, and angular scattering of stripping samples; and using an inverse calculation technique based on four-flux approximation of radiation transport theory. The technology was successfully used for depth dependence monitoring of epidermis optical parameters. An inverse Monte Carlo technique for determining the optical properties of tissues based on spectrophotometric measurements is developed. This technique takes into accounts the 2-D geometry of the experiment, finite sizes of incident beam and integrating sphere ports, boundary conditions, and sideways losses of light.

  16. 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. PMID:25747988

  17. Pharmacokinetics in risk assessment: drinking water and health. Volume 8

    SciTech Connect

    Not Available

    1987-01-01

    Contents include: risk assessment: historical perspectives; tissue dosimetry in risk assessment; modeling: an introduction; physiologically based pharmacokinetic modeling; allometry: body-size constraints in animal design; prediction of in vivo parameters of drug metabolism and distribution from in-vitro studies; dose, species, and route extrapolation; uncertainty in pharmacokinetic models using SIMUSOLV; interspecies and dose-route extrapolations; carcinogen DNA adducts as a measure of biological dose for risk analysis of carcinogenic data; resources available for simulation in toxicology; route-to-route extrapolation of dichloromethane exposure using a physiological pharmacokinetic model; sensitivity analysis in pharmacokinetic modeling; mutation accumulation: chronic cytotoxicant exposure; model for ethylene chloride and its application in risk assessment; mathematical modeling of ozone absorption in the lower respiratory tract; development of a physiologically based pharmacokinetic model for multiday inhalation of carbon tetrachloride; the delivered/administered dose relationship and its impact on formaldehyde risk estimates; pharmacokinetic simulation in risk assessment; hazard assessment: ozone; role of pharmacokinetic modeling in risk assessment; development of multispecies, multiroute pharmacokinetic models for methylene chloride and 1,1,1-trichloroethane (methyl chloroform); methotrexate: pharmacokinetics and assessment of toxicity; prospective predictions and validations in anticancer therapy; the application of pharmacokinetic data in carcinogenic risk assessment.

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

    PubMed

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

    2015-10-01

    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

  19. Tissue Distribution and Efficacy of Gold Nanorods Coupled with Laser Induced Photoplasmonic Therapy in Ehrlich Carcinoma Solid Tumor Model

    PubMed Central

    El-Sayed, Mostafa A.; Shabaka, Ali A.; El-Shabrawy, Osama A.; Yassin, Nemat A.; Mahmoud, Sawsan S.; El-Shenawy, Siham M.; Al-Ashqar, Emad; Eisa, Wael H.; Farag, Niveen M.; El-Shaer, Marwa A.; Salah, Nabila; Al-Abd, Ahmed M.

    2013-01-01

    Gold nanorods (GNR) within tumor microregions are characterized by their ability to absorb near IR light and emit heat in what is called photoplasmonic effect. Yet, the efficacy of nanoparticles is limited due to intratumoral tissue distribution reasons. In addition, distribution of GNRs to normal tissue might result in non specific toxicity. In the current study, we are assessing the intratumoral and tissue distribution of PEGylated GNRs on the top of its antitumor characteristics when given intravenously or intratumoral to solid tumor bearing mice and coupled with laser photoplasmonic sessions. PEGylated GNRs with a longitudinal size of less than 100 nm were prepared with aspect ratio of 4.6 showing strong surface plasmon absorption at wavelength 800 nm. Pharmacokinetics of GNR after single I.V. administration (0.1 mg/kg) showed very short systemic circulating time (less than 3 h). On the other hand, tissue distribution of I.V. GNR (0.1 mg/kg) to normal animals showed preferential deposition in spleen tissue. Repeated administration of I.V. GNR resulted in preferential accumulation in both liver and spleen tissues. In addition, I.V. administration of GNR to Ehrlich carcinoma tumor bearing mice resulted in similar tissue distribution; tumor accumulation and anti-tumor effect compared to intratumoral administration. In conclusion, the concentration of GNR achieved within tumors microregions after I.V. administration was comparable to I.T. administration and sufficient to elicit tumoral growth arrest when coupled with laser-aided photoplasmonic treatment. PMID:24098446

  20. Pharmacokinetics and distribution of fluvoxamine to the brain in rats under oxidative stress.

    PubMed

    Kobuchi, Shinji; Fukushima, Keizo; Ito, Yukako; Sugioka, Nobuyuki; Takada, Kanji

    2012-07-01

    The effects of oxidative stress (OS) on the pharmacokinetics of fluvoxamine (FLV), particularly on FLV distribution in the plasma, were studied in ferric-nitrilotriacetate-induced OS rat models (OS rats). The study protocol involved a continuous FLV infusion (25.0 μg/kg/min). The resulting mean plasma FLV concentration measured in steady state OS rats was 0.13 ± 0.01 μg/mL, which was significantly lower than plasma concentrations measured in control rats (0.19 ± 0.01 μg/mL). Moreover, the mean FLV concentration in the OS rat brain (0.51 ± 0.08 μg/g) was determined to be approximately half the concentration in control rat brains (0.95 ± 0.11 μg/g). The FLV concentrations in both the unbound fraction of plasma and erythrocytes of OS rats were significantly greater than that of control rats. These results suggest the potential attenuation of FLV's pharmacological effects in patients under OS. PMID:22486632

  1. 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.

  2. Avenanthramide bioavailability and tissue distribution in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Avenanthramides (AVA) are antioxidants found exclusively in oats. The aim of this study was to determine the time course of absorption of AVA into plasma, liver, and other tissues following their oral ingestion. Three fractions of AVA (AVN-A, AVN-B, and AVN-C) were fed to female Sprague-Dawley rat...

  3. Pharmacokinetics of Telithromycin in Plasma and Soft Tissues after Single-Dose Administration to Healthy Volunteers

    PubMed Central

    Gattringer, Rainer; Urbauer, Eleonora; Traunmüller, Friederike; Zeitlinger, Markus; Dehghanyar, Pejman; Zeleny, Petra; Graninger, Wolfgang; Müller, Markus; Joukhadar, Christian

    2004-01-01

    By use of microdialysis we assessed the concentrations of telithromycin in muscle and adipose tissue to test its ability to penetrate soft tissues. The ratios of the area under the concentration-versus-time curve from 0 to 24 h to the MIC indicated that free concentrations of telithromycin in tissue and plasma might be effective against Streptococcus pyogenes but not against staphylococci and human and animal bite pathogens. PMID:15561839

  4. A distributed parameter physiologically-based pharmacokinetic model for dermal and inhalation exposure to volatile organic compounds

    SciTech Connect

    Roy, A.; Weisel, C.P.; Lioy, P.J.; Georgopouelous, P.G.

    1996-04-01

    Estimates of dermal dose from exposures to toxic chemicals are typically derived using models that assume instantaneous establishment of steady-state dermal mass flux. However, dermal absorption theory indicates that this assumption is invalid for short-term exposures to volatile organic chemicals (VOCs). A generalized distributed parameter physiologically-based pharmacokinetic model (DP-PBPK), which describes unsteady state dermal mass flux via a partial differential equation (Fickian diffusion), has been developed for inhalation and dermal absorption of VOCs. In the present study, the DP-PBPK model has been parameterized for chloroform, and compared with two simpler PBPK models of chloroform. The latter are lumped parameter models, employing ordinary differential equations, that do not account for the dermal absorption time lag associated with the accumulation of permeant chemical in tissue represented by permeability coefficients. All three models were evaluated by comparing simulated post-exposure exhaled breath concentration profiles with measured concentrations following environmental chloroform exposures. The DP-PBPK model predicted a time-lag in the exhaled breath concentration profile, consistent with the experimental data. The DP-PBPK model also predicted significant volatilization of chloroform, for a simulated dermal exposure scenario. The end-exposure dermal dose predicted by the DP-PBPK model is similar to that predicted by the EPA recommended method for short-term exposures, and is significantly greater than the end-exposure dose predicted by the lumped parameter models. However, the net dermal dose predicted by the DP-PBPK model is substantially less than that predicted by the EPA method, due to the post-exposure volatilization predicted by the DP-PBPK model. The net dermal dose of chloroform predicted by all three models was nearly the same, even though the lumped parameter models did not predict substantial volatilization. 30 refs., 8 figs., 1 tab.

  5. Pharmacokinetic analysis of blood distribution of intravenously administered sup 153 Gd-labeled Gd(DTPA)2- and sup 99m Tc(DTPA) in rats

    SciTech Connect

    Wedeking, P.; Eaton, S.; Covell, D.G.; Nair, S.; Tweedle, M.F.; Eckelman, W.C. )

    1990-01-01

    Rat plasma distribution data obtained following IV administration of {sup 99m}Tc(DTPA) alone or after co-administration of {sup 99m}Tc(DTPA) and {sup 153}Gd-labeled Gd(DTPA)2- at 0.001, 0.1, and 1.0 mmol Gd/kg were evaluated using compartmental modeling techniques. A three-compartment open model was found to fit the data significantly better (P less than 0.01) than a two- or four-compartment open model. This model incorporates and links the plasma and urine data and includes a delay to account for the transit time through the kidneys/ureters. The two nonplasma compartments of the model were assumed to be related to rapidly and slowly equilibrating tissues. Tc(DTPA) and Gd(DTPA)2- had nearly identical pharmacokinetic profiles in plasma and the rate constants were essentially the same. No significant dose dependent pharmacokinetic differences were found for the range of Gd(DTPA)2- doses tested. Simulations of the proposed three-compartment model were used to generate concentration-time curves for each of the three compartments.

  6. Pharmacokinetic analysis of blood distribution of intravenously administered 153Gd-labeled Gd(DTPA)2- and 99mTc(DTPA) in rats.

    PubMed

    Wedeking, P; Eaton, S; Covell, D G; Nair, S; Tweedle, M F; Eckelman, W C

    1990-01-01

    Rat plasma distribution data obtained following IV administration of 99mTc(DTPA) alone or after co-administration of 99mTc(DTPA) and 153Gd-labeled Gd(DTPA)2- at 0.001, 0.1, and 1.0 mmol Gd/kg were evaluated using compartmental modeling techniques. A three-compartment open model was found to fit the data significantly better (P less than 0.01) than a two- or four-compartment open model. This model incorporates and links the plasma and urine data and includes a delay to account for the transit time through the kidneys/ureters. The two nonplasma compartments of the model were assumed to be related to rapidly and slowly equilibrating tissues. Tc(DTPA) and Gd(DTPA)2- had nearly identical pharmacokinetic profiles in plasma and the rate constants were essentially the same. No significant dose dependent pharmacokinetic differences were found for the range of Gd(DTPA)2- doses tested. Simulations of the proposed three-compartment model were used to generate concentration-time curves for each of the three compartments. PMID:2082126

  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. 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. The effect of quinidine, a strong P-glycoprotein inhibitor, on the pharmacokinetics and central nervous system distribution of naloxegol.

    PubMed

    Bui, Khanh; She, Fahua; Zhou, Diansong; Butler, Kathleen; Al-Huniti, Nidal; Sostek, Mark

    2016-04-01

    Naloxegol is a PEGylated, oral, peripherally acting μ-opioid receptor antagonist approved in the United States for treatment of opioid-induced constipation in patients with noncancer pain. Naloxegol is metabolized by CYP3A, and its properties as a substrate for the P-glycoprotein (PGP) transporter limit its central nervous system (CNS) permeability. This double-blind, randomized, 2-part, crossover study in healthy volunteers evaluated the effect of quinidine (600 mg PO), a CYP3A/PGP transporter inhibitor, on the pharmacokinetics and CNS distribution of naloxegol (25 mg PO). In addition, the effects of quinidine on morphine (5 mg/70 kg IV)-induced miosis and exposure to naloxegol were assessed. Coadministration of quinidine and naloxegol increased naloxegol's AUC 1.4-fold and Cmax 2.5-fold but did not antagonize morphine-induced miosis, suggesting that PGP inhibition does not increase the CNS penetration of naloxegol. Naloxegol pharmacokinetics was unaltered by coadministration of morphine and either quinidine or placebo; conversely, pharmacokinetics of morphine and its metabolites (in the presence of quinidine) were unaltered by coadministration of naloxegol. Naloxegol was safe and well tolerated, alone or in combination with quinidine, morphine, or both. The observed increase in exposure to naloxegol in the presence of quinidine is primarily attributed to quinidine's properties as a weak CYP3A inhibitor. PMID:26248047

  10. Intravitreal clearance and volume of distribution of compounds in rabbits: In silico prediction and pharmacokinetic simulations for drug development.

    PubMed

    del Amo, Eva M; Vellonen, Kati-Sisko; Kidron, Heidi; Urtti, Arto

    2015-09-01

    The aims of this research were to (1) create a curated universal database of intravitreal volumes of distribution (Vss, ivt) and clearances (CL ivt) of small molecular weight compounds and macromolecules and (2) to develop quantitative structure property relationship (QSPR) and pharmacokinetic models for the estimation of vitreal drug concentrations based on the compound structure. Vss, ivt and CL ivt values were determined from the available literature on intravitreal drug administration using compartmental models and curve fitting. A simple QSPR model for CL ivt of small molecular weight compounds was obtained with two descriptors: Log D7.4 and hydrogen bond donor capacity. The model predicted the internal and external test sets reliably with a mean fold error of 1.50 and 1.33, respectively (Q(2)Y=0.62). For 80% of the compounds the Vss, ivt was 1.18-2.28 ml; too narrow range for QSPR model building. Integration of the estimated Vss, ivt and predicted CL ivt parameters into pharmacokinetic simulation models allows prediction of vitreous drug concentrations after intravitreal administration. The present work presents for the first time a database of CL ivt and Vss, ivt values and the dependence of the CL ivt values on the molecular structure. The study provides also useful in silico tools to investigate a priori the intravitreal pharmacokinetic profiles for intravitreally injected candidate compounds and drug delivery systems. PMID:25603198

  11. Quantitative structure-activity relationship models of clinical pharmacokinetics: clearance and volume of distribution.

    PubMed

    Gombar, Vijay K; Hall, Stephen D

    2013-04-22

    Reliable prediction of two fundamental human pharmacokinetic (PK) parameters, systemic clearance (CL) and apparent volume of distribution (Vd), determine the size and frequency of drug dosing and are at the heart of drug discovery and development. Traditionally, estimated CL and Vd are derived from preclinical in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) measurements. In this paper, we report quantitative structure-activity relationship (QSAR) models for prediction of systemic CL and steady-state Vd (Vdss) from intravenous (iv) dosing in humans. These QSAR models avoid uncertainty associated with preclinical-to-clinical extrapolation and require two-dimensional structure drawing as the sole input. The clean, uniform training sets for these models were derived from the compilation published by Obach et al. (Drug Metab. Disp. 2008, 36, 1385-1405). Models for CL and Vdss were developed using both a support vector regression (SVR) method and a multiple linear regression (MLR) method. The SVR models employ a minimum of 2048-bit fingerprints developed in-house as structure quantifiers. The MLR models, on the other hand, are based on information-rich electro-topological states of two-atom fragments as descriptors and afford reverse QSAR (RQSAR) analysis to help model-guided, in silico modulation of structures for desired CL and Vdss. The capability of the models to predict iv CL and Vdss with acceptable accuracy was established by randomly splitting data into training and test sets. On average, for both CL and Vdss, 75% of test compounds were predicted within 2.5-fold of the value observed and 90% of test compounds were within 5.0-fold of the value observed. The performance of the final models developed from 525 compounds for CL and 569 compounds for Vdss was evaluated on an external set of 56 compounds. The predictions were either better or comparable to those predicted by other in silico models reported in the literature. To

  12. Pharmacokinetics and Pulmonary Distribution of Clarithromycin and Rifampicin after Concomitant and Consecutive Administration in Foals.

    PubMed

    Berlin, Sarah; Spieckermann, Lena; Oswald, Stefan; Keiser, Markus; Lumpe, Stefan; Ullrich, Anett; Grube, Markus; Hasan, Mahmoud; Venner, Monica; Siegmund, Werner

    2016-03-01

    Drug interactions often result from multiple pharmacokinetic changes, such as after rifampicin (RIF) and clarithromycin (CLA) in the treatment of abscessing lung diseases. Comedication of RIF may interact with CLA disposition by either induction of presystemic elimination processes and/or inhibition of uptake mechanisms because it regulates gene transcription and modulates function of various CYP enzymes, multidrug efflux and uptake transporters for which CLA is a substrate. To distinguish the transcriptional changes from the modulating interaction components upon CLA absorption and pulmonary distribution, we initiated a repeated-dose study in 12 healthy foals with CLA (7.5 mg/kg, p.o., b.i.d.) in comedication with RIF (10 mg/kg, p.o., b.i.d.) given either concomitantly with CLA or consecutively 4 h after CLA. Affinity of CLA to human P-gp, MRP2, and MRP3 and to OCT1, OCT3, and PEPT1 was measured using Sf9-derived inside-out membrane vesicles and transfected HEK293 cells, respectively. ABCB1 (P-gp) induction by RIF and affinity of CLA to equine P-gp were studied using primary equine hepatocytes. Absolute bioavailability of CLA was reduced from ∼40% to below 5% after comedication of RIF in both schedules of administration, and Tmax occurred ∼2-3 h earlier. The loss of bioavailability was not associated with increased 14-hydroxyclarithromycin (14-OH-CLA) exposure. After consecutive dosing, absolute bioavailability and pulmonary penetration of CLA increased ∼2-fold compared to concomitant use. In vitro, CLA showed affinity to human and equine P-gp. Expression of ABCB1 mRNA was upregulated by RIF in 7 of 8 duodenal biopsy specimens and in primary equine hepatocytes. In conclusion, the major undesired influence of RIF on oral absorption and pulmonary distribution of CLA is associated with induction of intestinal P-gp. Consecutive administration to avoid competition with its intestinal uptake transport results in significantly, although not clinically relevant

  13. [Cephalexin pharmacokinetics].

    PubMed

    Koroleva, V G; Vasil'ev, V K; Danilova, V I; Firsov, A A

    1981-03-01

    The pharmacokinetics of cephalexin monohydrate after its oral administration in a single dose was studied on rats and dogs. The analysis of the pharmacokinetic data obtained with the one-compartmental model showed that the rate of the antibiotic absorption in the rats was higher than that in the dogs. The periods of the cephalexin half-absorption and maximum concentration were 0.2 and 1.1 hour in the rats and 0.64 and 1.9 hours in the dogs respectively. The period of the antibiotic half-life was almost the same in both animal species. Selective localization of cephalexin in the kidney and liver tissues was noted. The antibiotic was mainly excreted by the kidneys (98.8 per cent for 24 hours). PMID:7235651

  14. Uptake and Tissue Distribution of Pharmaceuticals and Personal Care Products in Wild Fish from Treated-Wastewater-Impacted Streams.

    PubMed

    Tanoue, Rumi; Nomiyama, Kei; Nakamura, Haruna; Kim, Joon-Woo; Isobe, Tomohiko; Shinohara, Ryota; Kunisue, Tatsuya; Tanabe, Shinsuke

    2015-10-01

    A fish plasma model (FPM) has been proposed as a screening technique to prioritize potential hazardous pharmaceuticals to wild fish. However, this approach does not account for inter- or intraspecies variability of pharmacokinetic and pharmacodynamic parameters. The present study elucidated the uptake potency (from ambient water), tissue distribution, and biological risk of 20 pharmaceutical and personal care product (PPCP) residues in wild cyprinoid fish inhabiting treated-wastewater-impacted streams. In order to clarify the uncertainty of the FPM for PPCPs, we compared the plasma bioaccumulation factor in the field (BAFplasma = measured fish plasma/ambient water concentration ratio) with the predicted plasma bioconcentration factor (BCFplasma = fish plasma predicted by use of theoretical partition coefficients/ambient water concentration ratio) in the actual environment. As a result, the measured maximum BAFplasma of inflammatory agents was up to 17 times higher than theoretical BCFplasma values, leading to possible underestimation of toxicological risk on wild fish. When the tissue-blood partition coefficients (tissue/blood concentration ratios) of PPCPs were estimated, higher transportability into tissues, especially the brain, was found for psychotropic agents, but brain/plasma ratios widely varied among individual fish (up to 28-fold). In the present study, we provide a valuable data set on the intraspecies variability of PPCP pharmacokinetics, and our results emphasize the importance of determining PPCP concentrations in possible target organs as well as in the blood to assess the risk of PPCPs on wild fish. PMID:26348835

  15. Distribution of UDPglucuronosyltransferase in rat tissue.

    PubMed Central

    Chowdhury, J R; Novikoff, P M; Chowdhury, N R; Novikoff, A B

    1985-01-01

    UDPglucuronosyltransferase [UDPglucuronate beta-D-glucuronosyltransferase (acceptor-unspecific), EC 2.4.1.17] is a group of enzymes with distinct but partially overlapping substrate specificity. A rabbit antiserum raised against one purified rat liver UDPglycuronosyltransferase isoform was specific for UDPglucuronosyltransferase and recognized all transferase isoforms by immunodiffusion or immunotransblot analysis. The transferase activity toward all substrates was immunoabsorbed from solubilized rat liver microsomes by IgG purified from the antiserum. The purified IgG was used for immunocytochemical localization of UDP-glucuronosyltransferase in rat liver, jejunum, kidney, and adrenal gland. In the liver, UDPglucuronosyltransferase was present exclusively in hepatocytes and was uniformly distributed within all zones of the hepatic lobule. In the jejunum, the transferase was present exclusively in the epithelial cells and showed a progressive increase in concentration from the crypt to the villar tip. In the kidney, the greatest concentration of the transferase was observed in the epithelial cells of the proximal convoluted tubule. Adrenal medullary cells showed intense immunocytochemical staining; the zona glomerulosa and the zona reticularis of the adrenal cortex were more intensely stained than the zona fasciculata. By light microscopy, UDPglucuronosyltransferase was found in the endoplasmic reticulum and nuclear envelope of all the four organs; this was confirmed in the hepatocyte by electron microscopy. The transferase was not observed in mitochondria, Golgi apparatus, lysosomes, peroxisomes, and plasma membrane, even after 3- to 4-fold induction of various substrate-specific UDPglucuronosyltransferase activities. Images PMID:3921970

  16. Distribution of miRNA expression across human tissues.

    PubMed

    Ludwig, Nicole; Leidinger, Petra; Becker, Kurt; Backes, Christina; Fehlmann, Tobias; Pallasch, Christian; Rheinheimer, Steffi; Meder, Benjamin; Stähler, Cord; Meese, Eckart; Keller, Andreas

    2016-05-01

    We present a human miRNA tissue atlas by determining the abundance of 1997 miRNAs in 61 tissue biopsies of different organs from two individuals collected post-mortem. One thousand three hundred sixty-four miRNAs were discovered in at least one tissue, 143 were present in each tissue. To define the distribution of miRNAs, we utilized a tissue specificity index (TSI). The majority of miRNAs (82.9%) fell in a middle TSI range i.e. were neither specific for single tissues (TSI > 0.85) nor housekeeping miRNAs (TSI < 0.5). Nonetheless, we observed many different miRNAs and miRNA families that were predominantly expressed in certain tissues. Clustering of miRNA abundances revealed that tissues like several areas of the brain clustered together. Considering -3p and -5p mature forms we observed miR-150 with different tissue specificity. Analysis of additional lung and prostate biopsies indicated that inter-organism variability was significantly lower than inter-organ variability. Tissue-specific differences between the miRNA patterns appeared not to be significantly altered by storage as shown for heart and lung tissue. MiRNAs TSI values of human tissues were significantly (P = 10(-8)) correlated with those of rats; miRNAs that were highly abundant in certain human tissues were likewise abundant in according rat tissues. We implemented a web-based repository enabling scientists to access and browse the data (https://ccb-web.cs.uni-saarland.de/tissueatlas). PMID:26921406

  17. Distribution of miRNA expression across human tissues

    PubMed Central

    Ludwig, Nicole; Leidinger, Petra; Becker, Kurt; Backes, Christina; Fehlmann, Tobias; Pallasch, Christian; Rheinheimer, Steffi; Meder, Benjamin; Stähler, Cord; Meese, Eckart; Keller, Andreas

    2016-01-01

    We present a human miRNA tissue atlas by determining the abundance of 1997 miRNAs in 61 tissue biopsies of different organs from two individuals collected post-mortem. One thousand three hundred sixty-four miRNAs were discovered in at least one tissue, 143 were present in each tissue. To define the distribution of miRNAs, we utilized a tissue specificity index (TSI). The majority of miRNAs (82.9%) fell in a middle TSI range i.e. were neither specific for single tissues (TSI > 0.85) nor housekeeping miRNAs (TSI < 0.5). Nonetheless, we observed many different miRNAs and miRNA families that were predominantly expressed in certain tissues. Clustering of miRNA abundances revealed that tissues like several areas of the brain clustered together. Considering -3p and -5p mature forms we observed miR-150 with different tissue specificity. Analysis of additional lung and prostate biopsies indicated that inter-organism variability was significantly lower than inter-organ variability. Tissue-specific differences between the miRNA patterns appeared not to be significantly altered by storage as shown for heart and lung tissue. MiRNAs TSI values of human tissues were significantly (P = 10−8) correlated with those of rats; miRNAs that were highly abundant in certain human tissues were likewise abundant in according rat tissues. We implemented a web-based repository enabling scientists to access and browse the data (https://ccb-web.cs.uni-saarland.de/tissueatlas). PMID:26921406

  18. [Plasma- and tissue concentrations following intramuscular administration of etofenamat. Pharmacokinetics of etofenamat and flufenamic acid in plasma, synovium, and tissues of patients with chronic polyarthritis after administration of an oily solution of etofenamat].

    PubMed

    Köhler, G; Tressel, W; Dell, H D; Doersing, M; Fischer, W; Kamp, R; Langer, M; Richter, B; Wirzbach, E

    1992-12-01

    Studies on Plasma and Tissue Concentrations of Etofenamate following Intramuscular Application/Pharmacokinetics of etofenamate and flutenamic acid in plasma, synovia and tissues of patients with chronic polyarthritis after application of oily etofenamat solution Pharmacokinetics of etofenamate (ETO, CAS 30544-47-9; Rheumon i.m.) and flufenamic acid (FLU, CAS 530-78-9) were investigated in plasma, synovial fluid, and tissues after single intramuscular application of etofenamate to patients with rheumatoid arthritis. 62 patients with indicated operative procedure in the knee-joint received a single dose of etofenamate dissolved in oil before operation. At definite times between 1.5 and 48 h post injectionem samples from 6 patients of each time group were collected. Samples of plasma, synovial fluid, synovial membrane, muscle, bone, hyaline cartilage, and fat tissue and in some cases meniscus cartilage were taken. Concentrations of ETO and its active metabolite, FLU, were determined by HPTLC. In all tissues investigated, concentration/time courses of ETO and FLU were observed. ETO and FLU were measured first in all matrices 1.5 h at the latest 3 h post injectionem. Pharmacokinetics in tissues follows that in plasma. Rate-limiting step is the liberation of drug from the oil depot. For a long period pharmacokinetics of ETO and FLU is mainly determined by the constant liberation from the oil depot (zero order kinetics of liberation). Zero order kinetics is deduced from the linear ascent of the cumulated AUC (in percent) vs. time plot. It is directly related to the liberation of drug from the galenical formulation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1288513

  19. Pharmacokinetic study of arctigenin in rat plasma and organ tissue by RP-HPLC method.

    PubMed

    He, Fan; Dou, De-Qiang; Hou, Qiang; Sun, Yu; Kang, Ting-Guo

    2013-01-01

    A high-performance liquid chromatography (HPLC) technique was developed for the determination of arctigenin in plasma and various organs of rats after the oral administration of 30, 50 and 70 mgkg(-1) of arctigenin to the Sprague-Dawley rats. Results showed that the validated HPLC method was simple, fast, reproducible and suitable to the determination of arctigenin in rat plasma and organ tissue and one-compartmental model with zero-order absorption process can well describe the changes of arctigenin concentration in the plasma. The concentration of compound was highest in the spleen, less in the liver and the least in the lung. PMID:22404522

  20. Distribution and pharmacokinetics of double-radiolabeled endotoxin in the rat brain and peripheral organs.

    PubMed

    Kim, Chung S; Ross, Ivan A; Sapienza, Philip P; Hanes, Darcy E; Johnson, Widmark; Hutter, Joseph C

    2014-06-01

    The endotoxin, lipopolysaccharide (LPS), of Salmonella typhimurium was biosynthetically labeled with (3)H and (14)C incorporated into the fatty acyl chains and glucosamine residues, respectively. The radio-labeled LPS was isolated from the bacteria and then injected into Sprague-Dawley rats. The distribution of (14)C and (3)H-LPS in plasma and other organs was determined following intraperitoneal (IP) doses of (14)C and (3)H-LPS (200 μg/kg). Plasma concentrations of both fatty acyl chains and glucosamine residues were biphasic, with a relatively rapid decay followed by a slow decline for 48 h. Similar biphasic results were found in the peripheral organs (kidney and heart) and brain barrier tissues (meninges and choroid plexus). In other brain tissues (brain stem, caudate nucleus, hypothalamus, frontal cortex, cerebellum and hippocampus), the glucosamine residue was biphasic, whereas the fatty acyl chains showed accumulation. Highest concentrations of LPS were found in the plasma, spleen and the liver. In addition, in the liver, sustained elevations of (14)C-glucosamine and (3)H-fatty acyl chains were observed. This indicates LPS accumulation in the liver. By contrast, the spleen showed biphasic decay of glucosamine residues and accumulation of fatty acyl chains. In the brain barrier tissues, peak LPS concentrations were significantly reduced (about 70%) and were further reduced (about 95%) in other brain tissues. The high elevation of LPS in the spleen is considered indicative of an immune response. Our findings highlight the potential significant role of lipid A as shown with the sustained elevation of (3)H-fatty acyl chains in the brain. PMID:22933553

  1. Modeling Pharmacokinetics.

    PubMed

    Bois, Frederic Y; Brochot, Céline

    2016-01-01

    Pharmacokinetics is the study of the fate of xenobiotics in a living organism. Physiologically based pharmacokinetic (PBPK) models provide realistic descriptions of xenobiotics' absorption, distribution, metabolism, and excretion processes. They model the body as a set of homogeneous compartments representing organs, and their parameters refer to anatomical, physiological, biochemical, and physicochemical entities. They offer a quantitative mechanistic framework to understand and simulate the time-course of the concentration of a substance in various organs and body fluids. These models are well suited for performing extrapolations inherent to toxicology and pharmacology (e.g., between species or doses) and for integrating data obtained from various sources (e.g., in vitro or in vivo experiments, structure-activity models). In this chapter, we describe the practical development and basic use of a PBPK model from model building to model simulations, through implementation with an easily accessible free software. PMID:27311461

  2. Effects of tissue resistivities on electroencephalogram sensitivity distribution.

    PubMed

    Laarne, P; Kauppinen, P; Hyttinen, J; Malmivuo, J; Eskola, H

    1999-09-01

    The effects of tissue resistivities on EEG amplitudes were studied using an anatomically accurate computer model based on the finite difference method (FDM) and lead field analysis covering the whole brain area with 180,000 nodes. Five tissue types and three lead fields were considered for analysis. The changes in sensitivity distribution are directly comparable to changes in the potential distribution on the scalp. The results indicate that a 10% decrease in any tissue resistivity caused 3.0-4.1% differences in the sensitivity distributions of the selected EEG leads. The applied 10% decrease in the resistivity values covers only a fraction of the range of variation of 50% to 100% reported in the literature. The use of a 55% decreased skull resistivity value or a commonly applied three-compartment model increased the differences to 28% and 33%, respectively. In conclusion, both a realistic anatomy and accurate resistivity data are important in EEG head models. PMID:10723891

  3. Cold exposure induces alterations in porcine triiodothyronine tissue distribution

    SciTech Connect

    Quesada, M.H.; Reed, H.L.; Hesslink, R.; Licauco, G.; Castro, S.; Homer, L.; Young, B. Univ. of Alberta, Edmonton )

    1991-03-11

    Evidence suggests that thyroid hormone plays an active role in modulation of tissue metabolism in response to cold challenge. In an attempts to identify tissues that may have increased capacity for triiodothyronine (T{sub 3}) and be actively involved in the thermogenic process, the authors investigated the T{sub 3} tissue distribution in 5 month old swine exposed to cold (4C) (N = 5) for three weeks, compared with controls at a thermoneutral temperature (20C) (N = 4). Both groups were injected I.V. with ({sup 125}I)T{sub 3} three hours before sacrifice. ({sup 125}I)T{sub 3} was organically extracted from heart, kidney, thyroid gland, adrenal, brain, 4 different types of striated muscles and fat tissues and counted to determine the CPM/gm of tissue. Serum total T{sub 3} and free T{sub 3} were elevated. The bulk of the tissue/serum ratios of cold exposed swine compared with controls were unchanged. However, calculation of the T{sub 3} organ pools revealed that the majority was elevated 2 to 3 times over control. Increases in tissue distribution volume (TVD) occurred in hip fat. Body and organ weights tended to increase but not to a significant degree except for the thyroid gland, which increased 66% over the average control value. The physiological significance of the cold associated augmented organ pool and the increased TCD in hip fat needs to be explored.

  4. 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.

  5. Sialic acid tissue distribution and influenza virus tropism

    PubMed Central

    Kumlin, Urban; Olofsson, Sigvard; Dimock, Ken; Arnberg, Niklas

    2008-01-01

    Abstract  Avian influenza A viruses exhibit a strong preference for using α2,3‐linked sialic acid as a receptor. Until recently, the presumed lack of this receptor in human airways was believed to constitute an efficient barrier to avian influenza A virus infection of humans. Recent zoonotic outbreaks of avian influenza A virus have triggered researchers to analyse tissue distribution of sialic acid in further detail. Here, we review and extend the current knowledge about sialic acid distribution in human tissues, and discuss viruses with ocular tropism and their preference for α2,3‐linked sialic acid. PMID:19453419

  6. Quantitative profiling of tissue drug distribution by MS imaging.

    PubMed

    Pirman, David

    2015-01-01

    This article highlights recent advancements in the quantitative measurement of drug distribution by MS imaging (MSI). Quantitation by MSI was recently considering the primary disadvantage of MSI approaches particularly when compared with widely used autoradiography techniques. These approaches show significant progress in the area of quantitative MSI and have been used in numerous drug and metabolite distribution measurements. As quantitative limitations are overcome, the use of MSI in drug development should increase significantly providing key insights into both tissue-target validation as well as identifying off tissue-target issues with drug delivery. PMID:26495807

  7. Pharmacodynamics, tissue distribution, toxicity studies and antitumor efficacy of the vascular targeting fusion toxin VEGF121/rGel.

    PubMed

    Mohamedali, Khalid A; Niu, Gang; Luster, Troy A; Thorpe, Philip E; Gao, Haokao; Chen, Xiaoyuan; Rosenblum, Michael G

    2012-12-01

    As a part of an ongoing assessment of its mechanism of action, we evaluated the in vivo pharmacokinetics, tissue distribution, toxicity and antitumor efficacy of VEGF(121)/rGel, a novel fusion protein. Pharmacokinetic studies showed that VEGF(121)/rGel cleared from the circulation in a biphasic manner with calculated half-lives of 0.3 and 6h for the alpha and beta phases, respectively. Pharmacokinetic evaluation of (64)Cu-DOTA-VEGF(121)/rGel showed relatively high blood retention 30 min after injection (26.6 ± 1.73% ID/g), dropping to 11.8 ± 2.83% and 0.82 ± 0.11% ID/g at 60 and 240 min post injection, respectively. Tissue uptake studies showed that kidneys, liver and tumor had the highest drug concentrations 48 h after administration. The maximum tolerated dose (MTD), based on a QOD×5 i.v. administration schedule, was found to be 18 mg/kg with an LD(50) of 25mg/kg. Treatment of BALB/c mice with VEGF(121)/rGel at doses up to the MTD caused no alterations in hematologic parameters. However, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) parameters increased in a dose-related manner. The no-observable-adverse-effect-level (NOAEL) was determined to be 20% of the MTD (3.6 mg/kg). VEGF(121)/rGel treatment of mice bearing orthotopically-placed MDA-MB-231 breast tumors caused increased vascular permeability of tumor tissue by 53% compared to saline-treated controls. Immunohistochemical analysis showed significant tumor hypoxia and necrosis as a consequence of vascular damage. In summary, VEGF(121)/rGel appears to be an effective therapeutic agent causing focused damage to tumor vasculature with minimal toxic effects to normal organs. This agent appears to be an excellent candidate for further clinical development. PMID:23022224

  8. Liquid chromatography-electrospray tandem mass spectrometric method for quantification of monensin in plasma and edible tissues of chicken used in pharmacokinetic studies: applying a total error approach.

    PubMed

    Chéneau, Estelle; Henri, Jérôme; Pirotais, Yvette; Abjean, Jean-Pierre; Roudaut, Brigitte; Sanders, Pascal; Laurentie, Michel

    2007-05-01

    A liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for use in pharmacokinetic studies in order to determine the concentrations of monensin in plasma and edible tissues of chicken. Two sample preparations were performed, one for determining monensin concentrations in plasma using acetonitrile for protein precipitation and another one for determining monensin concentrations in muscle, liver, and fat using methanol-water followed by a clean up on a solid-phase extraction cartridge. Sample extracts were injected into the LC-MS/MS system, and a gradient elution was performed on a C18 column. Narasin was used as internal standard. The LC-MS/MS method was validated using an approach based on accuracy profiles, and applicability of the method was demonstrated for the determination of monensin in chicken plasma, muscle, liver, and fat in a pharmacokinetic study. PMID:17141581

  9. Development and validation of an UPLC-MS/MS method for the quantification of ethoxzolamide in plasma and bioequivalent buffers: Applications to absorption, brain distribution, and pharmacokinetic studies

    PubMed Central

    Gao, Song; Zhao, Jing; Yin, Taijun; Ma, Yong; Xu, Beibei; Moore, Anthony N.; Dash, Pramod K.; Hu, Ming

    2015-01-01

    The purpose of this study is to develop and validate an UPLC-MS/MS method to quantify ethoxzolamide in plasma (EZ) and apply the method to absorption, brain distribution, as well as pharmacokinetic studies. A C18 column was used with 0.1% of formic acid in acetonitrile and 0.1% of formic acid in water as the mobile phases to resolve EZ. The mass analysis was performed in a triple quadrupole mass spectrometer using multiple reaction monitoring (MRM) with positive scan mode. The results show that the linear range of EZ is 4.88–10,000.00 nM. The intra-day variance is less than 12.43 % and the accuracy is between 88.88–08.00 %. The inter-day variance is less than 12.87 % and accuracy is between 89.27–115.89 %. Protein precipitation was performed using methanol to extract EZ from plasma and brain tissues. Only 40 µL of plasma is needed for analysis due to the high sensitivity of this method, which could be completed in less than three minutes. This method was used to study the pharmacokinetics of EZ in SD rats, and the transport of EZ in Caco-2 and MDCK-MDR1 overexpressing cell culture models. Our data show that EZ is not a substrate for p-glycoprotein (P-gp) and its entry into the brain may not limited by the blood-brain barrier. PMID:25706567

  10. 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). PMID:27310088

  11. Tissue distribution of human acetylcholinesterase and butyrylcholinesterase messenger RNA

    SciTech Connect

    Jbilo, O.; Barteles, C.F.; Chatonnet, A.; Toutant, J.P.; Lockridge, O.

    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 butyrylcholinesterase may be a first line of defense against poisons that are eaten or inhaled.

  12. Pharmacokinetics and endometrial tissue concentrations of enrofloxacin and the metabolite ciprofloxacin after i.v. administration of enrofloxacin to mares.

    PubMed

    Papich, M G; Van Camp, S D; Cole, J A; Whitacre, M D

    2002-10-01

    Enrofloxacin was administered i.v. to five adult mares at a dose of 5 mg/kg. After administration, blood and endometrial biopsy samples were collected at regular intervals for 24 h. The plasma and tissue samples were analyzed for enrofloxacin and the metabolite ciprofloxacin by high-pressure liquid chromatography. In plasma, enrofloxacin had a terminal half-life (t(1/2)), volume of distribution (area method), and systemic clearance of 6.7 +/- 2.9 h, 1.9 +/- 0.4 L/kg, and 3.7 +/- 1.4 mL/kg/min, respectively. Ciprofloxacin had a maximum plasma concentration (Cmax) of 0.28 +/- 0.09 microg/mL. In endometrial tissue, the enrofloxacin Cmax was 1.7 +/- 0.5 microg/g, and the t(1/2) was 7.8 +/- 3.7 h. Ciprofloxacin Cmax in tissues was 0.15 +/- 0.04 microg/g and the t(1/2) was 5.2 +/- 2.0 h. The tissue:plasma enrofloxacin concentration ratios (w/w:w/v) were 0.175 +/- 0.08 and 0.47 +/- 0.06 for Cmax and AUC, respectively. For ciprofloxacin, these values were 0.55 +/- 0.13 and 0.58 +/- 0.31, respectively. We concluded that plasma concentrations achieved after 5 mg/kg i.v. are high enough to meet surrogate markers for antibacterial activity (Cmax:MIC ratio, and AUC:MIC ratio) considered effective for most susceptible gram-negative bacteria. Endometrial tissue concentrations taken from the mares after dosing showed that enrofloxacin and ciprofloxacin both penetrate this tissue adequately after systemic administration and would attain concentrations high enough in the tissue fluids to treat infections of the endometrium caused by susceptible bacteria. PMID:12423224

  13. Physiologically based pharmacokinetic modeling to investigate regional brain distribution kinetics in rats.

    PubMed

    Westerhout, Joost; Ploeger, Bart; Smeets, Jean; Danhof, Meindert; de Lange, Elizabeth C M

    2012-09-01

    One of the major challenges in the development of central nervous system (CNS)-targeted drugs is predicting CNS exposure in human from preclinical data. In this study, we present a methodology to investigate brain disposition in rats using a physiologically based modeling approach aiming at improving the prediction of human brain exposure. We specifically focused on quantifying regional diffusion and fluid flow processes within the brain. Acetaminophen was used as a test compound as it is not subjected to active transport processes. Microdialysis probes were implanted in striatum, for sampling brain extracellular fluid (ECF) concentrations, and in lateral ventricle (LV) and cisterna magna (CM), for sampling cerebrospinal fluid (CSF) concentrations. Serial blood samples were taken in parallel. These data, in addition to physiological parameters from literature, were used to develop a physiologically based model to describe the regional brain pharmacokinetics of acetaminophen. The concentration-time profiles of brain ECF, CSF(LV), and CSF(CM) indicate a rapid equilibrium with plasma. However, brain ECF concentrations are on average fourfold higher than CSF concentrations, with average brain-to-plasma AUC(0-240) ratios of 121%, 28%, and 35% for brain ECF, CSF(LV), and CSF(CM), respectively. It is concluded that for acetaminophen, a model compound for passive transport into, within, and out of the brain, differences exist between the brain ECF and the CSF pharmacokinetics. The physiologically based pharmacokinetic modeling approach is important, as it allowed the prediction of human brain ECF exposure on the basis of human CSF concentrations. PMID:22588644

  14. Tissue temperature distribution measurement and laser immunotherapy for cancer treatment

    NASA Astrophysics Data System (ADS)

    Chen, Yichao; Gyanwalib, Surya; Bjorlie, Jeremy; Andrienko, Kirill; Liu, Hong; Tesiram, Yasvir A.; Abbott, Andrew; Towner, Rheal A.; Chen, Wei R.

    2006-02-01

    Temperature distribution in tissue can be a crucial factor in laser treatment for inducing immunization responses. In this study, Magnetic Resonance Imaging (MRI) was used to measure thermal temperature distribution in target tissue in laser treatment of metastatic tumors. It is the only feasible method for in vivo, non-invasive temperature distribution measurement. The measurement was conducted using phantom gel and tumor-bearing rats. The thermal couple measurement of target temperature was also was used to calibrate the relative temperature increase. The phantom system was constructed with a dye-enhanced spherical gel embedded in uniform gel phantom, simulating a tumor within normal tissue. Irradiation by an 805-nm laser increased the system temperature. Using an MRI system and proper algorithm processing for small animal studies, a clear temperature distribution matrix was obtained. The temperature profiles of rat tumors, irradiated by the laser with a power in the range of 2-3.5W and injected with a light-absorbing dye, ICG, and an immunoadjuvant, GC, were obtained. The temperature distribution provided in vivo thermal information and future reference for optimizing dye concentration and irradiation parameters to reach the optimum tumor destruction and immunization effects.

  15. Effect of convective term on temperature distribution in biological tissue

    NASA Astrophysics Data System (ADS)

    Kengne, Emmanuel; Saydé, Michel; Lakhssassi, Ahmed

    2013-08-01

    We introduce a phase imprint into the order parameter describing the influence of blood flow on the temperature distribution in the tissue described by the one-dimensional Pennes equation and then engineer the imprinted phase suitably to generate a modified Pennes equation with a gradient term (known in the theory of biological systems as convective term) which is associated with the heat convected by the flowing blood. Using the derived model, we analytically investigate temperature distribution in biological tissues subject to two different spatial heating methods. The applicability of our results is illustrated by one of typical bio-heat transfer problems which is often encountered in therapeutic treatment, cancer hyperthermia, laser surgery, thermal injury evaluation, etc. Analyzing the effect of the convective term on temperature distribution, we found that an optimum heating of a biological system can be obtained through regulating the convective term.

  16. Route-dependent pharmacokinetics, distribution, and placental permeability of organic and inorganic selenium in hamsters.

    PubMed

    Willhite, C C; Ferm, V H; Zeise, L

    1990-10-01

    Inorganic selenium (Se) salts (selenite and selenate oxyanions) and the organic selenoamino acids (selenomethionine and seleniferous grains) are teratogenic and embryolethal in domestic and wild birds. Selenium bioaccumulation has been held responsible for reproductive failure among waterfowl at the Kesterson Reservoir (California), the Ouray and Stewart Lake Wildlife Refuges (Utah), and the Carson Sink (Nevada). Anecdotal field and controlled laboratory reports have implicated Se exposure in mammalian embryotoxicity (including human), but developmental toxicity studies in hamsters failed to demonstrate an adverse response, except at maternally toxic doses (Ferm et al., Reprod. Toxicol., in press). Uptake, distribution, and elimination of Se after a single bolus equimolar dose (60 mumol/kg) of selenate or selenomethionine by oral or intravenous administration were compared using day 8 pregnant hamsters. Intravenous selenate was eliminated ten times more rapidly from maternal plasma than oral selenate, but concentrated in liver, kidney, and placenta to the same degree. Intravenous (iv) L-selenomethionine achieved lower maximum circulating total [Se], but it was eliminated more slowly than iv selenate. Larger areas under the plasma and peripheral tissue [Se]:time curve (AUC) after oral or parenteral selenomethionine than after equimolar selenate were consistent with previous studies in rodents and in humans. Embryonic [Se] plateaued at 3 nmol/g after selenate, but embryonic [Se] after selenomethionine continued to accumulate (80 nmol/g) as gestation progressed. The lack of a teratogenic response in hamsters at doses of either selenate or selenomethionine less than those associated with maternal intoxication cannot be attributed to lack of Se accumulation in early embryonic and placental tissue. PMID:2256000

  17. 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.

  18. Pharmacokinetics of verapamil in lactating rabbits. Prediction of verapamil distribution into rabbit milk.

    PubMed

    Solans, C; Aramayona, J J; Bregante, M A; Fraile, L J; Rueda, S; Garcia, M A

    2000-04-01

    In this work, we have studied the pharmacokinetics and milk penetration of verapamil following intravenous administration in lactating rabbits. Milk-to-serum drug concentration ratios (M/B(obs)) have been determined using area under the milk and serum concentration-time profiles, and the resulting values have then been compared with those obtained by theoretical classical diffusion milk transfer models that were described by Fleishaker et al. [J. Pharm. Sci. 76 (1987) 189.], Atkinson and Begg [Br. J. Clin. Pharmacol. 25 (1990) 495.], and Stebler and Guentert [Pharm. Res. 9 (1992) 1299.]. The pharmacokinetic profile of verapamil in lactating rabbits following endovenous administration is described in the form of a two-compartment model. Moreover, we detected an important milk transfer after endovenous administration of verapamil in lactating rabbits. M/B(obs) was near 15. The classical diffusional models mentioned were not able to predict this extensive transfer of verapamil into rabbit milk. However, when the classical Fleishaker equation was modified and a stepwise regression was carried out, we found that the M/B(obs) value could be predicted using the plasma and milk protein binding. PMID:11282217

  19. Tissue distribution, disposition, and metabolism of cyclosporine in rats

    SciTech Connect

    Wagner, O.; Schreier, E.; Heitz, F.; Maurer, G.

    1987-05-01

    Tissue distribution, disposition, and metabolism of /sup 3/H-cyclosporine were studied in rats after single and repeated oral doses of 10 and 30 mg/kg and after an iv dose of 3 mg/kg. The oral doses of 10 and 30 mg/kg were dissolved in polyethylene glycol 200/ethanol or in olive oil/Labrafil/ethanol. Absorption from both formulations was slow and incomplete, with peak /sup 3/H blood levels at 3-4 hr. Approximately 30% of the radioactive dose was absorbed, which is consistent with oral bioavailability data for cyclosporine. More than 70% of the radioactivity was excreted in feces and up to 15% in urine. Elimination via the bile accounted for 10 and 60% of the oral and iv doses, respectively. Since unchanged cyclosporine predominated in both blood and tissues at early time points, the half-lives of the distribution phases (t 1/2 alpha) of parent drug and of total radioactivity were similar. In blood, kidney, liver, and lymph nodes, t 1/2 alpha of cyclosporine ranged from 6-10 hr. Elimination of radioactivity from the systemic circulation was multiphasic, with a terminal half-life of 20-30 hr. /sup 3/H-Cyclosporine was extensively distributed throughout the body, with highest concentrations in liver, kidney, endocrine glands, and adipose tissue. The concentrations of both total radioactivity and parent drug were greater in tissues than in blood, which is consistent with the high lipid solubility of cyclosporine and some of its metabolites. Skin and adipose tissue were the main storage sites for unchanged cyclosporine. Elimination half-lives were slower for most tissues than for blood and increased with multiple dosing. The amount of unchanged drug was negligible in urine and bile.

  20. Tissue distribution of subcutaneously administered aluminum chloride in weanling rabbits

    SciTech Connect

    Du Val, G.; Grubb, B.R.; Bentley, P.J.

    1986-01-01

    The purpose of the investigation was to determine blood and tissue levels of aluminum (Al) in normal young rabbits. Furthermore, tissue distribution and accumulation of Al were determined as related to blood concentration in Al-dosed rabbits. The levels of Al accumulated were determined in different tissues of growing rabbits after continuous subcutaneous administration of Al chloride (3.78 mg/d) for 28 d. No signs of toxicity were apparent from comparisons of hematocrit or weight gain between control and Al-dosed rabbits. The largest concentration of the Al was observed in bone, which was also found to have the highest levels in the control rabbit tissues. Following bone, the experimental animals showed the greatest increase of Al levels in kidney cortex, kidney medulla, liver, testes, skeletal muscle, heart, brain white matter, and brain hippocampus, in that order. No significant difference was found in brain grey matter between control and experimental animals. As the brain tissue of the Al-treated animals had the lowest Al level of the tissues measured, it appears that there is a partial blood-brain barrier to entry of Al.

  1. Continuous versus Short-Term Infusion of Cefuroxime: Assessment of Concept Based on Plasma, Subcutaneous Tissue, and Bone Pharmacokinetics in an Animal Model

    PubMed Central

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

    2014-01-01

    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. PMID:25313214

  2. Tissue Distribution and Gender-Divergent Expression of 78 Cytochrome P450 mRNAs in Mice

    PubMed Central

    Renaud, Helen J.; Cui, Julia Yue; Khan, Mohammed; Klaassen, Curtis D.

    2011-01-01

    Cytochrome P450 (Cyp) enzymes from the first four families (Cyp1–4) play a major role in metabolizing xenobiotics, affecting drug pharmacokinetics and chemical-induced toxicity. Due to cloning of the mouse genome, many novel Cyp isoforms have been identified, but their tissue distribution of expression is unknown. This study compared the tissue distribution of all 78 Cyps from the Cyp1–4 families in C57BL/6 mice providing not only an indication of which tissues novel Cyps may have their greatest importance but also a cohesive comparison of the tissue distribution of all Cyp1–4 isoforms. Transcripts of the 78 Cyps were quantified by multiplex suspension arrays and quantitative real-time PCR in 14 tissues. Hierarchical clustering indicated that in male mice, 52% of the Cyp species were expressed highest in liver, 10% in kidney, 10% in duodenum/jejunum, 10% in testes, 5% in lung, and < 4% in colon, brain, heart, and stomach. Female mice had a similar pattern of Cyp messenger RNA expression; however, compared with males, females had 7% more Cyps that were liver predominant, 2% more Cyps that were stomach predominant, but 1% less Cyps that were kidney and lung predominant. Differences in gender expression were observed in 29 of the Cyps, with 24 being higher in females than males. Additionally, the data suggest a correlation between the spatial arrangement of genes within a gene cluster and their organ-predominant expression, indicating a common regulatory mechanism may be present within these clusters. In conclusion, this study provides novel data on the tissue distribution and gender-divergent expression of 78 functional mouse Cyp isoforms. PMID:21920951

  3. 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.

  4. Tissue distribution of autoantigen specific for primary sclerosing cholangitis.

    PubMed Central

    Lo, S K; Chapman, R W; Fleming, K A

    1993-01-01

    AIM: To investigate the tissue distribution of the autoantigen specific for primary sclerosing cholangitis. METHODS: A range of normal frozen tissues including nervous system, muscle, uterus, ovary, prostate, pancreas, thyroid, salivary gland, adrenal gland, colon, gall bladder, stomach, jejunum, aorta, skin, kidney, liver, spleen and thymus was sectioned, fixed with acetone, and air-dried. Normal bone marrow and HL60, K562, and U937 cells were cytocentrifuged on to slides, air-dried, and alcohol fixed. Four sera from primary sclerosing cholangitis with high titre antibody (> 1/100) were used to screen the tissues using either two-step or APAAP immunohistochemistry. Normal sera were used as controls. RESULTS: Positive signal was detected in neutrophils in spleen with three out of four primary sclerosing cholangitis sera while one out of four primary sclerosing cholangitis sera stained spindle cells in the liver. All four sera stained mature neutrophils of the normal bone marrow. Some bone marrow neutrophil precursors (metamyelocytes and myelocytes) were also positive. All other tissues, including HL60, K562, and U937 cells, were negative. Normal sera were negative on all tissues. CONCLUSION: Antigen specific for primary sclerosing cholangitis seems to be unique to neutrophil polymorphs and is present only after myeloblast differentiation of the myeloid cell line. The antigen may be within the secondary granule of the neutrophil polymorph. Images PMID:7681855

  5. A continuous fiber distribution material model for human cervical tissue.

    PubMed

    Myers, Kristin M; Hendon, Christine P; Gan, Yu; Yao, Wang; Yoshida, Kyoko; Fernandez, Michael; Vink, Joy; Wapner, Ronald J

    2015-06-25

    The uterine cervix during pregnancy is the vital mechanical barrier which resists compressive and tensile loads generated from a growing fetus. Premature cervical remodeling and softening is hypothesized to result in the shortening of the cervix, which is known to increase a woman׳s risk of preterm birth. To understand the role of cervical material properties in preventing preterm birth, we derive a cervical material model based on previous mechanical, biochemical and histological experiments conducted on nonpregnant and pregnant human hysterectomy cervical tissue samples. In this study we present a three-dimensional fiber composite model that captures the equilibrium material behavior of the tissue in tension and compression. Cervical tissue is modeled as a fibrous composite material, where a single family of preferentially aligned and continuously distributed collagen fibers are embedded in a compressible neo-Hookean ground substance. The total stress in the collagen solid network is calculated by integrating the fiber stresses. The shape of the fiber distribution is described by an ellipsoid where semi-principal axis lengths are fit to optical coherence tomography measurements. The composite material model is fit to averaged mechanical testing data from uni-axial compression and tension experiments, and averaged material parameters are reported for nonpregnant and term pregnant human cervical tissue. The model is then evaluated by investigating the stress and strain state of a uniform thick-walled cylinder under a compressive stress with collagen fibers preferentially aligned in the circumferential direction. This material modeling framework for the equilibrium behavior of human cervical tissue serves as a basis to determine the role of preferentially-aligned cervical collagen fibers in preventing cervical deformation during pregnancy. PMID:25817474

  6. Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling

    PubMed Central

    Moss, Darren Michael; Siccardi, Marco

    2014-01-01

    The delivery of therapeutic agents is characterized by numerous challenges including poor absorption, low penetration in target tissues and non-specific dissemination in organs, leading to toxicity or poor drug exposure. Several nanomedicine strategies have emerged as an advanced approach to enhance drug delivery and improve the treatment of several diseases. Numerous processes mediate the pharmacokinetics of nanoformulations, with the absorption, distribution, metabolism and elimination (ADME) being poorly understood and often differing substantially from traditional formulations. Understanding how nanoformulation composition and physicochemical properties influence drug distribution in the human body is of central importance when developing future treatment strategies. A helpful pharmacological tool to simulate the distribution of nanoformulations is represented by physiologically based pharmacokinetics (PBPK) modelling, which integrates system data describing a population of interest with drug/nanoparticle in vitro data through a mathematical description of ADME. The application of PBPK models for nanomedicine is in its infancy and characterized by several challenges. The integration of property–distribution relationships in PBPK models may benefit nanomedicine research, giving opportunities for innovative development of nanotechnologies. PBPK modelling has the potential to improve our understanding of the mechanisms underpinning nanoformulation disposition and allow for more rapid and accurate determination of their kinetics. This review provides an overview of the current knowledge of nanomedicine distribution and the use of PBPK modelling in the characterization of nanoformulations with optimal pharmacokinetics. Linked Articles This article is part of a themed section on Nanomedicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-17 PMID:24467481

  7. Pharmacokinetics and distribution of voriconazole in body fluids of dogs after repeated oral dosing.

    PubMed

    Lemetayer, J D; Dowling, P M; Taylor, S M; Papich, M G

    2015-10-01

    The goal of this project was to determine the pharmacokinetics of voriconazole and its concentration in cerebrospinal fluid (CSF), aqueous humor, and synovial fluid in five healthy dogs following once daily oral dose of 6 mg/kg for 2 weeks. Body fluid and plasma drug concentrations were determined by high-performance liquid chromatography (HPLC). Mild to moderate gastrointestinal adverse effects were seen. The mean AUC0-24 : minimum inhibitory concentration (MIC) ratio was 15.23 for a chosen MIC of 1 μg/mL, which is lower than the recommended target of 20-25 and also lower than previously reported in dogs, perhaps reflecting induction of metabolizing enzymes by multiple dosing. Voriconazole concentrations in the CSF, aqueous humor, and synovial fluid were only 13-30% the concurrent plasma concentration, which is lower than previously reported in other species. Results of this study suggest that twice daily, administration may be necessary to maintain therapeutic plasma concentrations in dogs but further studies are warranted. PMID:25691353

  8. Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: a bench-to-bedside case study on tissue selective drug distribution.

    PubMed

    Pfefferkorn, Jeffrey A; Litchfield, John; Hutchings, Richard; Cheng, Xue-Min; Larsen, Scott D; Auerbach, Bruce; Bush, Mark R; Lee, Chitase; Erasga, Noe; Bowles, Daniel M; Boyles, David C; Lu, Gina; Sekerke, Catherine; Askew, Valerie; Hanselman, Jeffrey C; Dillon, Lisa; Lin, Zhiwu; Robertson, Andrew; Olsen, Karl; Boustany, Carine; Atkinson, Karen; Goosen, Theunis C; Sahasrabudhe, Vaishali; Chupka, Jonathan; Duignan, David B; Feng, Bo; Scialis, Renato; Kimoto, Emi; Bi, Yi-An; Lai, Yurong; El-Kattan, Ayman; Bakker-Arkema, Rebecca; Barclay, Paul; Kindt, Erick; Le, Vu; Mandema, Jaap W; Milad, Mark; Tait, Bradley D; Kennedy, Robert; Trivedi, Bharat K; Kowala, Mark

    2011-05-01

    The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors. PMID:21183342

  9. Plasma pharmacokinetics and tissue and brain distribution of cisplatin in musk shrews

    PubMed Central

    Eiseman, Julie L.; Beumer, Jan H.; Rigatti, Lora H.; Strychor, Sandra; Meyers, Kelly; Dienel, Samuel; Horn, Charles C.

    2014-01-01

    Purpose Cisplatin induces nausea and emesis, even with antiemetic supportive care. To assess platinum exposure, which could activate nausea and emesis, we quantitated platinum in the brain and various organs, and hindbrain and spinal cord substance P, a key neuropeptide for the neuronal signaling of nausea and emesis. Methods Musk shrews, a model species for nausea and emesis research, were dosed intraperitoneally with 20 mg/kg cisplatin and euthanized at up to 72 h after injection. Concentrations of platinum were quantitated in plasma ultrafiltrate, plasma, lung, kidney, combined forebrain and midbrain, hindbrain, and spinal cord by flameless atomic absorption spectrometry. Hindbrains and spinal cords were analyzed for substance P by immunohistochemistry after injection of 20 or 30 mg/kg. Results Plasma ultrafilterable platinum concentrations decreased rapidly till 60 min after dosing and then more slowly by 24 h. The concentrations of total platinum in both the fore- and midbrain and the hindbrain were similar at all time points and were at least 20-fold lower than plasma total platinum concentrations. There were no significant changes in substance P immunoreactivity after cisplatin dosing. Histology revealed damage to the renal cortex by 72 h after injection of cisplatin. Conclusions This is the first study to examine platinum concentrations in musk shrews after administration of cisplatin, and delineate substance P immunohistochemical staining in the hindbrain and spinal cord of this species. The platinum concentrations detected in the brain could potentially contribute to the neurological side effects of cisplatin, such as nausea and emesis. PMID:25398697

  10. Microanalysis, Pharmacokinetics and Tissue Distribution of Polysaccharide-Protein Complexes from Longan Pulp in Mice

    PubMed Central

    Min, Ting; Sun, Jie; Yi, Yang; Wang, Hong-Xun; Hang, Fei; Ai, You-Wei; Wang, Li-Mei

    2015-01-01

    A high performance size exclusion-fluorescence detection (HPSEC-FD) method combined with fluorescein isothiocyanate (FITC) prelabeling was established for the microanalysis of polysaccharide–protein complexes from longan pulp (LPP). FITC-labeled LPP (LPPF) was fractionated by gel filtration chromatography. The weight-average molecular weight and FITC substitution degree of LPPF were 39.01 kDa and 0.20%, respectively. The HPSEC-FD calibration curves linear over the range of 1–200 µg/mL in mouse plasma, spleen and lung samples with correlation coefficients greater than 0.995. The inter-day and intra-day precisions of the method were not more than 6.9%, and the relative recovery ranged from 93.7% to 106.4%. The concentration–time curve of LPPF in plasma following intravenous (i.v.) administration at 40 mg/kg body weight well fitted to a two-compartment model. LPPF rapidly eliminated from plasma according to the short half-lives (t1/2α = 2.23 min, t1/2β = 39.11 min) and mean retention times (MRT0–t = 1.15 h, MRT0–∞ = 1.39 h). After administration over 5 to 360 min, the concentration of LPPF in spleen homogenate decreased from 7.41 to 3.68 µg/mL; the concentration in lung homogenate decreased from 9.08 to 3.40 µg/mL. On the other hand, the increasing concentration of LPPF fraction with low molecular weight in heart homogenate was observed. PMID:26501257

  11. Microanalysis, Pharmacokinetics and Tissue Distribution of Polysaccharide-Protein Complexes from Longan Pulp in Mice.

    PubMed

    Min, Ting; Sun, Jie; Yi, Yang; Wang, Hong-Xun; Hang, Fei; Ai, You-Wei; Wang, Li-Mei

    2015-01-01

    A high performance size exclusion-fluorescence detection (HPSEC-FD) method combined with fluorescein isothiocyanate (FITC) prelabeling was established for the microanalysis of polysaccharide-protein complexes from longan pulp (LPP). FITC-labeled LPP (LPPF) was fractionated by gel filtration chromatography. The weight-average molecular weight and FITC substitution degree of LPPF were 39.01 kDa and 0.20%, respectively. The HPSEC-FD calibration curves linear over the range of 1-200 µg/mL in mouse plasma, spleen and lung samples with correlation coefficients greater than 0.995. The inter-day and intra-day precisions of the method were not more than 6.9%, and the relative recovery ranged from 93.7% to 106.4%. The concentration-time curve of LPPF in plasma following intravenous (i.v.) administration at 40 mg/kg body weight well fitted to a two-compartment model. LPPF rapidly eliminated from plasma according to the short half-lives (t1/2α=2.23 min, t1/2β=39.11 min) and mean retention times (MRT0-t=1.15 h, MRT0-∞=1.39 h). After administration over 5 to 360 min, the concentration of LPPF in spleen homogenate decreased from 7.41 to 3.68 µg/mL; the concentration in lung homogenate decreased from 9.08 to 3.40 µg/mL. On the other hand, the increasing concentration of LPPF fraction with low molecular weight in heart homogenate was observed. PMID:26501257

  12. Carbaryl distribution in rabbit tissues and body fluids.

    PubMed

    Malvisi, J; Zaghini, A; Stracciari, G L

    1992-12-01

    After single po administration of 14C-naphthylcarbamate, liquid scintillation assays evaluated the distribution of carbaryl in rabbit serum, liver, kidneys, small and large intestine, spleen, heart, muscles of the thigh and lungs and its excretion in urine and feces at 2, 4, 6 and 8 h after dosing. At 2 and 8 h radioactivity was not observed in spleen, heart, muscle and lungs, while all other tissues had increased values up to 6 h. The main excretory pathway of carbaryl was the kidneys. PMID:1287968

  13. 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. PMID:27125257

  14. Azithromycin pharmacokinetics in the serum and its distribution to the skin in healthy dogs and dogs with pyoderma.

    PubMed

    Zur, Gila; Soback, Stefan; Weiss, Yfat; Perry, Elad; Lavy, Eran; Britzi, Malka

    2014-04-01

    Serum and skin tissue azithromycin (AZM) concentrations were analysed in healthy and pyoderma affected dogs to determine AZM pharmacokinetics and to establish the effect of disease on AZM skin disposition. AZM was administered orally to two groups of healthy dogs: (1) at 7.02 mg/kg (n=7) and (2) at 11.2mg/kg (n=9). A crossover design was used on five of them. Seven dogs with pyoderma were treated with AZM at 10.7 mg/kg. The two groups of healthy dogs received AZM once daily over three consecutive days and dogs with pyoderma received the same treatment repeated twice with an interval of 1 week. AZM concentrations were determined by liquid chromatography-tandem mass spectrometry. AZM was rapidly absorbed and slowly excreted. In healthy dogs, maximum serum concentrations appeared 2h after administration and were (mean ± standard deviation) 0.60 ± 0.25 μg/mL and 1.03 ± 0.43 μg/mL, and the half-lives were 49.9 ± 5.10 and 51.9 ± 6.69 h for doses of 7.02 and 11.2mg/kg, respectively. Clearance (CL0-24/F) was similar in both dosing groups (1.24 ± 0.24 and 1.29 ± 0.24 L/h/kg) and the respective mean residence time (MRT0-24) was 11.1 ± 0.8 and 8.4 ± 2.2h. The skin concentration in healthy dogs was 3.5-6.5 and 5.0-12.0 times higher than the corresponding serum concentration after the two doses and increased after the cessation of AZM administration. The ratio increased significantly in inflamed tissue (9.5-26.2). PMID:24472431

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

    SciTech Connect

    Lehmann, Joerg; O'Donnell, Robert T.; Richman, Carol M. . E-mail: sjdenardo@ucdavis.edu

    2006-11-15

    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 each 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.

  16. 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.

  17. Compartmental Targeting for mTHPC-Based Photodynamic Treatment In Vivo: Correlation of Efficiency, Pharmacokinetics, and Regional Distribution of Apoptosis

    SciTech Connect

    Garrier, Julie; Bressenot, Aude; Graefe, Susanna

    2010-10-01

    Purpose: The present study investigates the efficacy of compartmental targeting in xenografted tumors treated by meta-tetra(hydroxyphenyl)chlorin (mTHPC)-mediated photodynamic therapy (PDT). The therapeutic efficacy was, furthermore, related to a regional photoinduced distribution of apoptosis and an mTHPC biodistribution profile. Methods and Materials: Mice bearing EMT6 tumors were subjected to a single irradiation (10 J/cm{sup 2}) of red laser light (652 nm) at different intervals after a single- (0.3 mg/kg or 0.15 mg/kg) or double-intravenous (2 x 0.15 mg/kg) injection(s) of mTHPC. Efficiency of the treatment was evaluated by monitoring tumor regrowth. mTHPC pharmacokinetics were assessed by high-performance liquid chromatography analysis of excised organs. The regional distribution of apoptosis in tumor sections was investigated with a newly developed colabelling immunohistochemistry technique. Results: A fractionated double-injection protocol of mTHPC with 24-h and 3-h drug-light intervals (DLI) yielded 100% tumor cure, with tumors presenting a massive apoptosis of neoplastic cells along with a distortion of vessels. The best efficiency for a single injection (0.3 mg/kg) was about 54% tumor cure and corresponded to a DLI of 3 h. At this DLI, tumors showed apoptosis of endothelial cells in residual vessels. Concentrations of mTHPC observed in plasma and tumor for the fractionated injection were not statistically different and were less than the total drug dose in each compartment. Conclusions: The present work suggests that clinical PDT protocols with mTHPC could be greatly improved by fractionation of the drug administration. Time points should be chosen based on the intratumoral spatiotemporal drug distribution.

  18. The pharmacokinetics, tissue penetration and in-vitro activity of loracarbef, a beta-lactam antibiotic of the carbacephem class.

    PubMed

    Lees, A S; Andrews, J M; Wise, R

    1993-12-01

    The pharmacokinetics of loracarbef in plasma and a mild inflammatory exudate were studied in human volunteers. After a single oral dose of 400 mg, a mean maximum drug concentration (Cmax) of 17.8 mg/L was achieved in the plasma at 1.2 h (mean Tmax). The mean plasma elimination half-life (T1/2) was 1.3 h. In the inflammatory exudate the mean Cmax was 8.9 mg/L at a mean Tmax of 2.0 h and with a mean T1/2 of 1.7 h. The mean penetration into the inflammatory exudate was 90.1%. The in-vitro activity of loracarbef was determined against Haemophilus influenzae and Moraxella catarrhalis (MIC90s of 4 mg/L and 1 mg/L respectively, regardless of beta-lactamase production), as well as Streptococcus pneumoniae (MIC90 of 2 mg/L). Loracarbef was also active against Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae (MIC90s of < or = 2 mg/L). The in-vitro activity and pharmacokinetics of loracarbef suggest that it would be efficative therapy for patients with community-acquired respiratory and urinary tract infections caused by the most frequently-encountered bacterial pathogens. PMID:8144425

  19. Pressure and temperature distribution in biological tissues by focused ultrasound

    NASA Astrophysics Data System (ADS)

    Mal, Ajit K.; Feng, Feng; Kabo, Michael; Wang, Jeffrey; Bar-Cohen, Yoseph

    2003-07-01

    The interaction between ultrasound and biological tissues has been the subject of a number of investigators for nearly half a century and the number of applications of high intensity, focused ultrasound for therapeutic purposes continues to grow. This paper is motivated by possible medical applications of focused ultrasound in minimally invasive treatment of a variety of musculoskeletal disorders that are responsive to thermal treatment. The mechanical and thermal effects in a subject"s body induced by high-frequency ultrasound are simulated using PZFlex, a finite element based program. The FEM model described in this report is of a transverse section of the body at the level of the second lumbar vertebra (L2) extracted from a CT image. In order to protect the nerves inside the spinal canal as well as to obtain an effective heating result at the focal region within the intervertebral disk, a suitable orientation of axis of the focused ultrasound lens have to be determined in advance. The pressure, energy loss distribution and temperature distribution are investigated in this paper with the different orientations of the axis and different transverse diameter of the spherical ultrasound lens. Since nonlinear effects are expected to be important in the therapeutic application in some literatures, this paper also demonstrates the effects of nonlinearities on the pressure and temperature distribution induced by focused ultrasound in a two dimensional model. Finally, a comparison of the results between linear and nonlinear cases is reported.

  20. 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. PMID:27283844

  1. Localized bacterial infection in a distributed model for tissue inflammation.

    PubMed

    Lauffenburger, D A; Kennedy, C R

    1983-01-01

    Phagocyte motility and chemotaxis are included in a distributed mathematical model for the inflammatory response to bacterial invasion of tissue. Both uniform and non-uniform steady state solutions may occur for the model equations governing bacteria and phagocyte densities in a macroscopic tissue region. The non-uniform states appear to be more dangerous because they allow large bacteria densities concentrated in local foci, and in some cases greater total bacteria and phagocyte populations. Using a linear stability analysis, it is shown that a phagocyte chemotactic response smaller than a critical value can lead to a non-uniform state, while a chemotactic response greater than this critical value stabilizes the uniform state. This result is the opposite of that found for the role of chemotaxis in aggregation of slimemold amoebae because, in the inflammatory response, the chemotactic population serves as an inhibitor rather than an activator. We speculate that these non-uniform steady states could be related to the localized cell aggregation seen in chronic granulomatous inflammation. The formation of non-uniform states is not necessarily a consequence of defective phagocyte chemotaxis, however. Rather, certain values of the kinetic parameters can yield values for the critical chemotactic response which are greater than the normal response. Numerical computations of the transient inflammatory response to bacterial challenge are presented, using parameter values estimated from the experimental literature wherever possible. PMID:6827185

  2. A rapid UPLC-MS/MS method for the determination of oleanolic acid in rat plasma and liver tissue: application to plasma and liver pharmacokinetics.

    PubMed

    Li, Tian-Xue; Chu, Chao-Sen; Zhu, Jia-Yu; Yang, Tian-Yi; Zhang, Jie; Hu, Yu-Tao; Yang, Xing-Hao

    2016-04-01

    A reliable high-throughput ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for oleanolic acid (OA) determination in rat plasma and liver tissue using glycyrrhetic acid as the internal standard (IS). Plasma and liver homogenate samples were prepared using solid-phase extraction. Chromatographic separation was achieved on a C18 column using an isocratic mobile phase system. The detection was performed by multiple reaction monitoring mode via positive electrospray ionization interface. The calibration curves showed good linearity (R(2) > 0.9997) within the tested concentration ranges. The lower limit of quantification for plasma and liver tissue was ≤0.75 ng/mL. The intra- and inter-day precision and accuracy deviations were within ±15% in plasma and liver tissue. The mean extraction recoveries ranged from 80.8 to 87.0%. In addition, the carryover, matrix effect, stability and robustness involved in the method were also validated. The method was successfully applied to the plasma and hepatic pharmacokinetics of OA after oral administration to rats. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26234772

  3. Differential bioavailability, clearance, and tissue distribution of the acyclic tomato carotenoids lycopene and phytoene in mongolian gerbils.

    PubMed

    Moran, Nancy Engelmann; Clinton, Steven K; Erdman, John W

    2013-12-01

    Lycopene (LYC) is the major tomato carotenoid and is the focus of substantial research. Phytoene (PE), a minor tomato carotenoid, is found in human blood and tissues in similar concentrations to LYC. To determine which metabolic differences underlie this phenomenon, Mongolian gerbils (Meriones unguiculatus, n = 56) were fed control or tomato powder (TP)-containing diets (to establish steady-state serum and tissue carotenoid concentrations similar to tomato-fed humans) for 26 d. The TP-fed gerbils were then provided either a single, oral, cottonseed oil (CO) vehicle dose and tissues were collected at 6 h or they were provided unlabeled PE or LYC in CO and tissues were evaluated at 6, 12, or 24 h. In vehicle-dosed, TP-fed gerbils, LYC was the major carotenoid (≥ 55% carotenoids) in liver, spleen, testes, and the prostate-seminal vesicle complex, whereas PE was the major serum and adipose carotenoid (≥ 37% total carotenoid) and phytofluene was the major carotenoid (≥ 38%) in adrenals and lungs. PE dosing increased hepatic, splenic, and serum PE concentrations compared with vehicle dosing (P < 0.05) from 6 to 24 h, whereas LYC dosing increased only serum LYC at 6 and 12 h (P < 0.05) compared with vehicle dosing. This suggested PE was more bioavailable and cleared more slowly than LYC. To precisely track absorptive and distributive differences, (14)C-PE or (14)C-LYC (n = 2/group) was provided to TP-fed gerbils. Bioavailability assessed by carcass (14)C-content was 23% for PE and 8% for LYC. Nearly every extra-hepatic tissue accumulated greater dose radioactivity after (14)C-PE than (14)C-LYC dosing. Thus, LYC and PE, which structurally differ only by saturation, pharmacokinetically differ in bioavailability, tissue deposition, and clearance. PMID:24108134

  4. Differential Bioavailability, Clearance, and Tissue Distribution of the Acyclic Tomato Carotenoids Lycopene and Phytoene in Mongolian Gerbils123

    PubMed Central

    Moran, Nancy Engelmann; Clinton, Steven K.; Erdman, John W.

    2013-01-01

    Lycopene (LYC) is the major tomato carotenoid and is the focus of substantial research. Phytoene (PE), a minor tomato carotenoid, is found in human blood and tissues in similar concentrations to LYC. To determine which metabolic differences underlie this phenomenon, Mongolian gerbils (Meriones unguiculatus, n = 56) were fed control or tomato powder (TP)-containing diets (to establish steady-state serum and tissue carotenoid concentrations similar to tomato-fed humans) for 26 d. The TP-fed gerbils were then provided either a single, oral, cottonseed oil (CO) vehicle dose and tissues were collected at 6 h or they were provided unlabeled PE or LYC in CO and tissues were evaluated at 6, 12, or 24 h. In vehicle-dosed, TP-fed gerbils, LYC was the major carotenoid (≥55% carotenoids) in liver, spleen, testes, and the prostate-seminal vesicle complex, whereas PE was the major serum and adipose carotenoid (≥37% total carotenoid) and phytofluene was the major carotenoid (≥38%) in adrenals and lungs. PE dosing increased hepatic, splenic, and serum PE concentrations compared with vehicle dosing (P < 0.05) from 6 to 24 h, whereas LYC dosing increased only serum LYC at 6 and 12 h (P < 0.05) compared with vehicle dosing. This suggested PE was more bioavailable and cleared more slowly than LYC. To precisely track absorptive and distributive differences, 14C-PE or 14C-LYC (n = 2/group) was provided to TP-fed gerbils. Bioavailability assessed by carcass 14C-content was 23% for PE and 8% for LYC. Nearly every extra-hepatic tissue accumulated greater dose radioactivity after 14C-PE than 14C-LYC dosing. Thus, LYC and PE, which structurally differ only by saturation, pharmacokinetically differ in bioavailability, tissue deposition, and clearance. PMID:24108134

  5. Distribution and pharmacokinetics of methamphetamine in the human body: clinical implications

    SciTech Connect

    Volkow, N.D.; Fowler, J.; Volkow, N.D.; Fowler, J.S.; Wang, G.-J.; Shumay, E.; Telang, F.; Thanos, P.; Alexoff, D.

    2010-12-01

    Methamphetamine is one of the most toxic of the drugs of abuse, which may reflect its distribution and accumulation in the body. However no studies have measured methamphetamine's organ distribution in the human body. Positron Emission Tomography (PET) was used in conjunction with [{sup 11}C]d-methamphetamine to measure its whole-body distribution and bioavailability as assessed by peak uptake (% Dose/cc), rate of clearance (time to reach 50% peak-clearance) and accumulation (area under the curve) in healthy participants (9 Caucasians and 10 African Americans). Methamphetamine distributed through most organs. Highest uptake (whole organ) occurred in lungs (22% Dose; weight {approx}1246 g), liver (23%; weight {approx}1677 g) and intermediate in brain (10%; weight {approx}1600 g). Kidneys also showed high uptake (per/cc basis) (7%; weight 305 g). Methamphetamine's clearance was fastest in heart and lungs (7-16 minutes), slowest in brain, liver and stomach (>75 minutes), and intermediate in kidneys, spleen and pancreas (22-50 minutes). Lung accumulation of [{sup 11}C]d-methamphetamine was 30% higher for African Americans than Caucasians (p < 0.05) but did not differ in other organs. The high accumulation of methamphetamine, a potent stimulant drug, in most body organs is likely to contribute to the medical complications associated with methamphetamine abuse. In particular, we speculate that methamphetamine's high pulmonary uptake could render this organ vulnerable to infections (tuberculosis) and pathology (pulmonary hypertension). Our preliminary findings of a higher lung accumulation of methamphetamine in African Americans than Caucasians merits further investigation and questions whether it could contribute to the infrequent use of methamphetamine among African Americans.

  6. Human subcutaneous tissue distribution of fluconazole: comparison of microdialysis and suction blister techniques

    PubMed Central

    Sasongko, Lucy; Williams, Kenneth M; Day, Richard O; McLachlan, Andrew J

    2003-01-01

    Aims To investigate uptake of fluconazole into the interstitial fluid of human subcutaneous tissue using the microdialysis and suction blister techniques. Methods A sterile microdialysis probe (CMA/60) was inserted subcutaneously into the upper arm of five healthy volunteers following an overnight fast. Blisters were induced on the lower arm using gentle suction prior to ingestion of a single oral dose of fluconazole (200 mg). Microdialysate, blister fluid and blood were sampled over 8 h. Fluconazole concentrations were determined in each sample using a validated HPLC assay. In vivo recovery of fluconazole from the microdialysis probe was determined in each subject by perfusing the probe with fluconazole solution at the end of the 8 h sampling period. Individual in vivo recovery was used to calculate fluconazole concentrations in subcutaneous interstitial fluid. A physiologically based pharmacokinetic (PBPK) model was used to predict fluconazole concentrations in human subcutaneous interstitial fluid. Results There was a lag-time (approximately 0.5 h) between detection of fluconazole in microdialysate compared with plasma in each subject. The in vivo recovery of fluconazole from the microdialysis probe ranged from 57.0 to 67.2%. The subcutaneous interstitial fluid concentrations obtained by microdialysis were very similar to the unbound concentrations of fluconazole in plasma with maximum concentration of 4.29 ± 1.19 µg ml−1 in subcutaneous interstitial fluid and 3.58 ± 0.14 µg ml−1 in plasma. Subcutaneous interstitial fluid-to-plasma partition coefficient (Kp) of fluconazole was 1.16 ± 0.22 (95% CI 0.96, 1.35). By contrast, fluconazole concentrations in blister fluid were significantly lower (P < 0.05, paired t-test) than unbound plasma concentrations over the first 3 h and maximum concentrations in blister fluid had not been achieved at the end of the sampling period. There was good agreement between fluconazole concentrations derived from microdialysis

  7. Pharmacokinetics of ciprofloxacin in ponies.

    PubMed

    Dowling, P M; Wilson, R C; Tyler, J W; Duran, S H

    1995-02-01

    The pharmacokinetics of ciprofloxacin was investigated in healthy, mature ponies. Ciprofloxacin was administered intravenously to six ponies at a dose of 5 mg per kg body weight. Seven days later, ciprofloxacin was administered orally to each pony at the same dose. Intravenous ciprofloxacin concentration vs. time data best fit a two-compartment open model with first-order elimination from the central compartment. Mean plasma half-life, based on the terminal phase, was 157.89 min (harmonic mean). Total body clearance of ciprofloxacin was 18.12 +/- 3.99 mL/min/kg. Volume of distribution at steady-state was 3.45 +/- 0.72 L/kg. From the pharmacokinetic data and reported minimum inhibitory concentrations for equine gram-negative pathogens, the appropriate dosage of ciprofloxacin was determined to be 5.32 mg per kg body weight at 12 h intervals. Bioavailability of oral ciprofloxacin in ponies was 6.8 +/- 5.33%. Owing to the poor bioavailability, a dosage regimen could not be proposed for oral ciprofloxacin administration in horses. Ciprofloxacin concentrations were determined in tissues and body fluids at 1, 2 and 4 h after intravenous administration. At all times, tissue concentrations exceeded plasma concentrations of ciprofloxacin. Highest concentrations were achieved in kidneys and urine. Potentially therapeutic concentrations were obtained in cerebrospinal and joint fluid, but low concentrations were achieved in aqueous humour. PMID:7752310

  8. Organophosphorus Insecticide Pharmacokinetics

    SciTech Connect

    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 and 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.

  9. Use of a physiologically based pharmacokinetic model to study the time to reach brain equilibrium: an experimental analysis of the role of blood-brain barrier permeability, plasma protein binding, and brain tissue binding.

    PubMed

    Liu, Xingrong; Smith, Bill J; Chen, Cuiping; Callegari, Ernesto; Becker, Stacey L; Chen, Xi; Cianfrogna, Julie; Doran, Angela C; Doran, Shawn D; Gibbs, John P; Hosea, Natilie; Liu, Jianhua; Nelson, Frederick R; Szewc, Mark A; Van Deusen, Jeffery

    2005-06-01

    This study was designed 1) to examine the effects of blood-brain barrier (BBB) permeability [quantified as permeability-surface area product (PS)], unbound fraction in plasma (f(u,plasma)), and brain tissue (f(u,brain)) on the time to reach equilibrium between brain and plasma and 2) to investigate the drug discovery strategies to design and select compounds that can rapidly penetrate the BBB and distribute to the site of action. The pharmacokinetics of seven model compounds: caffeine, CP-141938 [methoxy-3-[(2-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide], fluoxetine, NFPS [N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine], propranolol, theobromine, and theophylline in rat brain and plasma after subcutaneous administration were studied. The in vivo log PS and log f(u,brain) calculated using a physiologically based pharmacokinetic model correlates with in situ log PS (R(2) = 0.83) and in vitro log f(u,brain) (R(2) = 0.69), where the in situ PS and in vitro f(u,brain) was determined using in situ brain perfusion and equilibrium dialysis using brain homogenate, respectively. The time to achieve brain equilibrium can be quantitated with a proposed parameter, intrinsic brain equilibrium half-life [t(1/2eq,in) = V(b)ln2/(PS . f(u,brain))], where V(b) is the physiological volume of brain. The in vivo log t(1/2eq,in) does not correlate with in situ log PS (R(2) < 0.01) but correlates inversely with log(PS . f(u,brain)) (R(2) = 0.85). The present study demonstrates that rapid brain equilibration requires a combination of high BBB permeability and low brain tissue binding. A high BBB permeability alone cannot guarantee a rapid equilibration. The strategy to select compounds with rapid brain equilibration in drug discovery should identify compounds with high BBB permeability and low nonspecific binding in brain tissue. PMID:15743928

  10. Pharmacokinetics and Drug Dosing in Obese Children

    PubMed Central

    Kendrick, Jennifer G.; Carr, Roxane R.; Ensom, Mary H.H.

    2010-01-01

    OBJECTIVES To review pharmacokinetics in obese children and to provide medication dosing recommendations. METHODS EMBASE, MEDLINE, and International Pharmaceutical Abstracts databases were searched using the following terms: obesity, morbid obesity, overweight, pharmacokinetics, drug, dose, kidney function test, creatinine, pediatric, and child. RESULTS We identified 10 studies in which the authors examined drug dosing or pharmacokinetics for obese children. No information was found for drug absorption or metabolism. Obese children have a higher percent fat mass and a lower percent lean mass compared with normal-weight children. Therefore, in obese children, the volume of distribution of lipophilic drugs is most likely higher, and that of hydrophilic drugs is most likely lower, than in normal-weight children. Serum creatinine concentrations are higher in obese than normal-weight children. Total body weight is an appropriate size descriptor for calculating doses of antineoplastics, cefazolin, and succinylcholine in obese children. Initial tobramycin doses may be determined using an adjusted body weight, although using total body weight in the context of monitoring serum tobramycin concentrations would also be an appropriate strategy. We found no information for any of the opioids; antibiotics such as penicillins, carbapenems, vancomycin, and linezolid; antifungals; cardiac drugs such as digoxin and amiodarone; corticosteroids; benzodiazepines; and anticonvulsants. In particular, we found no information about medications that are widely distributed to adipose tissue or that can accumulate there. CONCLUSIONS The available data are limited because of the small numbers of participating children, study design, or both. The number and type of drugs that have been studied limit our understanding of the pharmacokinetics in obese children. In the absence of dosing information for obese children, it is important to consider the nature and severity of a child's illness

  11. Pharmacokinetic/pharmacodynamic modeling identifies SN30000 and SN29751 as tirapazamine analogs with improved tissue penetration and hypoxic cell killing in tumors

    PubMed Central

    Hicks, Kevin O.; Siim, Bronwyn G.; Jaiswal, Jagdish K.; Pruijn, Frederik B.; Fraser, Annie M.; Patel, Rita; Hogg, Alison; Liyanage, H.D. Sarath; Jo Dorie, Mary; Brown, J. Martin; Denny, William. A.; Hay, Michael P.; Wilson, William R.

    2012-01-01

    Purpose Tirapazamine (TPZ) has attractive features for targeting hypoxic cells in tumors but limited clinical activity, in part because of poor extravascular penetration. Here we identify improved TPZ analogs by using a spatially resolved pharmacokinetic/pharmacodynamic (SR-PKPD) model that considers tissue penetration explicitly during lead optimization. Experimental design The SR-PKPD model was used to guide progression of 281 TPZ analogs through a hierarchical screen. For compounds exceeding hypoxic selectivity thresholds in single cell cultures, SR-PKPD model parameters (kinetics of bioreductive metabolism, clonogenic cell killing potency, diffusion coefficients in multicellular layers, plasma pharmacokinetics at well tolerated doses in mice) were measured to prioritize testing in xenograft models in combination with radiation. Results SR-PKPD-guided lead optimization identified SN29751 and SN30000 as the most promising hypoxic cytotoxins from two different structural subseries. Both were reduced to the corresponding 1-oxide selectively under hypoxia by HT29 cells, with an oxygen dependence quantitatively similar to that of TPZ. SN30000, in particular, showed higher hypoxic potency and selectivity than TPZ in tumor cell cultures and faster diffusion through HT29 and SiHa multicellular layers. Both compounds also provided superior plasma PK in mice and rats at equivalent toxicity. In agreement with SR-PKPD predictions, both were more active than TPZ with single dose or fractionated radiation against multiple human tumor xenografts. Conclusions SN30000 and SN29751 are improved TPZ analogs with potential for targeting tumor hypoxia in humans, and illustrate the utility of novel SR-PKPD modeling approaches for lead optimization during anticancer drug development. PMID:20732963

  12. Pharmacokinetics and distribution of heparin-binding growth factor I (endothelial cell growth factor) in the rat

    SciTech Connect

    Rosengart, T.K.; Kuperschmid, J.P.; Maciag, T.; Clark, R.E.

    1989-02-01

    Heparin-binding growth factor I (HBGF I), previously designated as endothelial cell growth factor, is a potent mitogen for endothelial cells in vitro, which may prove useful for promoting endothelial regeneration in vivo. Analysis of the pharmacokinetics and organ distribution of HBGF I is necessary before use of HBGF I as a pharmacological agent. Consequently, pharmacological studies were carried out with (125I)HBGF I in the rat. Intravenous injections of HBGF I were given with or without heparin (2.5 units/ng HBGF I). Blood concentrations of HBGF I decreased by one half 17 seconds after HBGF I bolus. This time was prolonged to 60 seconds when HBGF I was injected with heparin. The elimination half-life of HBGF I was 14 minutes in the presence of heparin. The highest concentrations of HBGF I following intravenous bolus were found in kidney, liver, and spleen, and the lowest in fat and brain. Heparin increased HBGF I concentrations in blood and all organs measured except kidney, which was significantly decreased (p less than 0.01). Intact HBGF I was recoverable from blood 5 minutes following intravenous administration. HBGF I underwent near-complete proteolytic digestion after more prolonged ex vivo incubation with rat plasma, but HBGF I was protected from proteolysis when incubations were conducted in the presence of heparin. Thus, it is feasible that HBGF I can be administered as a pharmacological agent in the presence of heparin. Further studies assessing acceleration of in vivo endothelial growth using HBGF I with heparin appear warranted.

  13. Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil.

    PubMed

    Matzneller, Peter; Lackner, Edith; Lagler, Heimo; Wulkersdorfer, Beatrix; Österreicher, Zoe; Zeitlinger, Markus

    2016-06-01

    Ceftaroline fosamil (CPT-F) is currently approved for use for the treatment of complicated skin and soft tissue infections and community-acquired pneumonia at 600 mg twice daily (q12h), but other dosing regimens are under evaluation. To date, very limited data on the soft tissue pharmacokinetics (PK) of the active compound, ceftaroline (CPT), are available. CPT concentrations in the plasma, muscle, and subcutis of 12 male healthy volunteers were measured by microdialysis after single and repeated intravenous administration of 600 mg CPT-F q12h or three times daily (q8h) in two groups of 6 subjects each. Relevant PK and PK/pharmacodynamic (PD) parameters were calculated and compared between groups. In plasma, the area under the concentration-time curve (AUC) from 0 to 24 h for total CPT and the cumulative percentage of the dosing interval during which the free drug concentrations exceeded the MIC (fTMIC) for unbound CPT for the currently established threshold of 1 mg/liter were significantly higher in the group receiving CPT-F q8h. Exposure to free drug in soft tissues was higher in the group receiving CPT-F q8h, but high interindividual variability in relevant PK parameters was observed. The mean ratios of the AUC from time zero to the end of the dosing interval (AUC0-τ) for free CPT in soft tissues and the AUC0-τ for the calculated free fraction in plasma at steady state ranged from 0.66 to 0.75. Administration of CPT-F q8h led to higher levels of drug exposure in all investigated compartments. When MIC values above 1 mg/liter were assumed, the calculated fTMIC after dosing q12h was markedly lower than that after dosing q8h. The clinical implications of these differences are discussed in light of recently completed clinical phase III and PK/PD studies. PMID:27044549

  14. Serum, milk, and tissue monensin concentrations in cattle with adequate and potentially toxic dietary levels of monensin: pharmacokinetics and diagnostic interpretation.

    PubMed

    Puschner, B; Bautista, A C; McKemie, D S; Gallego, S M; Woods, L W; Moore, C E; Knych, H K

    2016-08-01

    Used in both beef cattle and dairy cows, monensin can provide many health benefits but can, when unintended overexposures occur, result in adverse effects. Information on serum and tissue concentrations following overexposure and/or overt toxicosis which may aid in diagnostics and clinical outcome is lacking. The aim of this study was to determine concentrations of monensin in biological specimens following oral exposure for 10 days to an approved dose (1 mg/kg) and a higher dose (5 mg/kg) of monensin given daily on a body weight basis to 10 dairy cows. No deaths were reported; cows receiving 5 mg/kg showed early signs of toxicosis including depression, decreased feed intake, and diarrhea after 4 days of exposure. Histopathological findings were minimal in most cows. Pharmacokinetic modeling of the detected serum concentrations for the 1 and 5 mg/kg dose groups determined the Cmax , Tmax, and t1/2λ to be 0.87 and 1.68 ng/mL, 2.0 and 1.0 h, and 1.76 and 2.32 days, respectively. Mixed regression models showed that the dose level and days since last dose were significantly associated with monensin concentrations in all four tissues, and with cardiac troponin levels. The high dose resulted in a significant elevation of monensin in tissues at approximately 4.7 times compared to the monensin concentrations in the tissues of animals from the low-dose group. The cTnI concentrations in the high-dose group were 2.1 times that of cTnI in the low-dose group. Thus, the ability to diagnose monensin overexposure and/or toxicosis will improve from knowledge of biological monensin concentrations from this study. PMID:26763112

  15. Pharmacokinetics and tumor and neural tissue penetrating properties of SR-2508 and SR-2555 in the dog-hydrophilic radiosensitizers potentially less toxic than misonidazole

    SciTech Connect

    White, R.A.S.; Workman, P.; Brown, J.M.

    1980-12-01

    The behavior of three 2-nitroimidazole drugs of similar electron affinity to misonidazole but with varying octanol: water partition coefficients has been compared in normal and tumor-bearing dogs. In particular the pharmacokinetic behavior, urinary excretion, and tumor and neural tissue penetrating properties of the three drugs have been studied. Peak plasma concentrations and plasma clearance rates increased with decreasing lipophilicity. Penetration into both the central and peripheral nervous system was significantly slower for the more polar drugs, and as a result of this and the increased plasma clearance rates, the drug exposure to these sites of potential neurotoxicity was reduced. Peak tumor concentrations increased with decreasing lipophilicity, and those for the two SR drugs were more than twice those for equimolar iv doses of misonidazole. It would seem on the basis of the increased plasma clearance rates, improved peak tumor concentrations, and reduced drug exposure to neural tissue that lowering lipophilicity may be an important means of designing radiosensitizing drugs which are less toxic than and superior to misonidazole.

  16. Primary structure and tissue distribution of the orphanin FQ precursor.

    PubMed Central

    Nothacker, H P; Reinscheid, R K; Mansour, A; Henningsen, R A; Ardati, A; Monsma, F J; Watson, S J; Civelli, O

    1996-01-01

    The heptadecapeptide orphanin FQ (OFQ) is a recently discovered neuropeptide that exhibits structural features reminiscent of the opioid peptides and that is an endogenous ligand to a G protein-coupled receptor sequentially related to the opioid receptors. We have cloned both the human and rat cDNAs encoding the OFQ precursor proteins, to investigate whether the sequence relationships existing between the opioid and OFQ systems are also found at the polypeptide precursor level, in particular whether the OFQ precursor would encode several bioactive peptides as do the opioid precursors, and to study the regional distribution of OFQ sites of synthesis. The entire precursor protein displays structural homology to the opioid peptide precursors, especially preprodynorphin and preproenkephalin. The predicted amino acid sequence of the OFQ precursor contains a putative signal peptide and one copy of the OFQ sequence flanked by pairs of basic amino acid residues. Carboxyl-terminal to the OFQ sequence, the human and rat precursors contain a stretch of 28 amino acids that is 100% conserved and thus may encode novel bioactive peptides. Two peptides derived from this stretch were synthesized but were found to be unable to activate the OFQ receptor, suggesting that if they are produced in vivo, these peptides would likely recognize receptors different from the OFQ receptor. To begin analyzing the sites of OFQ mRNA synthesis, Northern analysis of human and rat tissues were carried out and showed that the OFQ precursor mRNA is mainly expressed in the brain. In situ hybridization of rat brain slices demonstrated a regional distribution pattern of the OFQ precursor mRNA, which is distinct from that of the opioid peptide precursors. These data confirm that the OFQ system differs from the opioid system at the molecular level, although the OFQ and opioid precursors may have arisen from a common ancestral gene. Images Fig. 4 Fig. 5 PMID:8710930

  17. HPLC-FLD methods to quantify chloroaluminum phthalocyanine in nanoparticles, plasma and tissue: application in pharmacokinetic and biodistribution studies.

    PubMed

    Oliveira, Líliam Teixeira; Garcia, Giani Martins; Kano, Eunice Kazue; Tedesco, Antônio Cláudio; Mosqueira, Vanessa Carla Furtado

    2011-08-25

    Analytical and bioanalytical methods of high-performance liquid chromatography with fluorescence detection (HPLC-FLD) were developed and validated for the determination of chloroaluminum phthalocyanine in different formulations of polymeric nanocapsules, plasma and livers of mice. Plasma and homogenized liver samples were extracted with ethyl acetate, and zinc phthalocyanine was used as internal standard. The results indicated that the methods were linear and selective for all matrices studied. Analysis of accuracy and precision showed adequate values, with variations lower than 10% in biological samples and lower than 2% in analytical samples. The recoveries were as high as 96% and 99% in the plasma and livers, respectively. The quantification limit of the analytical method was 1.12 ng/ml, and the limits of quantification of the bioanalytical method were 15 ng/ml and 75 ng/g for plasma and liver samples, respectively. The bioanalytical method developed was sensitive in the ranges of 15-100 ng/ml in plasma and 75-500 ng/g in liver samples and was applied to studies of biodistribution and pharmacokinetics of AlClPc. PMID:21596512

  18. Target site pharmacokinetics of linezolid after single and multiple doses in diabetic patients with soft tissue infection.

    PubMed

    Eslam, Roza Badr; Burian, Angela; Vila, Greisa; Sauermann, Robert; Hammer, Alexandra; Frenzel, Dorothea; Minichmayr, Iris K; Kloft, Charlotte; Matzneller, Peter; Oesterreicher, Zoe; Zeitlinger, Markus

    2014-09-01

    The underlying pathology of diabetic wounds, i.e. impairment of macro- and microcirculation, might also impact target site penetration of antibacterial drugs. To compare tissue concentrations of linezolid in infected and not infected tissue 10 patients suffering from type 2 diabetes with foot infection were included in the study. Tissue penetration of linezolid was assessed using in vivo microdialysis at the site of infection as well as in non-inflamed subcutaneous adipose tissue. All patients were investigated after receiving a single dose of linezolid and five patients in addition at steady state. After a single dose of linezolid significantly higher area under the concentration vs. time curve over 8 hours (AUC0-8 ) and maximum concentrations (Cmax )-values were observed in plasma (65.5 ± 21.2 mg*h/L and 16.4 ± 4.6 mg/L) as compared to inflamed (36.3 ± 22.9  mg*h/L and 6.6 ± 3.6 mg/L) and non-inflamed tissue (33.0 ± 17.7 mg*h/L and 6.7 ± 3.6 mg/L). Multiple administrations of linezolid led to disappearance of significant differences in Cmax and AUC0-8 between plasma, inflamed, and non-inflamed tissue. Approximately 2-fold increase of Cmax and AUC0-8 -values in tissue was observed at steady state as compared to the first administration. Penetration of linezolid is not impaired in diabetic foot infection but equilibrium between plasma and tissue might be delayed. PMID:24677034

  19. Effect of Tissue Composition on Dose Distribution in Electron Beam Radiotherapy

    PubMed Central

    Ghorbani, M.; Tabatabaei, Z. S.; Vejdani Noghreiyan, A.; Vosoughi, H.; Knaup, C.

    2015-01-01

    Objective The aim of this study is to evaluate the effect of tissue composition on dose distribution in electron beam radiotherapy. Methods A Siemens Primus linear accelerator and a phantom were simulated using MCNPX Monte Carlo code. In a homogeneous cylindrical phantom, six types of soft tissue and three types of tissue-equivalent materials were investigated. The tissues included muscle (skeletal), adipose tissue, blood (whole), breast tissue, soft tissue (9-components) and soft tissue (4-component). The tissue-equivalent materials were water, A-150 tissue-equivalent plastic and perspex. Electron dose relative to dose in 9-component soft tissue at various depths on the beam’s central axis was determined for 8, 12, and 14 MeV electron energies. Results The results of relative electron dose in various materials relative to dose in 9-component soft tissue were reported for 8, 12 and 14 MeV electron beams as tabulated data. While differences were observed between dose distributions in various soft tissues and tissue-equivalent materials, which vary with the composition of material, electron energy and depth in phantom, they can be ignored due to the incorporated uncertainties in Monte Carlo calculations. Conclusion Based on the calculations performed, differences in dose distributions in various soft tissues and tissue-equivalent materials are not significant. However, due to the difference in composition of various materials, further research in this field with lower uncertainties is recommended. PMID:25973407

  20. Brain distribution pharmacokinetics and integrated pharmacokinetics of Panax Notoginsenoside R1, Ginsenosides Rg1, Rb1, Re and Rd in rats after intranasal administration of Panax Notoginseng Saponins assessed by UPLC/MS/MS.

    PubMed

    Guo, Qingli; Li, Pengyue; Wang, Zhen; Cheng, Yanke; Wu, Huichao; Yang, Bing; Du, Shouying; Lu, Yang

    2014-10-15

    Panax notoginseng saponins (PNS) constitute the main active components of a traditional Chinese medicine, Panax notoginseng (Burk.) F.H. Chen (Sanqi). To investigate brain distribution of Panax Notoginsenoside R1, Ginsenosides Rg1, Rb1, Re, and Rd, and the integrated PNS in rats, their contents in cortex, striatum, hypothalamus, medulla oblongata, hippocampus and olfactory bulb were simultaneously measured by UPLC-MS/MS. Sample preparation was carried out by the protein precipitation technique with an internal Digoxin standard. The method described here was highly efficient, with short run time, excellent specificity and sensitivity, and successfully applied for pharmacokinetics studies. NGR1, GRg1, GRb1, GRe and GRd from PNS have been detected in all six brain regions studied and quantified accurately. These findings provide more insight for further understanding of the main ways from the nasal cavity to brain as well as the migration of nasally applied drugs into the CNS parenchyma. PMID:25203723

  1. Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist.

    PubMed

    Bruderer, Shirin; Aänismaa, Päivi; Homery, Marie-Claude; Häusler, Stephanie; Landskroner, Kyle; Sidharta, Patricia N; Treiber, Alexander; Dingemanse, Jasper

    2012-03-01

    Macitentan is a dual endothelin receptor antagonist under phase 3 investigation in pulmonary arterial hypertension. We investigated the effect of cyclosporine (Cs) and rifampin on the pharmacokinetics of macitentan and its metabolites ACT-132577 and ACT-373898 in healthy male subjects. In addition, in vitro studies were performed to investigate interactions between macitentan and its active metabolite ACT-132577 with human organic anion-transporting polypeptides (OATPs). The clinical study (AC-055-111) was conducted as a two-part, one-sequence, crossover study. Ten subjects in each part received multiple-dose macitentan followed by multiple-dose co-administration of Cs (part A) or rifampin (part B). In the presence of Cs, steady-state area under the plasma concentration-time profiles during a dose interval (AUC(τ)) for macitentan and ACT-373898 increased 10% and 7%, respectively, and decreased 3% for ACT-132577. Steady-state AUC(τ) of macitentan and ACT-373898 in the presence of rifampin decreased 79% and 64%, respectively. For ACT-132577, no relevant difference in AUC(τ) between the two treatments was observed. Macitentan co-administered with Cs or rifampin was well tolerated. The complementary in vitro studies demonstrated no marked differences in uptake rates of macitentan and ACT-132577 between the wild-type and OATP over-expressing cells over the concentration range tested. Concomitant treatment with Cs did not have any clinically relevant effect on the exposure to macitentan or its metabolites, at steady-state. Concomitant treatment with rifampin reduced significantly the exposure to macitentan and its metabolite ACT-373898 at steady-state but did not affect the exposure to the active metabolite ACT-132577 to a clinically relevant extent. PMID:22189899

  2. Pharmacokinetics of azithromycin in rats and dogs.

    PubMed

    Shepard, R M; Falkner, F C

    1990-01-01

    After intravenous or oral administration to rats and dogs, azithromycin was rapidly distributed into the tissues, where concentrations frequently exceeded those in serum by 100-fold or more within 24 h of a single dose. Tissue concentrations were proportional to the dose following single administrations of 10 to 40 mg/kg in rats and dogs. Tissue concentrations were higher after multiple dosing and became greater as the dose was increased from 10 to 40 mg/kg. Elimination half-lives were similar in most tissues and were about 40 h in rats after seven doses of 20 mg/kg and about 90 h in dogs after five doses of 30 mg/kg. Serum concentrations declined in a multi-exponential manner, reflecting initial rapid distribution into tissues and then slow return to serum from tissues. Azithromycin had good oral bioavailability in rats and dogs (46% and 97%, respectively). Rapid uptake of azithromycin by tissues from serum and slow redistribution from tissues to serum are apparently factors governing the pharmacokinetics of azithromycin in rats and dogs. Serum concentrations do not reflect the availability of azithromycin in tissues. PMID:2154438

  3. Melatonin deacetylation: retinal vertebrate class distribution and Xenopus laevis tissue distribution.

    PubMed

    Grace, M S; Cahill, G M; Besharse, J C

    1991-09-13

    Deacetylation is a rapid clearance mechanism for ocular melatonin. We have studied the distribution of retinal melatonin deacetylase activity among vertebrate classes. Exogenous radiolabeled melatonin is metabolized by ocular tissue prepared from the amphibian Xenopus laevis, the reptile Anolis carolinensis, the teleost fish Carassius auratus, and the bird Gallus domesticus. In contrast, we were unable to detect ocular melatonin breakdown in rat or pig. In each species exhibiting ocular melatonin breakdown, melatonin is first deacetylated to 5-methoxytryptamine, which is deaminated, producing 5-methoxyindoleacetic acid and 5-methoxytryptophol. Deacetylation of melatonin is inhibited by eserine (physostigmine), causing a reduction in the levels of all 3 metabolites. Deamination of 5-methoxytryptamine is inhibited by the monoamine oxidase inhibitor pargyline, such that 5-methoxyindoleacetic acid and 5-methoxytryptophol levels are decreased while levels of 5-methoxytryptamine are increased. Incubation with the deacetylase inhibitor eserine increases endogenous melatonin levels in Xenopus and Carassius eyecups, indicating that endogenous melatonin is metabolized via the deacetylase. We also studied the tissue distribution of the deacetylase in Xenopus laevis. Melatonin deacetylation occurs in retina, retinal pigment epithelium, and skin, all of which are sites of melatonin action. These results indicate that among non-mammalian vertebrates, deacetylation is a common clearance mechanism for ocular melatonin, and may degrade melatonin at other sites of action as well. Melatonin deacetylation may help regulate local melatonin concentration, and generates other biologically active methoxyindoles. PMID:1782560

  4. 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

  5. Quantification of dexamethasone and corticosterone in rat biofluids and fetal tissue using highly sensitive analytical methods: assay validation and application to a pharmacokinetic study

    PubMed Central

    Samtani, Mahesh N.; Jusko, William J.

    2014-01-01

    A sensitive, specific, accurate and precise LC/MS/MS method was developed for the simultaneous measurement of dexamethasone and corticosterone in rat plasma. The method was extended to dexamethasone analysis in rat plasma ultrafiltrate and fetal tissues. Samples were processed using SPE involving Oasis HLB cartridges, which offered complete extraction recovery for the analytes. Samples were subsequently analyzed using LC/MS/MS. A structurally related corticosteroid, prednisolone, was used as the internal standard. Using a 500 μL plasma sample, limits of quantification of 0.2 and 2.0 ng/mL were achievable for dexamethasone and corticosterone. This level of sensitivity allowed characterization of maternal/fetal dexamethasone profiles after administration of multiple doses of dexamethasone sodium phosphate to rats. However, this sensitivity was not satisfactory for corticosterone during pharmacokinetic studies involving dexamethasone due to its strong adrenosuppressive effect. This led us to investigate the suitability of a commercially available radioimmunoassay kit, which through extensive testing and minor modifications was found to offer extremely sensitive, specific, accurate and precise analysis of corticosterone. Knowledge of the steroid profiles captured using these highly sensitive analytical tools may potentially help in the optimization of corticosteroid therapy during pregnancy. PMID:17385808

  6. Metabolism of 2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3-[5-(trifluoromethyl)-2-pyridyloxy]propyl ether (pyridalyl) in rats after repeated oral administration and a simple physiologically based pharmacokinetic modeling in brown and white adipose tissues.

    PubMed

    Nagahori, Hirohisa; Matsunaga, Haruyuki; Tomigahara, Yoshitaka; Isobe, Naohiko; Kaneko, Hideo

    2010-05-01

    Male and female Sprague-Dawley rats received repeated oral administration of 14C-2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3- [5-(trifluoromethyl)-2-pyridyloxy]propyl ether (14C-pyridalyl) at 5 mg/kg/day for 14 consecutive days, and 14C excretion, 14C concentration in tissues, and the metabolic fate were determined. Most 14C was excreted into feces. The 14C concentrations in the blood and tissues attained steady-state levels at days 6 to 10, whereas those in white adipose tissues increased until day 14. Tissue 14C concentrations were highest in brown and white adipose tissue (38.37-57.50 ppm) but were 5.60 ppm or less in all the other tissues. Total 14C residues in blood and tissues on the 27th day after the first administration accounted for 2.6 to 3.2% of the total dose. A major fecal metabolite resulted from O-dealkylation. Analysis of metabolites in tissues revealed that the majority of 14C in perirenal adipose tissue and lungs was pyridalyl, accounting for greater than 90 and 60%, respectively, of the total, whereas a major metabolite in whole blood, kidneys, and liver was a dehalogenated metabolite. The experimental data were simulated with simple physiologically based pharmacokinetics using four-compartment models with assumption of lymphatic absorption and membrane permeability in adipose tissues. The different kinetics in brown and white adipose tissues was reasonably predicted in this model, with large distribution volume in adipose tissues and high hepatic clearance in liver. Sex-related difference of pyridalyl concentration in liver was considered to be a result of different unbound fraction times the hepatic intrinsic clearance (f x CL(int)) of 1.8 and 12 l/h for male and female, respectively. PMID:20164113

  7. Uptake and distribution of fluorescently labeled cobalamin in neoplastic and healthy breast tissue

    NASA Astrophysics Data System (ADS)

    Cannon, Michelle J.; McGreevy, James M.; Holden, Joseph A.; West, Frederick G.; Grissom, Charles B.

    2000-05-01

    Fluorescent analogs of cobalamin (vitamin B12) have been developed as diagnostic markers of cancer cells. These compounds are recognized by transcobalamin, a cobalamin transport protein, with high affinity, as shown by surface plasmon resonance. The cellular sequestration and gross distribution of fluorescent cobalamin bioconjugates in breast tissue is being examined by epifluorescence microscopy. The distribution of each compound is being evaluated in proliferative and non-proliferative tissue, i.e. normal tissue and breast carcinoma. The results of preliminary studies suggest that fluorescent analogs of cobalamin may be a useful tool in therapeutic breast operations to define tumor margins and to distinguish neoplastic breast tissue from healthy breast tissue.

  8. Quantitatively differentiating microstructures of tissues by frequency distributions of Mueller matrix images.

    PubMed

    He, Chao; He, Honghui; Li, Xianpeng; Chang, Jintao; Wang, Ye; Liu, Shaoxiong; Zeng, Nan; He, Yonghong; Ma, Hui

    2015-10-01

    We present a new way to extract characteristic features of the Mueller matrix images based on their frequency distributions and the central moments. We take the backscattering Mueller matrices of tissues with distinctive microstructures, and then analyze the frequency distribution histograms (FDHs) of all the matrix elements. For anisotropic skeletal muscle and isotropic liver tissues, we find that the shapes of the FDHs and their central moment parameters, i.e., variance, skewness, and kurtosis, are not sensitive to the sample orientation. Comparisons among different tissues further indicate that the frequency distributions of Mueller matrix elements and their corresponding central moments can be used as indicators for the characteristic microstructural features of tissues. A preliminary application to human cervical cancerous tissues shows that the distribution curves and central moment parameters may have the potential to give quantitative criteria for cancerous tissues detections. PMID:26502227

  9. Quantitatively differentiating microstructures of tissues by frequency distributions of Mueller matrix images

    NASA Astrophysics Data System (ADS)

    He, Chao; He, Honghui; Li, Xianpeng; Chang, Jintao; Wang, Ye; Liu, Shaoxiong; Zeng, Nan; He, Yonghong; Ma, Hui

    2015-10-01

    We present a new way to extract characteristic features of the Mueller matrix images based on their frequency distributions and the central moments. We take the backscattering Mueller matrices of tissues with distinctive microstructures, and then analyze the frequency distribution histograms (FDHs) of all the matrix elements. For anisotropic skeletal muscle and isotropic liver tissues, we find that the shapes of the FDHs and their central moment parameters, i.e., variance, skewness, and kurtosis, are not sensitive to the sample orientation. Comparisons among different tissues further indicate that the frequency distributions of Mueller matrix elements and their corresponding central moments can be used as indicators for the characteristic microstructural features of tissues. A preliminary application to human cervical cancerous tissues shows that the distribution curves and central moment parameters may have the potential to give quantitative criteria for cancerous tissues detections.

  10. 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.

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

    SciTech Connect

    Genina, E A; Fedosov, I V; Bashkatov, A N; Zimnyakov, D A; Tuchin, V V; Altshuler, G B

    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)

  12. Nanodrugs: pharmacokinetics and safety.

    PubMed

    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

  13. Plasma, tumor and tissue pharmacokinetics of Docetaxel delivered via nanoparticles of different sizes and shapes in mice bearing SKOV-3 human ovarian carcinoma xenograft

    PubMed Central

    Chu, Kevin S.; Hasan, Warefta; Rawal, Sumit; Walsh, Mark D.; Enlow, Elizabeth M.; Luft, J. Christopher; Bridges, Arlene S.; Kuijer, Jennifer L.; Napier, Mary E.; Zamboni, William C.; DeSimone, Joseph M.

    2013-01-01

    The particle fabrication technique PRINT® was used to fabricate monodisperse size and shape specific poly(lactide-co-glycolide) particles loaded with the chemotherapeutic Docetaxel. The pharmacokinetics of two cylindrical shaped particles with diameter=80nm; height=320nm (PRINT-Doc-80×320) and d=200nm; h=200nm (PRINT-Doc-200×200) were compared to Docetaxel in mice bearing human ovarian carcinoma SKOV-3 flank xenografts. The Docetaxel plasma exposure was ~20-fold higher for both particles compared to docetaxel. Additionally, the volume of distribution (Vd) of Docetaxel in PRINT formulations was ~18-fold (PRINT-Doc-80×320) and ~33-fold (PRINT-Doc-200×200) lower than Docetaxel. The prolonged duration of Docetaxel in plasma when dosed with PRINT formulations subsequently lead to increased tumor exposure of Docetaxel from 0-168 hours (~53% higher for PRINT-Doc-80×320 and ~76% higher for PRINT-Doc-200×200 particles). PRINT-Doc-80×320 had lower exposures in the liver, spleen and lung compared with PRINT-Doc-200×200. Thus, the use of particles with smaller feature size may be preferred to decrease clearance by organs of the mononuclear phagocyte system. PMID:23219874

  14. Distribution of lead and mercury in tissues of raccoons

    SciTech Connect

    Khan, A.T.; Thompson, S.J.; Mielke, H.W.

    1994-12-31

    Liver and kidney tissues of raccoons from Tuskegee, Alabama, were analyzed for Hg and Pb contents. The mean levels of Hg and Pb were 0.41 and 3.24 ppm in livers and 0.24 and 4.95 ppm in kidneys, respectively. These metal levels showed no significant differences between livers and kidneys or between males and females.

  15. Distribution of opiate-like substances in rat tissues.

    PubMed

    Neidle, A; Manigault, I; Wajda, I J

    1979-06-01

    Rat tissues were tested for their ability to inhibit the binding of [3H]dihydromorphine or [3H]naloxone to membrane-bound opiate receptors. By this criterion, morphine-like substances were found in lung, heart, liver, and kidney as well as in brain. The relative activity of the extracts, based on initial tissue weight, differed with the radioactive lignand employed. With dihydromorphine, the order was as above. With naloxone, lung was most active, followed by heart, brain, liver, and kidney. The ability of all tissue extracts to inhibit opiate binding was reduced by 100 mM NaC1 and slightly reduced by 1 mM MnC1(2). Gel filtration using Sephadex G-25 indicated that the inhibitory substances were heterogeneous in molecular weight. Only with brain and kidney extracts was there significant activity at the elution volume where enkephalins would be expected. Fractionation using Amberlite XAD-2, a resin which selectively absorbs hydrophobic materials, again indicated that the major protion of activity in all tissue extracts was due to substances other than enkephalins. PMID:223080

  16. Uptake, Metabolism, and Tissue Distribution of Chemicals in Organisms

    EPA Science Inventory

    This talk will explain how chemicals get into aquatic species, what tissues and organs the chemicals move into, and what can happen to the chemicals once they get there. This will be presented using examples from recent studies conducted using state-of-the-art microscopy with em...

  17. Antibiotic residues distribute uniformly in broiler chicken breast muscle tissue.

    PubMed

    Reyes-Herrera, Ixchel; Donoghue, Dan J

    2008-01-01

    Use of antibiotics by the poultry industry has the potential to produce residues in edible tissues. In order to protect consumers, the U.S. federal government performs extensive evaluations to quantify residues in edible tissues to ensure that concentrations do not exceed the tolerance level. However, in the case of muscle tissue, the regulatory process does not differentiate between different edible muscle types in poultry. Previous studies performed by our laboratory determined higher fluoroquinolone residue concentrations in breast versus thigh muscle. Thus, if thigh tissues were used for residue monitoring, it would not accurately depict the higher concentrations. It is also possible that residue concentrations vary within tissues. To evaluate this possibility, fluoroquinolone antibiotic residues were determined for different breast sections. One hundred sixty chickens were randomly divided into four groups and dosed at 33 days of age with the fluoroquinolone antibiotic, enrofloxacin (Baytril), at either 25 ppm for 3 days, 25 ppm for 7 days, 50 ppm for 3 days, or 50 ppm for 7 days. Breast fillets were collected from each bird (n = 5 birds per day per group) during the dosing and withdrawal period. Each breast was divided into four sections (upper left, upper right, lower left, and lower right) that were analyzed as individual samples for determination of fluoroquinolone concentration. Our results indicated no significant difference (P > 0.05) in the levels of enrofloxacin residues between breast sections during the dosing or withdrawal periods. Consequently, samples can be collected from any breast section to evaluate fluoroquinolone residue concentrations during the regulatory monitoring process. PMID:18236689

  18. Tissue, cellular, and subcellular distribution of /sup 241/Pu in the rat testes

    SciTech Connect

    Miller, S.C.; Bowman, B.M.

    1983-05-01

    The distribution and localization of /sup 241/Pu in rat testes were determined by quantitative autoradiography. Rats were given intravenous injection of /sup 241/Pu citrate and tissues were collected 1 week later. The tissue distribution of /sup 241/Pu was determined by light microscope autoradiography. Significant concentrations of /sup 241/Pu were observed in the interstitial tissue but not in seminiferous tubules. The cellular distribution and subcellular localization of /sup 241/Pu were determined by electron microscope autoradiography. Within the interstitial tissue, /sup 241/Pu was concentrated in microphages. There was no preferential localization of /sup 241/Pu in any other interstitial tissue components. Within interstitial tissue macrophages, /sup 241/Pu was concentrated in the lysosomal system of the cell. Other organellar compartments of the cell did not preferentially incorporate /sup 241/Pu. The association of /sup 241/Pu with the macrophage lysosomal system may explain the long retention times of Pu in testes as observed in experimental studies.

  19. 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

  20. Phase I Pharmacokinetic and Pharmacodynamic Study of Pazopanib in Children With Soft Tissue Sarcoma and Other Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report

    PubMed Central

    Glade Bender, Julia L.; Lee, Alice; Reid, Joel M.; Baruchel, Sylvain; Roberts, Timothy; Voss, Stephan D.; Wu, Bing; Ahern, Charlotte H.; Ingle, Ashish M.; Harris, Pamela; Weigel, Brenda J.; Blaney, Susan M.

    2013-01-01

    Purpose Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors. Patients and Methods Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m2) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD. Results Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m2 for tablet and 160 mg/m2 for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41). Conclusion Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma. PMID:23857966

  1. Pharmacokinetics of tildipirosin in porcine plasma, lung tissue, and bronchial fluid and effects of test conditions on in vitro activity against reference strains and field isolates of Actinobacillus pleuropneumoniae.

    PubMed

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

    2013-04-01

    The pharmacokinetics of tildipirosin (Zuprevo(®) 40 mg/mL solution for injection for pigs), a novel 16-membered-ring macrolide for the treatment for swine respiratory disease (SRD), was investigated in studies collecting blood plasma and postmortem samples of lung tissue and bronchial fluid (BF) from swine. In view of factors influencing the in vitro activity of macrolides, and for the interpretation of tildipirosin pharmacokinetics in relation to minimum inhibitory concentrations (MIC), additional experiments were conducted to study the effects of pH, carbon dioxide-enriched atmosphere, buffers, and serum on tildipirosin MICs for various reference strains and Actinobacillus (A.) pleuropneumoniae field isolates. After single intramuscular (i.m.) injection at 4 mg/kg body weight, maximum plasma concentration (Cmax) was 0.9 μg/mL observed within 23 min (Tmax ). Mean residence time from the time of dosing to the time of last measurable concentration (MRTlast) and terminal half-life (T1/2) both were about 4 days. A dose-response relationship with no significant sex effect is observed for area under the plasma concentration-time curve from time 0 to the last sampling time with a quantifiable drug concentration (AUClast) over the range of doses up to 6 mg/kg. However, linear dose proportionality could not be proven with statistical methods. The time-concentration profile of tildipirosin in BF and lung far exceeded that in blood plasma. In lung, tildipirosin concentrations reached 3.1 μg/g at 2 h, peaked at 4.3 μg/g at day 1, and slowly declined to 0.8 μg/g at day 17. In BF, tildipirosin levels were 14.3, 7.0, and 6.5 μg/g at days 5, 10, and 14. T1/2 in lung was ∼7 days. Tildipirosin is rapidly and extensively distributed to the respiratory tract followed by slow elimination. Culture media pH and carbon dioxide-enriched atmosphere (CO2 -EA) had a marked impact on in vitro activity of tildipirosin in reference strains of various rapidly growing aerobic and

  2. Pharmacokinetic evaluation of ceftiofur in serum, tissue chamber fluid and bronchial secretions from healthy beef-bred calves.

    PubMed Central

    Halstead, S L; Walker, R D; Baker, J C; Holland, R E; Stein, G E; Hauptman, J G

    1992-01-01

    Ceftiofur is a new broad spectrum cephalosporin marketed for the treatment of acute bovine respiratory disease. In this investigation ceftiofur was administered by intramuscular injection, at 24 h intervals, to healthy beef-bred calves for four days at dosages of 2.2 and 4.4 mg/kg of body weight, with 4 wk intervals between dosing regimens. Serum, tissue chamber fluid (TCF), and bronchial secretion (BS) concentrations of ceftiofur were measured by microbiological assay after the first and fourth dose of each dosing regimen. Peak serum concentrations (Cmax) of 8.8 micrograms/mL and 17.3 micrograms/mL were obtained approximately 2 h (Tmax), the time of mean peak concentration) after single injections of 2.2 mg/kg and 4.4 mg/kg, respectively. The Cmax was increased approximately twofold following multiple doses of 2.2 mg/kg (Cmax = 13.1 micrograms/mL) and 4.4 mg/kg (Cmax = 24.1 micrograms/mL). Ceftiofur accumulated slowly into TCF and peak concentrations were found to be approximately 14% of those observed in serum after the first dose and approximately 24% after multiple dosing. Concentrations of ceftiofur in BS were obtained rapidly with peak concentrations reaching 45% of the serum Cmax after the first dose. After multiple dosing the Cmax for BS was approximately 25% of the serum Cmax. This study found that both the 2.2 mg/kg and 4.4 mg/kg dosing regimens resulted in continuous serum, TCF and BS concentrations of ceftiofur that exceeded the minimal concentration required to inhibit the bacteria most frequently isolated from calves with acute bovine respiratory disease. PMID:1477795

  3. Tissue distribution and elimination of rotenone in rainbow trout

    USGS Publications Warehouse

    Gingerich, W.H.

    1986-01-01

    The fate of a single i.v. dose (120 μg/kg) of the piscicide [14C]rotenone was evaluated in rainbow trout for periods up to 72 h after dosing. Rotenone was rapidly cleared from the plasma; less than 2% of the dose remained in the plasma compartment after 20 min. The highest concentrations of rotenone residues (% dose/g tissue) were in the hepatobiliary system, bile, intestine, and in heart, lateral line swimming muscle, and posterior kidney; tissues that are highly dependent on oxidative metabolism. Although rotenone activity was present in all cell fractions examined, greater than 40% was associated with the mitochondrial fraction of liver, kidney, and muscle. More than 85% of the activity extracted from these tissues, except the liver, was parent rotenone. Elimination from whole body and major tissue depots conformed to simple first-order kinetics; the estimated half-life from whole body was 68.5 h. Branchial elimination accounted for 5% of the injected dose over a 4-h period, and urinary elimination was less than 2% over a 48-h period. Rotenone was eliminated essentially unchanged across the gills; however, parent rotenone was not found in either urine or bile. More than 80% of the activity in both urine and bile eluted from HPLC chromatographs as a highly polar fraction that was not hydrolyzed by incubation with either β-glucuronidase or sulfatase. The results imply that hepatobiliary excretion is the major route of elimination for rotenone residues in the trout and that metabolism to a more polar form is a prerequisite for elimination in both the bile and the urine

  4. Distribution and chemical form of mercury in commercial fish tissues.

    PubMed

    Watanabe, Naoko; Tayama, Misato; Inouye, Minoru; Yasutake, Akira

    2012-01-01

    We analyzed total Hg concentrations in various tissue samples obtained from 7 commercially available fish species. MeHg contents were also estimated for muscle and liver samples by a selective analysis of inorganic Hg. Among the tissues, high Hg accumulations were shown in liver, muscle, heart and spleen throughout all fish species. Carnivorous fish, such as scorpion fish, sea bream and Japanese whiting, tended to show higher Hg accumulations in the muscle, with the highest Hg levels being shown by scorpion fish. Although the liver was expected to show the highest Hg accumulations among tissues throughout all fish species, the highest accumulation in the liver was observed only in scorpion fish. In contrast, the muscle level was significantly higher than the liver in Pacific saury and Japanese whiting. MeHg accumulated in fish is considered to show a sustained increase throughout the life of the fish, due to its long biological half-life. In fact, in the present study, muscle Hg levels in Japanese whiting, Japanese flying fish, and halfbeak showed good correlations with body weights. However, such correlations were not clear in scorpion fish, sea bream, Jack mackerel and Pacific saury. Selective analyses of inorganic Hg levels revealed that most of the Hg (> 95%) in fish muscle existed as MeHg, while the rates of MeHg contents in the liver varied from 56% in scorpion fish to 84% in Jack mackerel. As a result, fish muscle showed the highest MeHg accumulations in all fish species examined. These results suggest that reliable information on total Hg contents in fish muscle might be sufficient to avoid the risk of MeHg exposure caused by eating fish, even when one consumes other tissues such as fish liver. PMID:22863865

  5. Toxicokinetics and tissue distribution of nivalenol in broiler chickens.

    PubMed

    Kongkapan, Jutamart; Giorgi, Mario; Poapolathep, Saranya; Isariyodom, Supaporn; Poapolathep, Amnart

    2016-03-01

    Nivalenol (NIV), a type B trichothecene mycotoxin, is mainly produced by the fungi of Fusarium genus, which naturally occurs in agricultural commodities. Consumers are particularly concerned over the toxicity and safety of NIV in food animal products. To evaluate the toxicokinetics and persistence of residues of NIV, NIV was administered intravenously (iv) or orally (po) to broiler chickens at a dosage of 0.8 mg/kg body weight. The concentration of NIV in the plasma and various tissues was detected using liquid chromatography tandem-mass spectrometry. The plasma concentration of NIV in broilers could be measured up to 24 h and 12 h after iv and po administration, respectively. The value of elimination half-life of NIV was 5.27 ± 0.82 h and 2.51 ± 0.88 h after iv and po administration, respectively. The absolute oral bioavailability was 3.98 ± 0.08%. NIV was detected in the intestine, kidney, muscle, heart and liver after po administration. Regarding tissue residues, largest quantities of NIV were found in the small intestine. These results suggest that NIV is absorbed from the gastrointestinal tract with low bioavailability and it has the ability to diffuse into various tissues of broilers. PMID:26739759

  6. Distribution of clobetasone in rabbit eye tissues after topical application.

    PubMed

    Rink, H; Connors, B; Wegener, A; Umlauf, A; Hockwin, O

    1989-01-01

    This study describes the bioavailability of Clobetasone, which is topically applied as an anti-inflammatory drug. Right eyes of Chinchilla rabbits received Clobetasone eye drops 3 times daily over a period of consecutive 14 days. 30 min up to 96 h after the last application animals were killed at different times and the eyes removed immediately. Nine different eye tissue samples were prepared for Clobetasone estimation by radioimmunoassay (RIA) using 3H-labeled Clobetasone and an antibody directed against Clobetasone. Results indicate that Clobetasone penetrates relatively fast into the different eye tissues. The concentrations are different in the various tissues and show a relationship to the distance from cornea to vitreous. Concentrations decline in the following order: cornea greater than conjunctiva, sclera, iris (200 ng/g) greater than lens, vitreous, aqueous humour (5-15 ng/g). In all samples investigated Clobetasone levels decrease with time. No accumulation of the drug has been measured at any time. Clobetasone levels in the left, untreated eye, indicate that the compound has a small systemic resorption. PMID:2488027

  7. Pharmacokinetics & Neurophysiology

    ERIC Educational Resources Information Center

    Davis, Andrew S.; Salpekar, Jay A.

    2009-01-01

    Medications administered in clinical practice obtain their therapeutic effect only to the extent that the drug is present in the appropriate concentration at the desired site. To achieve this goal, the prescribing clinician must be aware of how a drug may interact with the physiology of the patient. Pharmacokinetics is the study of this process…

  8. Clinical pharmacokinetics of dapsone.

    PubMed

    Zuidema, J; Hilbers-Modderman, E S; Merkus, F W

    1986-01-01

    Dapsone (DDS) has for about 4 decades been the most important antileprosy drug. Concentrations of dapsone and its monoacetyl metabolite, MADDS, can be determined in biological media by high-performance liquid chromatography. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. However, the extent of absorption has not been adequately determined. The elimination half-life of dapsone is about 30 hours. The drug shows linear pharmacokinetics within the therapeutic range and the time-course after oral administration fits a 2-compartment model. The concentration-time profile of dapsone after parenteral administration is reviewed. Of clinical importance is the development of a new long acting injection, which permits monthly supervised administration as recommended by the World Health Organization. Following dapsone injection in gluteal subcutaneous adipose tissue, a sufficiently sustained absorption for this purpose has been reported. Dapsone is about 70 to 90% protein bound and its monoacetylated metabolite (MADDS) is almost completely protein bound. The volume of distribution of dapsone is estimated to be 1.5 L/kg. It is distributed in most tissues, but M. leprae living in the Schwann cells of the nerves might be unaffected. Dapsone crosses the placenta and is excreted in breast milk and saliva. Dapsone is extensively metabolised. Dapsone, some MADDS and their hydroxylated metabolites are found in urine, partly conjugated as N-glucuronides and N-sulphates. The acetylation ratio (MADDS:dapsone) shows a genetically determined bimodal distribution and allows the definition of 'slow' and 'rapid' acetylators. As enterohepatic circulation occurs, the elimination half-life of dapsone is markedly decreased after oral administration of activated charcoal. This permits successful treatment in cases of intoxication. The daily dose of dapsone in leprosy is 50 to

  9. [11C]-Labeled Metformin Distribution in the Liver and Small Intestine Using Dynamic Positron Emission Tomography in Mice Demonstrates Tissue-Specific Transporter Dependency.

    PubMed

    Jensen, Jonas B; Sundelin, Elias I; Jakobsen, Steen; Gormsen, Lars C; Munk, Ole L; Frøkiær, Jørgen; Jessen, Niels

    2016-06-01

    Metformin is the most commonly prescribed oral antidiabetic drug, with well-documented beneficial preventive effects on diabetic complications. Despite being in clinical use for almost 60 years, the underlying mechanisms for metformin action remain elusive. Organic cation transporters (OCT), including multidrug and toxin extrusion proteins (MATE), are essential for transport of metformin across membranes, but tissue-specific activity of these transporters in vivo is incompletely understood. Here, we use dynamic positron emission tomography with [(11)C]-labeled metformin ([(11)C]-metformin) in mice to investigate the role of OCT and MATE in a well-established target tissue, the liver, and a putative target of metformin, the small intestine. Ablation of OCT1 and OCT2 significantly reduced the distribution of metformin in the liver and small intestine. In contrast, inhibition of MATE1 with pyrimethamine caused accumulation of metformin in the liver but did not affect distribution in the small intestine. The demonstration of OCT-mediated transport into the small intestine provides evidence of direct effects of metformin in this tissue. OCT and MATE have important but separate roles in uptake and elimination of metformin in the liver, but this is not due to changes in biliary secretion. [(11)C]-Metformin holds great potential as a tool to determine the pharmacokinetic properties of metformin in clinical studies. PMID:26993065

  10. Five-layer realistic head model based on inhomogeneous and anisotropic conductivity distribution of different tissues

    NASA Astrophysics Data System (ADS)

    Yan, Dandan; Zhang, Jianwei; Wu, Weijuan; Ying, Xiaoyan; Wu, Xiangping

    2009-10-01

    This paper is focused on the sophisticated realistic head modeling based on inhomogeneous and anisotropic conductivity distribution of the head tissues. The finite element method (FEM) was used to model the five-layer head volume conductor models with hexahedral elements from segmentation and mapping of DT-MRI data. Then the inhomogeneous conductivities of the scalp, CSF and gray matter tissue were distributed according a normal distribution based on the mean value of respective tissues. The electric conductivity of the brain tissues dictates different inhomogeneous and anisotropic at some different microscopic levels. Including the inhomogeneous and anisotropy of the tissue would improve the accuracy of the MREIT, EEG and MEG problems in the simulation research.

  11. Distribution of purine nucleotides in uremic fluids and tissues.

    PubMed

    Rutkowski, Bolesław; Rutkowski, Przemysław; Słomińska, Ewa; Swierczyński, Julian

    2010-09-01

    There are almost 100 different substances called uremic toxins. In this study, we analyze all findings concerning the new family of uremic compounds--nicotinamide end products: N-methyl-2-pyridone-5-carboxamide (Met2PY), N-methyl-4-pyridone-5-carboxamide, newly described 4-pyridone-3-carboxamide-1-beta-D-ribonucleoside (4PYR) and 4-pyridone-3-carboxamide-1-beta-D-ribonucleoside triphosphate (4PYTP). After few years of studies, we have found that these substances have higher plasma concentration in patients with chronic renal failure (CRF) in comparison with the healthy population. We noted a 40-fold increase in plasma 4PYR concentration in patients with CRF. This increment correlates significantly with the decline of kidney function measured as an increase of serum creatinine concentration and decrease of estimated glomerular filtration rate. Tested compounds are present and measurable in physiological fluids and tissues. We found higher saliva Met2PY concentration in patients with CRF in comparison with controls. Saliva Met2PY correlated negatively with estimated glomerular filtration rate and positively with serum creatinine concentration. One-third of studied group had higher concentration of Met2PY in the saliva than in plasma, and this segment of patients may be called as "good excretors." In rats with experimental CRF, we found that both Met2PY and N-methyl-4-pyridone-5-carboxamide accumulated in selected tissues. We also demonstrated formation of 4PYTP in intact human erythrocytes during incubation with the precursor 4PYR. Incubation with 4PYR leads to lowering concentration of adenosine-5'-triphosphate. 4PYTP formation may be a way to remove 4PYR from the circulation and save adenosine-5'-triphosphate depletion. Summarizing, end products of the nicotinamide family are members of uremic toxins; however, exact pathophysiological role of these compounds in the development of uremic syndrome needs further studies. PMID:20797575

  12. In vivo experiments of laser thermotherapy on liver tissue with FBG temperature distribution sensor

    NASA Astrophysics Data System (ADS)

    Chen, Na; Chen, Shaofeng; Zhu, Hongfei; Liu, Shupeng; Chen, Zhenyi; Pang, Fufei; Wang, Tingyun

    2012-06-01

    In this paper, we report an in vivo experimental study of liver tissue during Laser Induced Interstitial Thermotherapy (LITT). Single FBG was used in the experiments to measure the temperature distribution profile of the bio tissue in real time. Ideally, the goal of LITT is to kill pathological tissue thoroughly and minimize its damage to surrounding healthy tissue, especially vital organs. The extent of treated tissue damage in the therapy is mainly dependent on the irradiation time and the laser power density at the tissue surface. Therefore, monitoring the dynamic change of the exact temperature distribution of the tissue is a key point for the safety of this treatment. In our experiments, FBG was embedded in the laser irradiated bio tissues and used as fully distributed temperature sensor. During the therapy, its reflection spectra were recorded and transmitted to PC in real time. The temperature profile along the FBG axial was reconstructed from its reflection spectrum by the spectra inversion program running on the PC. We studied the dependence of the temperature distribution and the laser output power experimentally and compared the results of in vivo and in vitro under similar laser irradiating conditions. Experimental results demonstrate the effectiveness of this method. Due to influence of body temperature, the in vivo measured temperature is higher than the in vitro one with an almost constant temperature difference value, but the slope and trend of the measured temperature curves in vivo and in vitro are almost identical.

  13. Simulation and Study of Temperature Distribution in Living Biological Tissues under Laser Irradiation

    PubMed Central

    Shurrab, Kawther Mohammad; Sayem EL-Daher, Moustafa

    2014-01-01

    Introduction: With the rapid increase in use of lasers in medical treatments, it is important to understand the mechanisms of heat transfer in biological tissues in order to minimize damage to the tissues resulting from extra heat applied. The aim of this study is to investigate the temperature distribution in living biological tissues when laser irradiation is used in a treatment. Methods: In this work a model was suggested to study the impact of several parameters such as (laser power, exposure time, laser spot size) on the temperature distribution within skin tissues when subjected to a laser source. A three-dimensional finite element thermal model of biological tissues was developed using bio-heat equation to describe heat transfer in living tissues. Results: Temperature distribution within skin tissues subjected to laser heating is calculated in details using the Finite element method and a suggested model; the results are presented in figures and tables showing the effects of Laser spot size, power and exposure time on temperature distribution within treated tissue. Conclusion: the results presented in this work are expected to be useful in optimizing Laser spot size, power and exposure time for a variety of laser applications medicine and surgery. PMID:25653812

  14. Investigating the pharmacokinetics and biological distribution of silver-loaded polyphosphoester-based nanoparticles using 111Ag as a radiotracer

    PubMed Central

    Aweda, Tolulope A.; Zhang, Shiyi; Mupanomunda, Chiedza; Burkemper, Jennifer; Heo, Gyu Seong; Bandara, Nilantha; Lin, Mai; Cutler, Cathy S.; Cannon, Carolyn L.; Youngs, Wiley; Wooley, Karen L.; Lapi, Suzanne E.

    2015-01-01

    Purified 111Ag was used as a radiotracer to investigate silver loading and release, pharmacokinetics and biodistribution of polyphosphoester-based degradable shell crosslinked knedel-like (SCK) nanoparticles as a comparison to the previously reported small molecule, N-heterocyclic silver carbene complex analogue (SCC1) for the delivery of therapeutic silver ions in mouse models. Biodistribution studies were conducted by aerosol administration of 111Ag acetate, [111Ag]SCC1 and [111Ag]SCK doses directly into the lungs of C57BL/6 mice. Nebulization of the 111Ag antimicrobials resulted in an average uptake of 1.07 ± 0.12% of the total aerosolized dose given per mouse. The average dose taken into the lungs of mice was estimated to be 2.6 ± 0.3% of the dose inhaled per mouse for [111Ag]SCC1 and twice as much dose was observed for the [111Ag]SCKs (5.0 ± 0.3% and 5.9 ± 0.8% for [111Ag]aSCK and [111Ag]zSCK, respectively) at 1 h post administration (p.a.). [111Ag]SCKs also exhibited higher dose retention in the lungs; 62 – 68% for [111Ag]SCKs and 43% for [111Ag]SCC1 of the initial 1 h dose was observed in the lungs at 24 h post administration (p.a.). This study demonstrates the utility of 111Ag as a useful tool for monitoring the pharmacokinetics of silver loaded antimicrobials in vivo. PMID:25952472

  15. Investigating the pharmacokinetics and biological distribution of silver-loaded polyphosphoester-based nanoparticles using (111) Ag as a radiotracer.

    PubMed

    Aweda, Tolulope A; Zhang, Shiyi; Mupanomunda, Chiedza; Burkemper, Jennifer; Heo, Gyu Seong; Bandara, Nilantha; Lin, Mai; Cutler, Cathy S; Cannon, Carolyn L; Youngs, Wiley J; Wooley, Karen L; Lapi, Suzanne E

    2015-05-30

    Purified (111) Ag was used as a radiotracer to investigate silver loading and release, pharmacokinetics, and biodistribution of polyphosphoester-based degradable shell crosslinked knedel-like (SCK) nanoparticles as a comparison to the previously reported small molecule, N-heterocyclic silver carbene complex analog (SCC1) for the delivery of therapeutic silver ions in mouse models. Biodistribution studies were conducted by aerosol administration of (111) Ag acetate, [(111) Ag]SCC1, and [(111) Ag]SCK doses directly into the lungs of C57BL/6 mice. Nebulization of the (111) Ag antimicrobials resulted in an average uptake of 1.07 ± 0.12% of the total aerosolized dose given per mouse. The average dose taken into the lungs of mice was estimated to be 2.6 ± 0.3% of the dose inhaled per mouse for [(111) Ag]SCC1 and twice as much dose was observed for the [(111) Ag]SCKs (5.0 ± 0.3% and 5.9 ± 0.8% for [(111) Ag]aSCK and [(111) Ag]zSCK, respectively) at 1 h post administration (p.a.). [(111) Ag]SCKs also exhibited higher dose retention in the lungs; 62-68% for [(111) Ag]SCKs and 43% for [(111) Ag]SCC1 of the initial 1 h dose were observed in the lungs at 24 h p.a.. This study demonstrates the utility of (111) Ag as a useful tool for monitoring the pharmacokinetics of silver-loaded antimicrobials in vivo. PMID:25952472

  16. Formalizing an electronic institution for the distribution of human tissues.

    PubMed

    Vázquez-Salceda, J; Padget, J A; Cortés, U; López-Navidad, A; Caballero, F

    2003-03-01

    The use of multi-agent systems (MAS) in health-care domains is increasing. Such agent-mediated medical systems can manage complex tasks and have the potential to adapt gracefully to unexpected events. However, in these kinds of systems the issues of privacy, security and trust are particularly sensitive in relation to matters such as agents' access to patient records, what is acceptable behaviour for an agent in a particular role and the development of trust both between (heterogeneous) agents and between users and agents. To address these issues we propose a formal normative framework, deriving from and developing the notion of an electronic institution. Such institutions provide a framework to define and police norms that guide, control and regulate the behaviour of the heterogeneous agents that participate in the institution. These norms define the acceptable actions that each agent may perform depending on the role or roles it is playing, and clearly specifies the data it may access and/or modify in playing those roles. In this paper, we present the formalization of Carrel, a virtual organization for the procurement of organs and tissues for transplantation purposes, as an electronic institution using the ISLANDER institution specification language as formalizing languages. We demonstrate aspects of the formalization of such an institution, example fragments in the language used for the textual specification, and how such formalization can be used as a blueprint in the implementation of the final agent architecture, through techniques such as skeleton generation. PMID:12667738

  17. Tissue distribution of newer anticonvulsant drugs in postmortem cases.

    PubMed

    Levine, Barry; Phipps, Rebecca Jufer; Naso, Clare; Fahie, Kisha; Fowler, David

    2010-10-01

    Levetiracetam, hydroxycarbazepine (the primary product of oxcarbazepine use), and topiramate were quantified using the acid/neutral drug screening procedure employed by this laboratory. Briefly, blood or tissue homogenate spiked with an internal standard (cyclopentobarbital) was buffered to pH 5 and applied to Chem Elut® columns. The columns were washed with methylene chloride, collected, and evaporated to dryness. The residue was reconstituted with 0.033 M trimethylanilinium hydroxide and injected into a gas chromatograph equipped with a DB-5 analytical column (25 m × 0.32-mm i.d.) and a nitrogen-phosphorus detector. A calibration curve using four calibrators ranging in concentration from 2 to 20 mg/L was used for quantification. Despite the limited number of cases for each drug, there were some trends suggested by the data. None of the drugs displayed significant differences in concentration between the heart blood and peripheral (subclavian) blood specimens. Only the hydroxycarbazepine quantifications in one case (case 5) showed significant differences between the two blood sites. This is consistent with other acid/neutral drugs such as acetaminophen and meprobamate. It also appears that the liver and kidney concentrations of the three drugs are on the same order of magnitude as the blood concentrations. Only the levetiracetam concentration in one case (case 3) reflected a liver or kidney concentration greater than 5 times the blood concentration. PMID:21819796

  18. Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis.

    PubMed

    Wring, Stephen; Gaukel, Eric; Nare, Bakela; Jacobs, Robert; Beaudet, Beth; Bowling, Tana; Mercer, Luke; Bacchi, Cyrus; Yarlett, Nigel; Randolph, Ryan; Parham, Robin; Rewerts, Cindy; Platner, Jacob; Don, Robert

    2014-01-01

    SUMMARY This review presents a progression strategy for the discovery of new anti-parasitic drugs that uses in vitro susceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic-pharmacodynamic (PK-PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promising in vitro activity and selectivity for the target organism over mammalian cells are advanced to in vitro metabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly, in vitro time-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) with in vitro activity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic-pharmacodyamic studies in animal infection models. PMID:24007596

  19. 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...

  20. Biochemical, thrombolytic and pharmacokinetic properties of rt-PA P47G, K49N, a substitution variant of human tissue-type plasminogen activator.

    PubMed

    Nelles, L; Li, X K; Vanlinthout, I; De Cock, F; Lijnen, H R; Collen, D

    1992-04-01

    rt-PA P47G, K49N, a substitution variant of recombinant human tissue-type plasminogen activator (rt-PA), in which proline at position 47 and lysine at position 49 were replaced by glycine and asparagine respectively, was previously described by Ahern et al. (J Biol Chem 1990; 265:5540-5) to have an extended in vivo half-life with unaltered in vitro fibrinolytic properties. Because this variant might possess an increased in vivo thrombolytic potency, we have constructed its cDNA, expressed it in Chinese hamster ovary cells and determined its biochemical, thrombolytic and pharmacokinetic properties relative to those of home-made rt-PA and of alteplase (Actilyse). The specific fibrinolytic activities on fibrin plates were 160,000 +/- 17,000, 210,000 +/- 88,000 and 460,000 +/- 72,000 IU/mg (mean +/- SEM) for rt-PA P47G, K49N, rt-PA and alteplase, respectively, while the catalytic efficiencies for plasminogen activation (k2/Km) in the absence of fibrin were comparable (1.1 to 1.7 x 10(-3) microM-1s-1). Fibrin enhanced the rate of plasminogen activation by rt-PA P47G, K49N 100-fold and by both wild-type molecules 390-fold. Binding of the variant rt-PA to fibrin was significantly reduced, but its affinity for lysine-Sepharose was unaltered. In an in vitro clot lysis system, consisting of a radiolabeled human plasma clot submersed in plasma, 50% clot lysis in 2 h required 0.67 +/- 0.14 micrograms/ml rt-PA P47G, K49N, 0.36 +/- 0.01 micrograms/ml rt-PA and 0.17 +/- 0.01 micrograms/ml alteplase, respectively (mean +/- SEM; n = 3 or 4). At these doses residual fibrinogen levels at 2 h were in excess of 80%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1631793

  1. Influence of tissue- and cell-scale extracellular matrix distribution on the mechanical properties of tissue-engineered cartilage.

    PubMed

    Khoshgoftar, Mehdi; Wilson, Wouter; Ito, Keita; van Donkelaar, Corrinus C

    2013-10-01

    The insufficient load-bearing capacity of today's tissue- engineered (TE) cartilage limits its clinical application. Generally, cartilage TE studies aim to increase the extracellular matrix (ECM) content, as this is thought to determine the load-bearing properties of the cartilage. However, there are apparent inconsistencies in the literature regarding the correlation between ECM content and mechanical properties of TE constructs. In addition to the amount of ECM, the spatial inhomogeneities in ECM distribution at the tissue scale as well as at the cell scale may affect the mechanical properties of TE cartilage. The relative importance of such structural inhomogeneities on mechanical behavior of TE cartilage is unknown. The aim of the present study was, therefore, to theoretically elucidate the influence of these inhomogeneities on the mechanical behavior of chondrocyte-agarose TE constructs. A validated non-linear fiber-reinforced poro-elastic swelling cartilage model that can accommodate for effects of collagen reinforcement and swelling by proteoglycans was used. At the tissue scale, ECM was gradually varied from predominantly localized in the periphery of the TE construct toward an ECM-rich inner core. The effect of these inhomogeneities in relation to the total amount of ECM was also evaluated. At the cell scale, ECM was gradually varied from localized in the pericellular area, toward equally distributed throughout the interterritorial area. Results from the tissue-scale model indicated that localization of ECM in either the construct periphery or in the inner core may reduce construct stiffness compared with that of constructs with homogeneous ECM. Such effects are more significant at high ECM amounts. At the cell scale, localization of ECM around the cells significantly reduced the overall stiffness, even at low ECM amounts. The compressive stiffness gradually increased when ECM distribution became more homogeneous and the osmotic swelling pressure in the

  2. Engineered nanomaterial uptake and tissue distribution: from cell to organism

    PubMed Central

    Kettiger, Helene; Schipanski, Angela; Wick, Peter; Huwyler, Jörg

    2013-01-01

    Improved understanding of interactions between nanoparticles and biological systems is needed to develop safety standards and to design new generations of nanomaterials. This article reviews the molecular mechanisms of cellular uptake of engineered nanoparticles, their intracellular fate, and their distribution within an organism. We have reviewed the available literature on the uptake and disposition of engineered nanoparticles. Special emphasis was placed on the analysis of experimental systems and their limitations with respect to their usefulness to predict the in vivo situation. The available literature confirms the need to study particle characteristics in an environment that simulates the situation encountered in biological systems. Phenomena such as protein binding and opsonization are of prime importance since they may have a strong impact on cellular internalization, biodistribution, and immunogenicity of nanoparticles in vitro and in vivo. Extrapolation from in vitro results to the in vivo situation in the whole organism remains a challenge. However, improved understanding of physicochemical properties of engineered nanoparticles and their influence on biological systems facilitates the design of nanomaterials that are safe, well tolerated, and suitable for diagnostic or therapeutic use in humans. PMID:24023514

  3. Engineered nanomaterial uptake and tissue distribution: from cell to organism.

    PubMed

    Kettiger, Helene; Schipanski, Angela; Wick, Peter; Huwyler, Jörg

    2013-01-01

    Improved understanding of interactions between nanoparticles and biological systems is needed to develop safety standards and to design new generations of nanomaterials. This article reviews the molecular mechanisms of cellular uptake of engineered nanoparticles, their intracellular fate, and their distribution within an organism. We have reviewed the available literature on the uptake and disposition of engineered nanoparticles. Special emphasis was placed on the analysis of experimental systems and their limitations with respect to their usefulness to predict the in vivo situation. The available literature confirms the need to study particle characteristics in an environment that simulates the situation encountered in biological systems. Phenomena such as protein binding and opsonization are of prime importance since they may have a strong impact on cellular internalization, biodistribution, and immunogenicity of nanoparticles in vitro and in vivo. Extrapolation from in vitro results to the in vivo situation in the whole organism remains a challenge. However, improved understanding of physicochemical properties of engineered nanoparticles and their influence on biological systems facilitates the design of nanomaterials that are safe, well tolerated, and suitable for diagnostic or therapeutic use in humans. PMID:24023514

  4. Penetration of piperacillin-tazobactam into human prostate tissue and dosing considerations for prostatitis based on site-specific pharmacokinetics and pharmacodynamics.

    PubMed

    Kobayashi, Ikuo; Ikawa, Kazuro; Nakamura, Kogenta; Nishikawa, Genya; Kajikawa, Keishi; Yoshizawa, Takahiko; Watanabe, Masahito; Kato, Yoshiharu; Zennami, Kenji; Kanao, Kent; Tobiume, Motoi; Yamada, Yoshiaki; Mitsui, Kenji; Narushima, Masahiro; Morikawa, Norifumi; Sumitomo, Makoto

    2015-08-01

    This study aimed to investigate the penetration of PIPC-TAZ into human prostate, and to assess effectiveness of PIPC-TAZ against prostatitis by evaluating site-specific PK-PD. Patients with prostatic hypertrophy (n = 47) prophylactically received a 0.5 h infusion of PIPC-TAZ (8:1.2-0.25 g or 4-0.5 g) before transurethral resection of the prostate. PIPC-TAZ concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were analyzed with a three-compartment PK model. The estimated model parameters were, then used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T > MIC, the PD indicator for antibacterial effects) in prostate tissue for six PIPC-TAZ regimens (2.25 or 4.5 g; once, twice, three times or four times daily; 0.5 h infusions). Prostate tissue/plasma ratio of PIPC was about 36% both for the maximum drug concentration (Cmax) and the area under the drug concentration-time curve (AUC). Against MIC distributions for isolates of Escherichia coli, Klebsiella species and Proteus species, regimens of 4.5 g twice daily and 2.25 g three times daily achieved a >90% probability of attaining the bacteriostatic target for PIPC (30% T > MIC) in prostate tissue; regimens of 4.5 g three times daily and 2.25 g four times daily achieved a >90% probability of attaining the bactericidal target for PIPC (50% T > MIC) in prostate tissue. However, against Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability. PIPC-TAZ is appropriate for the treatment of prostatitis from the site-specific PK-PD perspective. PMID:26050020

  5. Tissue distribution of amiodarone and desethylamiodarone in rats after multiple intraperitoneal administration of various amiodarone dosages.

    PubMed

    Plomp, T A; Wiersinga, W M; Maes, R A

    1985-01-01

    Tissue distribution of amiodarone (Cordarone) and desethylamiodarone in the rat was studied after repeated intraperitoneal administration of the drug. Tissue and serum concentrations of amiodarone and desethylamiodarone were determined by high-performance liquid chromatography. The levels of amiodarone and desethylamiodarone in serum and tissues obtained after repeated intraperitoneal application of doses varying from 25 mg to 200 mg/kg show that the accumulation of amiodarone and desethylamiodarone in the rat is dose-dependent and both drugs are preferentially distributed in decreasing order in adipose tissue, lung, liver, kidney and thyroid gland. The penetration of the drug and its metabolite into brain was poor and with all the applied dosages brain levels were considerably lower than the corresponding serum levels. Desethylamiodarone serum and tissue concentrations were substantially lower than the corresponding amiodarone concentrations and varied from 1 to 48% (mean 15%) depending on the dosage used and the kind of tissue. The amiodarone tissue/serum concentration ratios were exceptionally high in adipose tissue (1,000-4,000) and moderate to high in the other tissues except brain (5-90), and indicate an extensive distribution of the drug with fat as a reservoir with a large storage capacity. The levels of amiodarone and desethylamiodarone, obtained with 50 mg/kg and 100 mg/kg dosages, showed in function of time clearly an increase in serum and tissues. The observed amiodarone tissue/serum ratios in function of time revealed no further significant increase (p less than or equal to 0.05) after 3 injections over a 6-day period, indicating the attainment of "steady-state".(ABSTRACT TRUNCATED AT 250 WORDS) PMID:4039141

  6. 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) DISTRIBUTION AND CYTOCHROME P4501A INDUCTION IN YOUNG ADULT AND SENESCENT MALE MICE

    EPA Science Inventory

    While the developmental toxicology of TCDD and its congeners has received considerable attention, the impact of advanced age on the biochemical effects and the pharmacokinetics of dioxins remains largely undetermined. n the present investigation, TCDD tissue distribution and cyto...

  7. Pharmacokinetics and bio-distribution of novel super paramagnetic iron oxide nanoparticles (SPIONs) in the anaesthetized pig.

    PubMed

    Edge, Deirdre; Shortt, Christine M; Gobbo, Oliviero L; Teughels, Stephanie; Prina-Mello, Adriele; Volkov, Yuri; MacEneaney, Peter; Radomski, Marek W; Markos, Farouk

    2016-03-01

    Manufactured nanomaterials have a variety of medical applications, including diagnosis and targeted treatment of cancer. A series of experiments were conducted to determine the pharmacokinetic, biodistribution and biocompatibility of two novel magnetic nanoparticles (MNPs) in the anaesthetized pig. Dimercaptosuccinic acid (DMSA) coated superparamagnetic iron oxide nanoparticles (MF66-labelled 12 nm, core nominal diameter and OD15 15 nm); at 0.5, or 2.0 mg/kg) were injected intravenously. Particles induced a dose-dependent decrease in blood pressure following administration which recovered to control levels several minutes after injection. Blood samples were collected for a 5-h period and stored for determination of particle concentration using particle electron paramagnetic resonance (pEPR). Organs were harvested post-mortem for magnetic resonance imaging (MRI at 1.5 T field strength) and histology. OD15 (2.0 mg/kg) MNP had a plasma half-life of approximately 15 min. Both doses of the MF66 (0.5 and 2.0 mg/kg) MNP were below detection limits. MNP accumulation was observed primarily in the liver and spleen with MRI scans which was confirmed by histology. MRI also showed that both MNPs were present in the lungs. The results show that further modifications may be required to improve the biocompatibility of these particles for use as diagnostic and therapeutic agents. PMID:26707795

  8. 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.

  9. Temperature distribution in target tumor tissue and photothermal tissue destruction during laser immunotherapy

    NASA Astrophysics Data System (ADS)

    Doughty, Austin; Hasanjee, Aamr; Pettitt, Alex; Silk, Kegan; Liu, Hong; Chen, Wei R.; Zhou, Feifan

    2016-03-01

    Laser Immunotherapy is a novel cancer treatment modality that has seen much success in treating many different types of cancer, both in animal studies and in clinical trials. The treatment consists of the synergistic interaction between photothermal laser irradiation and the local injection of an immunoadjuvant. As a result of the therapy, the host immune system launches a systemic antitumor response. The photothermal effect induced by the laser irradiation has multiple effects at different temperature elevations which are all required for optimal response. Therefore, determining the temperature distribution in the target tumor during the laser irradiation in laser immunotherapy is crucial to facilitate the treatment of cancers. To investigate the temperature distribution in the target tumor, female Wistar Furth rats were injected with metastatic mammary tumor cells and, upon sufficient tumor growth, underwent laser irradiation and were monitored using thermocouples connected to locally-inserted needle probes and infrared thermography. From the study, we determined that the maximum central tumor temperature was higher for tumors of less volume. Additionally, we determined that the temperature near the edge of the tumor as measured with a thermocouple had a strong correlation with the maximum temperature value in the infrared camera measurement.

  10. Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue DCs

    PubMed Central

    Kuan, Emma L.; Ivanov, Stoyan; Bridenbaugh, Eric A.; Victora, Gabriel; Wang, Wei; Childs, Ed W.; Platt, Andrew M.; Jakubzick, Claudia V.; Mason, Robert J.; Gashev, Anatoliy A.; Nussenzweig, Michel; Swartz, Melody A.; Dustin, Michael L.; Zawieja, David C.; Randolph, Gwendalyn J.

    2015-01-01

    Collecting lymphatic vessels (CLVs), surrounded by fat and endowed with contractile muscle and valves, transport lymph from tissues after it is absorbed into lymphatic capillaries. CLVs are not known to participate in immune responses. Here, we observed that the inherent permeability of CLVs allowed broad distribution of lymph components within surrounding fat for uptake by adjacent macrophages and dendritic cells (DCs) that actively interacted with CLVs. Endocytosis of lymph-derived antigens by these cells supported recall T cell responses in the fat and also generated antigen-bearing DCs for emigration into adjacent lymph nodes. Enhanced recruitment of DCs to inflammation-reactive lymph nodes significantly relied on adipose tissue DCs to maintain sufficient numbers of antigen-bearing DCs as the lymph node expanded. Thus, CLVs coordinate inflammation and immunity within adipose depots and foster the generation of an unexpected pool of APCs for antigen transport into the adjacent lymph node. PMID:25917096

  11. Use of a novel rapid and resource-efficient cassette dosing approach to determine the pharmacokinetics and CNS distribution of small molecule 7-transmembrane receptor allosteric modulators in rat

    PubMed Central

    Bridges, Thomas M; Morrison, Ryan D; Byers, Frank W; Luo, Shuanghui; Scott Daniels, J

    2014-01-01

    Approaches to efficiently and accurately define the pharmacokinetics (PK) of large sets of small molecules in rodents have been previously described. Likewise, a variety of methods for determining brain tissue distribution (BTD) have been reported for use in the discovery of therapeutics targeting the central nervous system (CNS). Herein we describe a novel cassette approach to efficiently obtain concurrent PK and BTD data from a dose of up to five compounds in one rat over 24 h. In conjunction with fraction unbound (fu) data obtained in plasma and brain homogenate, this approach serves as an efficient means to determine compound unbound brain:unbound plasma partition coefficients (Kp,uu), thereby providing insight to compounds bearing poor permeability and/or active transporter activity impacting their permeation of the blood–brain barrier (BBB). This integrated approach was utilized in a lead optimization effort towards the discovery of CNS-penetrant allosteric modulators of a seven-transmembrane (7TM) receptor target. Rat PK and brain distribution was rapidly obtained for 70 compounds and correlated to data obtained from in vitro assessments. Two compounds that were evaluated in cassette and discrete studies, displayed agreement in PK (compound 1: cassette CLp = 1.6 mL min−1 kg−1, discrete CLp = 1.6 mL min−1 kg−1; compound 2: cassette CLp = 11 mL min−1 kg−1, discrete CLp = 8.1 mL min−1 kg−1) and BTD (compound 1: cassette Kp = 0.11, discrete Kp = 0.09; compound 2: cassette Kp < 0.05, discrete Kp = 0.04). The resulting data were used to guide medicinal chemistry efforts and to enable the progression of optimized compounds to in vivo pharmacodynamic assessments. PMID:25505618

  12. Steady-state temperature distribution in living tissue modeled as cylindrical shells.

    NASA Technical Reports Server (NTRS)

    Shitzer, A.; Chato, J. C.

    1971-01-01

    Closed form, analytical solutions to the problem of steady-state heat transfer in living tissue modeled as cylindrical shells are presented and discussed. These solutions are particularly useful for the study of temperature distributions in the extremities. Metabolic heat generation, conduction, and heat transported by the blood perfusing the tissue are considered in the model. The results demonstrate the important role that the blood stream plays in the transfer of heat inside living tissue. Solutions are also presented for the limiting cases of diminishing blood flow that would occur during vasoconstriction or occlusion of blood by external means.

  13. 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. PMID:27101355

  14. Tissue distribution of oxacillin and ampicillin in the isolated perfused bovine udder.

    PubMed

    Ehinger, A M; Kietzmann, M

    2000-04-01

    In vivo, tissue distribution of intra-mammarily administered antibiotics is mostly only assessed by sampling milk and blood. Therefore, the described study analysed whether measurement of tissue concentrations makes sense in vitro instead. Isolated bovine udders were perfused with gassed and warmed Tyrode solution. To four front and rear quarters each, 1000 mg oxacillin in 7.5 ml vehicle was administered intracisternally, completely formulated as sodium monohydrate in two lactation ointments (with or without sodium dodecylsulphate) or 80% as benzathine salt in a dry-off ointment. Over 3 h, perfusate and glandular tissue from different locations were sampled and analysed by high pressure liquid chromatography. With increasing vertical distance to the teat base, the tissue concentration of antibiotics decreased. With the lactation ointment containing sodium dodecylsulphate, lower oxacillin concentrations were reached in glandular tissue and lymph nodes compared to those without. The ointments led to a higher recovery of oxacillin in glandular tissue than in perfusate. Aluminium monostearate in the dry-off ointment caused an even poorer absorption of oxacillin into perfusate. The isolated perfused bovine udder is suitable to study the tissue distribution of antibiotics, since the results were mainly comparable with the few existing in vivo studies and show the influence of different formulations. PMID:10842465

  15. Effect of tissue inhomogeneities on dose distributions from Cf-252 brachytherapy source.

    PubMed

    Ghassoun, J

    2013-01-01

    The Monte Carlo method was used to determine the effect of tissue inhomogeneities on dose distribution from a Cf-252 brachytherapy source. Neutron and gamma-ray fluences, energy spectra and dose rate distributions were determined in both homogenous and inhomogeneous phantoms. Simulations were performed using the MCNP5 code. Obtained results were compared with experimentally measured values published in literature. Results showed a significant change in neutron dose rate distributions in presence of heterogeneities. However, their effect on gamma rays dose distribution is minimal. PMID:23069196

  16. Compound and metabolite distribution measured by MALDI mass spectrometric imaging in whole-body tissue sections

    NASA Astrophysics Data System (ADS)

    Stoeckli, Markus; Staab, Dieter; Schweitzer, Alain

    2007-02-01

    The determination of the compound distribution in laboratory animal tissue in early development is a standard process in pharmaceutical research. While this information is traditionally obtained by means of whole-body autoradiography using radiolabeled compounds, this technology does not distinguish between metabolites and parent compound. The technique described in this article, termed matrix-assisted laser desorption/ionization (MALDI) mass spectrometric imaging, can fill this gap by simultaneously measuring compound and multiple metabolites distributed in whole-body tissue sections, using non-labeled compounds.

  17. Tissue distribution, metabolism, and clearance of the convulsant trimethylolpropane phosphate in rats.

    PubMed

    Rossi, J; Jung, A E; Ritchie, G D; Lindsey, J W; Nordholm, A F

    1998-11-01

    The distribution, metabolism, and clearance of trimethylolpropane phosphate (TMPP), a potent, bicyclophosphate, gamma-aminobutyric acid-ergic convulsant, were studied in male Fischer-344 rats. Intraperitoneal administration of TMPP was compared with oral gavage with respect to rates of absorption, distribution, and clearance. Distribution of TMPP to major body tissues was evaluated for the first 24 hr after administration or, in the case of regional brain distribution, immediately after the first TMPP-induced clinical seizure. Samples purified from the urine, feces, and bile of rats exposed to TMPP, as well as from rat liver microsomes incubated with TMPP in vitro, were analyzed for possible phase I and phase II metabolism, using HPLC. The disposition and clearance of TMPP in the blood and major body tissues were measured. TMPP was found to be well distributed to highly vascularized tissue compartments, with little retention >24 hr after administration. TMPP was eliminated through the urine and feces as the parent compound, with no evidence of phase I or phase II metabolism. TMPP was rapidly cleared from the blood during the first 30 min after exposure, with slower clearance of >87% of the drug during the following 8-hr period and >99.5% clearance by 100 hr after injection. Repeated daily exposure to TMPP for up to 5 successive days resulted in no measurable accumulation in the brain or other major tissue compartments. Possible mechanisms for TMPP-induced, short- and long-term, neurobehavioral modulation are discussed. PMID:9806946

  18. Acute toxicity, bioactivity, and enantioselective behavior with tissue distribution in rabbits of myclobutanil enantiomers.

    PubMed

    Sun, Mingjing; Liu, Donghui; Qiu, Xinxu; Zhou, Qian; Shen, Zhigang; Wang, Peng; Zhou, Zhiqiang

    2014-12-01

    The enantioselective bioactivity against pathogens (Cercospora arachidicola, Fulvia fulva, and Phytophthora infestans) and acute toxicity to Daphnia magna of the fungicide myclobutanil enantiomers were studied. The (+)-enantiomer in an antimicrobial activity test was about 1.79-1.96 times more active than the (-)-enantiomer. In the toxicity assay, the calculated 24-h LC50 values of the (-)-form, rac-form and (+)-form were 16.88, 13.17, and 11.91 mg/L, and the 48-h LC50 values were 10.15, 9.24, and 5.48 mg/L, respectively, showing that (+)-myclobutanil was more toxic. Meanwhile, the enantioselective metabolism of myclobutanil enantiomers following a single intravenous (i.v.) administration was investigated in rabbits. Total plasma clearance value (CL) of the (+)-enantiomer was 1.68-fold higher than its antipode. Significant differences in pharmacokinetics parameters between the two enantiomers indicated that the high bioactive (+)-enantiomer was preferentially metabolized and eliminated in plasma. Consistent consequences were found in the tissues (liver, brain, heart, kidney, fat, and muscle), resulting in a relative enrichment of the low-activity (-)-myclobutanil. These systemic assessments of the stereoisomers of myclobutanil cannot be used only to investigate environmental and biological behavior, but also have human health implications because of the long persistence of triazole fungicide and enantiomeric enrichment in mammals and humans. PMID:25043148

  19. Analysis and distribution of esculetin in plasma and tissues of rats after oral administration.

    PubMed

    Kim, Ji-Sun; Ha, Tae-Youl; Ahn, Jiyun; Kim, Suna

    2014-12-01

    In this study, we developed a method to quantify esculetin (6,7-dihydroxycoumarin) in plasma and tissues using HPLC coupled with ultraviolet detection and measured the level of esculetin in rat plasma after oral administration. The calibration curve for esculetin was linear in the range of 4.8 ng/mL to 476.2 ng/mL, with a correlation coefficient (r(2)) of 0.996, a limit of detection value of 33.2 ng/mL, and a limit of quantification value of 100.6 ng/mL. Recovery rates for the 95.2 ng/mL and 190.5 ng/mL samples were 95.2% and 100.3%, within-runs and 104.8% and 101.0% between-runs, respectively. The relative standard deviation was less than 7% for both runs. In the pharmacokinetic analysis, the peak plasma esculetin level was reached 5 min after administration (Cmax=173.3 ng/mL; T1/2=45 min; AUC0 ~180 min=5,167.5 ng · min/mL). At 180 min post-administration (i.e., after euthanasia), esculetin was only detectable in the liver (30.87±11.33 ng/g) and the kidney (20.29±7.02 ng/g). PMID:25580397

  20. 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...

  1. Simultaneous detection of tissue autofluorescence decay distribution and time-gated photo-bleaching rates

    NASA Astrophysics Data System (ADS)

    Lihachev, Alexey; Ferulova, Inesa; Spigulis, Janis; Tamosiunas, Mindaugas

    2015-05-01

    Experimental methodology for parallel measurements of in-vivo skin autofluorescence (AF) lifetimes and photobleaching dynamic has been developed and tested. The AF lifetime decay distributions were periodically collected from fixed tissue area with subsequent detection of the fluorescence intensity decrease dynamic at different time gates after the pulse excitation. Temporal distributions of human in-vivo skin AF lifetimes and bleaching kinetics were collected and analyzed by means of commercial time-correlated single photon counting system.

  2. Tissue distribution of ochratoxin A as determined by HPLC and ELISA and histopathological effects in chickens.

    PubMed

    Biró, Krisztina; Solti, László; Barna-Vetró, Ildikó; Bagó, György; Glávits, Róbert; Szabó, Erzsébet; Fink-Gremmels, Johanna

    2002-04-01

    Ochratoxin A is a common feed contaminant, which may impair animal health and may lead to residues in edible tissues of slaughter animals. To simulate field conditions, broiler chicks were exposed to a total of 0.5 mg ochratoxin A per week for each of 4 weeks. Plasma toxin levels and tissue residues were measured by high-performance liquid chromatography (HPLC) and microplate enzyme-linked immunosorbent assay (ELISA). Results indicate an accumulation in plasma and wide distribution into all organs, with high levels in the liver and the kidney. Microscopical changes that could primarily be associated with toxin exposure were glomerulonephrosis, tubulonephrosis, focal tubular epithelial cell proliferation and multiple, adenoma-like structures in the renal parenchyma. The HPLC and ELISA methods gave similar results for both tissue distribution and depletion. Differences in absolute tissue toxin concentrations obtained by the two methods might be attributed to the different extraction and clean-up procedures, along with antibody specificity. The findings indicate that the dose applied causes subclinical tissue lesions and measurable tissue residues. PMID:12396358

  3. Pharmacokinetics and metabolism of the plant cannabinoids, delta9-tetrahydrocannabinol, cannabidiol and cannabinol.

    PubMed

    Huestis, M A

    2005-01-01

    Increasing interest in the biology, chemistry, pharmacology, and toxicology of cannabinoids and in the development of cannabinoid medications necessitates an understanding of cannabinoid pharmacokinetics and disposition into biological fluids and tissues. A drug's pharmacokinetics determines the onset, magnitude, and duration of its pharmacodynamic effects. This review of cannabinoid pharmacokinetics encompasses absorption following diverse routes of administration and from different drug formulations, distribution of analytes throughout the body, metabolism by different tissues and organs, elimination from the body in the feces, urine, sweat, oral fluid, and hair, and how these processes change over time. Cannabinoid pharmacokinetic research has been especially challenging due to low analyte concentrations, rapid and extensive metabolism, and physicochemical characteristics that hinder the separation of drugs of interest from biological matrices--and from each other--and lower drug recovery due to adsorption of compounds of interest to multiple surfaces. delta9-Tetrahydrocannabinol, the primary psychoactive component of Cannabis sativa, and its metabolites 11-hydroxy-delta9-tetrahydrocannabinol and 11-nor-9-carboxy-tetrahydrocannabinol are the focus of this chapter, although cannabidiol and cannabinol, two other cannabinoids with an interesting array of activities, will also be reviewed. Additional material will be presented on the interpretation of cannabinoid concentrations in human biological tissues and fluids following controlled drug administration. PMID:16596792

  4. Characterization and tissue distribution of conjugated metabolites of pyrene in the rat

    PubMed Central

    SAENGTIENCHAI, Aksorn; IKENAKA, Yoshinori; DARWISH, Wageh Sobhy; NAKAYAMA, Shouta M.M.; MIZUKAWA, Hazuki; ISHIZUKA, Mayumi

    2015-01-01

    Pyrene (PY) is a polycyclic aromatic hydrocarbon (PAH) that is often used as a biomarker for human and wildlife exposure to PAHs. As the metabolites of PAHs, similar to their parent compounds, pose public health risks, it is necessary to study their characteristics and tissue-specific distribution. The present study was performed to experimentally characterize PY metabolites and analyze the tissue-specific distribution of the conjugated metabolites after oral administration of PY to rats. PY metabolites, such as pyrenediol-disulfate (PYdiol-diS), pyrenediol-sulfate (PYdiol-S), pyrene-1-sufate (PYOS), pyrene-1-glucuronide (PYOG) and 1-hydroxypyrene (PYOH), were detected in rat urine. Although glucuronide conjugate was the predominant metabolite, the metabolite composition varied among tissues. Interestingly, the proportion of PYOH was high in the large intestine. Furthermore, PYOH was the only PY metabolite detected in feces. PMID:26028020

  5. Determination of surface temperature distribution in biological tissues during laser-immunotherapy

    NASA Astrophysics Data System (ADS)

    Gnyawali, Surya C.; Chen, Yichao; Wu, Feng; Bartels, Kenneth E.; Ritchey, Jerry W.; Wicksted, James P.; Liu, Hong; Chen, Wei R.

    2007-02-01

    An ideal cancer treatment method should not only cause primary tumor suppression but also induce an antitumor immunity, which is essential for control of metastatic tumors. A combination therapy using a laser, a laser-absorbing dye, and an immunoadjuvant guided by temperature measurement probes such as magnetic resonance imaging thermometry (MRT) and infrared thermography (IRT) can be an ideal treatment modality. Temperature distribution inside the target tissue is important in laser treatment. The surface temperature often serves as an indicator of the treatment effect. However, real-time monitoring of surface temperature during laser irradiation poses a great challenge. In this study, we investigated the surface temperature distribution using direct measurement and theoretical simulation. The preliminary results of in vitro and in vivo studies are presented. Gel phantom and chicken breast tissue were irradiated by an 805 nm laser and the surface temperature distribution was obtained using an infrared thermal camera. EMT-6 breast tumors in mice were treated using the 805 nm laser and with different dye and immunoadjuvant combinations, including intratumor injections of indocyanine green (ICG) and glycated chitosan (GC). Monte Carlo simulation for selective photothermal-tissue interaction was also performed for the surface temperature distributions. Our results demonstrated that the tissue temperature can be accurately monitored in real time and can be controlled by appropriate treatment parameters.

  6. 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

  7. 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. PMID:19807971

  8. Mapping drug distribution in brain tissue using liquid extraction surface analysis mass spectrometry imaging.

    PubMed

    Swales, John G; Tucker, James W; Spreadborough, Michael J; Iverson, Suzanne L; Clench, Malcolm R; Webborn, Peter J H; Goodwin, Richard J A

    2015-10-01

    Liquid extraction surface analysis mass spectrometry (LESA-MS) is a surface sampling technique that incorporates liquid extraction from the surface of tissue sections with nanoelectrospray mass spectrometry. Traditional tissue analysis techniques usually require homogenization of the sample prior to analysis via high-performance liquid chromatography mass spectrometry (HPLC-MS), but an intrinsic weakness of this is a loss of all spatial information and the inability of the technique to distinguish between actual tissue penetration and response caused by residual blood contamination. LESA-MS, in contrast, has the ability to spatially resolve drug distributions and has historically been used to profile discrete spots on the surface of tissue sections. Here, we use the technique as a mass spectrometry imaging (MSI) tool, extracting points at 1 mm spatial resolution across tissue sections to build an image of xenobiotic and endogenous compound distribution to assess drug blood-brain barrier penetration into brain tissue. A selection of penetrant and "nonpenetrant" drugs were dosed to rats via oral and intravenous administration. Whole brains were snap-frozen at necropsy and were subsequently sectioned prior to analysis by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and LESA-MSI. MALDI-MSI, as expected, was shown to effectively map the distribution of brain penetrative compounds but lacked sufficient sensitivity when compounds were marginally penetrative. LESA-MSI was used to effectively map the distribution of these poorly penetrative compounds, highlighting its value as a complementary technique to MALDI-MSI. The technique also showed benefits when compared to traditional homogenization, particularly for drugs that were considered nonpenetrant by homogenization but were shown to have a measurable penetration using LESA-MSI. PMID:26350423

  9. Drug pharmacokinetics and pharmacodynamics: Technological considerations

    SciTech Connect

    Fowler, J.S.; Volkow, N.D.; Wolf, A.P.

    1992-01-01

    Additionally, the use of PET to examine drug pharmacokinetics and pharmacadynamics and the relationship of these properties to the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. The pharmacokinetic properties of a drug, which comprises all of the biological processes which determine the fraction of the drug available, can be measured using the labeled drug itself. For example, the labeled drug can be used to measure the absolute uptake, regional distribution and kinetics of a drug at its site of action in the body. Additionally the labeled drug and whole body its labeled metabolites and thus provide information an potential toxic effects as well as tissue half lives. On the other hand, different labeled tracers can be used to assess drug pharmacodynamics which include the biological Processes involved in the drug's effects. For example, with appropriate radiotracers, the effects of a drug on metabolism, neurotransmitter activity, blood flew, enzyme activity or other processes can be probed.

  10. Drug pharmacokinetics and pharmacodynamics: Technological considerations

    SciTech Connect

    Fowler, J.S.; Volkow, N.D.; Wolf, A.P.

    1992-12-31

    Additionally, the use of PET to examine drug pharmacokinetics and pharmacadynamics and the relationship of these properties to the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. The pharmacokinetic properties of a drug, which comprises all of the biological processes which determine the fraction of the drug available, can be measured using the labeled drug itself. For example, the labeled drug can be used to measure the absolute uptake, regional distribution and kinetics of a drug at its site of action in the body. Additionally the labeled drug and whole body its labeled metabolites and thus provide information an potential toxic effects as well as tissue half lives. On the other hand, different labeled tracers can be used to assess drug pharmacodynamics which include the biological Processes involved in the drug`s effects. For example, with appropriate radiotracers, the effects of a drug on metabolism, neurotransmitter activity, blood flew, enzyme activity or other processes can be probed.

  11. Aztreonam pharmacokinetics in burn patients.

    PubMed Central

    Friedrich, L V; White, R L; Kays, M B; Brundage, D M; Yarbrough, D

    1991-01-01

    The pharmacokinetics of aztreonam in eight adult patients with severe burn injuries (total body surface area burn, 49% +/- 21% [mean +/- standard deviation]) were studied. The time of initiation of study following burn injury was 7.0 +/- 1.4 days. Four patients at first dose and at steady state were studied. Aztreonam concentrations were measured by high-performance liquid chromatography, and a two-compartment model was used to fit the data. No significant differences in any pharmacokinetic parameters between first dose and steady state were observed. Volume of distribution of the central compartment after first dose (0.14 liters/kg) and volume of distribution at steady state (0.31 liters/kg) were approximately 30% higher than those reported for other patient populations. Total drug clearance and renal drug clearance when normalized to creatinine clearance (CLCR) were similar to those previously reported for other critically ill patients. CLCR was strongly correlated with renal drug clearance (r = 0.94) and total drug clearance (r = 0.95). The extent and degree of burn (percent second or third degree burn) were poorly correlated with all pharmacokinetic parameters with the exception of the volume of distribution at steady state, which was correlated with both total body surface area burn (r = 0.95) and percent second degree burn (r = 0.83). Aztreonam pharmacokinetics are altered as a result of thermal injury; however, CLCR can be used to assess the clearance of aztreonam in burn patients. PMID:2014982

  12. Tissue distribution of sup 3 H-nicotine in rats after bolus or constant injection

    SciTech Connect

    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 was 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.

  13. Modeling Therapy Response and Spatial Tissue Distribution of Erlotinib in Pancreatic Cancer.

    PubMed

    Grüner, Barbara M; Winkelmann, Isabel; Feuchtinger, Annette; Sun, Na; Balluff, Benjamin; Teichmann, Nicole; Herner, Alexander; Kalideris, Evdokia; Steiger, Katja; Braren, Rickmer; Aichler, Michaela; Esposito, Irene; Schmid, Roland M; Walch, Axel; Siveke, Jens T

    2016-05-01

    Pancreatic ductal adenocarcinoma (PDAC) is likely the most aggressive and therapy-resistant of all cancers. The aim of this study was to investigate the emerging technology of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) as a powerful tool to study drug delivery and spatial tissue distribution in PDAC. We utilized an established genetically engineered mouse model of spontaneous PDAC to examine the distribution of the small-molecule inhibitor erlotinib in healthy pancreas and PDAC. MALDI IMS was utilized on sections of single-dose or long-term-treated mice to measure drug tissue distribution. Histologic and statistical analyses were performed to correlate morphology, drug distribution, and survival. We found that erlotinib levels were significantly lower in PDAC compared with healthy tissue (P = 0.0078). Survival of long-term-treated mice did not correlate with overall levels of erlotinib or with overall histologic tumor grade but did correlate both with the percentage of atypical glands in the cancer (P = 0.021, rs = 0.59) and the level of erlotinib in those atypical glands (P = 0.019, rs = 0.60). The results of this pilot study present MALDI IMS as a reliable technology to study drug delivery and spatial distribution of compounds in a preclinical setting and support drug imaging-based translational approaches. Mol Cancer Ther; 15(5); 1145-52. ©2016 AACR. PMID:26823494

  14. Changes in lung composition and regional perfusion and tissue distribution in patients with ARDS

    PubMed Central

    Dakin, Jonathan; Jones, Andrew T; Hansell, David M; Hoffman, Eric A; Evans, Timothy W

    2011-01-01

    Background & objective ARDS is characterised by bilateral pulmonary infiltrates and refractory hypoxemia attributed to V/Q mismatch. We used dynamic CT to characterise changes in lung composition, regional perfusion and tissue distribution in patients with ARDS in comparison to healthy subjects. Methods The Fick principle was applied to serial attenuation measurements constructed from sequential CT images acquired during the passage of a bolus of iodinated contrast medium in healthy subjects (n=3) and patients with ARDS (n=11). Perfusion was calculated by the Mullani-Gould method and mapped throughout both lungs. Gradients of perfusion and tissue density against vertical height were constructed. Results In comparison to normal individuals, the tissue component of lungs from patients with ARDS was significantly increased (p<0.05). Blood fraction was unchanged. There was a discernable gradient in tissue density from non dependent to dependent regions in the patients with ARDS that was significantly different from controls. The proportion of perfusion applied to consolidated areas (ie shunt) correlated significantly (p<0.05) with the severity of hypoxaemia. Conclusions In patients with ARDS there are changes in both lung composition and the distribution of tissue and perfusion that may account in part for the physiological changes that define the syndrome. PMID:21883676

  15. Peripharyngeal tissue deformation, stress distributions, and hyoid bone movement in response to mandibular advancement.

    PubMed

    Amatoury, Jason; Kairaitis, Kristina; Wheatley, John R; Bilston, Lynne E; Amis, Terence C

    2015-02-01

    Mandibular advancement (MA) increases upper airway (UA) patency and decreases collapsibility. Furthermore, MA displaces the hyoid bone in a cranial-anterior direction, which may contribute to MA-associated UA improvements via redistribution of peripharyngeal tissue stresses (extraluminal tissue pressure, ETP). In the present study, we examined effects of MA on ETP distributions, deformation of the peripharyngeal tissue surface (UA geometry), and hyoid bone position. We studied 13 supine, anesthetized, tracheostomized, spontaneously breathing adult male New Zealand White rabbits. Graded MA was applied from 0 to ∼4.5 mm. ETP was measured at six locations distributed throughout three UA regions: tongue, hyoid, and epiglottis. Axial computed tomography images of the UA (nasal choanae to glottis) were acquired and used to measure lumen geometry (UA length; regional cross-sectional area) and hyoid displacement. MA resulted in nonuniform decreases in ETP (greatest at tongue region), ranging from -0.11 (-0.15 to -0.06) to -0.82 (-1.09 to -0.54) cmH2O/mm MA [linear mixed-effects model slope (95% confidence interval)], across all sites. UA length decreased by -0.5 (-0.8 to -0.2) %/mm accompanied by nonuniform increases in cross-sectional area (greatest at hyoid region) ranging from 7.5 (3.6-11.4) to 18.7 (14.9-22.5) %/mm. The hyoid bone was displaced in a cranial-anterior direction by 0.42 (0.36-0.44) mm/mm MA. In summary, MA results in nonuniform changes in peripharyngeal tissue pressure distributions and lumen geometry. Displacement of the hyoid bone with MA may play a pivotal role in redistributing applied MA loads, thus modifying tissue stress/deformation distributions and determining resultant UA geometry outcomes. PMID:25505028

  16. A compartment model of VEGF distribution in blood, healthy and diseased tissues

    PubMed Central

    Stefanini, Marianne O; Wu, Florence TH; Mac Gabhann, Feilim; Popel, Aleksander S

    2008-01-01

    Background Angiogenesis is a process by which new capillaries are formed from pre-existing blood vessels in physiological (e.g., exercise, wound healing) or pathological (e.g., ischemic limb as in peripheral arterial disease, cancer) contexts. This neovascular mechanism is mediated by the vascular endothelial growth factor (VEGF) family of cytokines. Although VEGF is often targeted in anti-angiogenic therapies, there is little knowledge about how its concentration may vary between tissues and the vascular system. A compartment model is constructed to study the VEGF distribution in the tissue (including matrix-bound, cell surface receptor-bound and free VEGF isoforms) and in the blood. We analyze the sensitivity of this distribution to the secretion rate, clearance rate and vascular permeability of VEGF. Results We find that, in a physiological context, VEGF concentration varies approximately linearly with the VEGF secretion rate. VEGF concentration in blood but not in tissue is dependent on the vascular permeability of healthy tissue. Model simulations suggest that relative VEGF increases are similar in blood and tissue during exercise and return to baseline within several hours. In a pathological context (tumor), we find that blood VEGF concentration is relatively insensitive to increased vascular permeability in tumors, to the secretion rate of VEGF by tumors and to the clearance. However, it is sensitive to the vascular permeability in the healthy tissue. Finally, the VEGF distribution profile in healthy tissue reveals that about half of the VEGF is complexed with the receptor tyrosine kinase VEGFR2 and the co-receptor Neuropilin-1. In diseased tissues, this binding can be reduced to 15% while VEGF bound to the extracellular matrix and basement membranes increases. Conclusion The results are of importance for physiological conditions (e.g., exercise) and pathological conditions (e.g., peripheral arterial disease, coronary artery disease, cancer). This

  17. Distribution of lead, cadmium, and zinc in tissues of hens and chickens from Slovenia

    SciTech Connect

    Doganoc, D.Z.

    1996-12-01

    Lead (Pb) and cadmium (Cd) are environmental contaminants which are present in almost all living organisms and are non-essential for plants, animals and human beings. Zinc (Zn) is an essential element which occurs together with Cd and is linked with it. Little information exists about the contamination of tissues of hens and chickens with these elements. The primary aim of this study was to investigate the distribution of lead, cadmium, and zinc in different tissues of poultry and eggs in Slovenia. 10 refs., 7 tabs.

  18. Comparisons of the Rayleigh and K-distribution models using in vivo breast and liver tissue.

    PubMed

    Molthen, R C; Shankar, P M; Reid, J M; Forsberg, F; Halpern, E J; Piccoli, C W; Goldberg, B B

    1998-01-01

    There is a strong interest in finding out which statistical model is the most appropriate for describing the envelope of the backscattered ultrasonic echoes from different types of tissues. The Rayleigh model is commonly employed, but this requires conditions, such as the presence of large number of randomly located scatterers with fairly uniform cross-sections, that are not always met. However, our research indicates that a model based on the K-distribution may provide a better fit to empirical data over a range of scattering conditions than the standard Rayleigh model. In this study, we looked at the K-distribution as a descriptor of the backscattered envelope of the breast and liver tissues (in vivo). By examining data from various tissue regions, a goodness-of-fit test (a least squares error method) was used to determine whether a Rayleigh or K-distribution model is more appropriate. From a large group of patients and volunteer scans (a total of 72 subjects), the fit between the K-distribution and the data is shown to have a much smaller error than the Rayleigh model. PMID:9483775

  19. Influence of gestational diabetes on the stereoselective pharmacokinetics and placental distribution of metoprolol and its metabolites in parturients

    PubMed Central

    Antunes, Natalícia de Jesus; Cavalli, Ricardo Carvalho; Marques, Maria Paula; Moisés, Elaine Christine Dantas; Lanchote, Vera Lucia

    2015-01-01

    AIM To investigate the influence of gestational diabetes mellitus (GDM) on the kinetic disposition and transplacental and amniotic fluid distribution of metoprolol and its metabolites O-desmethylmetoproloic acid and α-hydroxymetoprolol stereoisomers in hypertensive parturients receiving a single dose of the racemic drug. METHODS The study was conducted on hypertensive parturients with well-controlled GDM (n = 11) and non-diabetic hypertensive parturients (n = 24), all receiving a single 100 mg oral dose of racemic metoprolol tartrate before delivery. Serial maternal blood samples (0–24 h) and umbilical blood and amniotic fluid samples were collected for the quantitation of metoprolol and its metabolite stereoisomers using LC-MS/MS or fluorescence detection. RESULTS The kinetic disposition of metoprolol and its metabolites was stereoselective in the diabetic and control groups. Well-controlled GDM prolonged tmax for both enantiomers of metoprolol (1.5 vs. 2.5 h R-(+)-MET; 1.5 vs. 2.75 h S-(−)-MET) and O-desmethylmetoproloic acid (2.0 vs. 3.5 h R-(+)-AOMD; 2.0 vs. 3.0 h S-(−)-OAMD), and for the four stereoisomers of α-hydroxymetoprolol (2.0 vs. 3.0 h for 1′S,2R-, 1′R,2R- and 1′R,2S-OHM; 2.0 vs. 3.5 h for 1′S,2S-OHM) and reduced the transplacental distribution of 1′S,2S-, 1′R,2R-, and 1′R,2S-OHM by approximately 20%. CONCLUSIONS The kinetic disposition of metoprolol was enantioselective, with plasma accumulation of the S-(−)-MET eutomer. Well-controlled GDM prolonged the tmax of metoprolol and O-desmethylmetoproloic acid enantiomers and the α-hydroxymetoprolol stereoisomers and reduced by about 20% the transplacental distribution of 1′S,2S-, 1′R,2R-, and 1′R,2S-OHM. Thus, well-controlled GDM did not change the activity of CYP2D6 and CYP3A involved in metoprolol metabolism. PMID:25291152

  20. 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.

  1. Distribution pattern and reduction of polychlorinated biphenyls (PCB) in bluefish fillets through adipose tissue removal

    SciTech Connect

    Sanders, M.; Haynes, B.L.

    1988-11-01

    Bluefish, Pomatomus saltatrix, a migratory pelagic species of fish usually travel in large groups of like size along the Atlantic coast. Bluefish of all sizes are caught both commercially and recreationally for human consumption. Owing to its predacious nature, bluefish feed throughout the water column on a large variety of smaller fish and invertebrates. Bluefish bioaccumulate contaminants such as polychlorinated biphenyls (PCB) into various adipose tissues from the water column and through the marine food chain. Two recent reports concluded that PCB concentrations for all except some of the large bluefish caught along the Atlantic coast fell below the limit of 2 ..mu..g/g set by FDA. The purpose of this study was to observe the distribution pattern of PCB in the various edible tissues. Further, it was to determine if the removal of adipose tissues would result in reduced PCB level and therefore decrease PCB exposure to the consumer.

  2. Immunohistochemical distribution of leptin in kidney tissues of melatonin treated diabetic rats.

    PubMed

    Elis Yildiz, S; Deprem, T; Karadag Sari, E; Bingol, S A; Koral Tasci, S; Aslan, S; Nur, G; Sozmen, M

    2015-05-01

    We examined using immunohistochemistry the distribution of leptin in kidney tissues of melatonin treated, streptozotocin (STZ) diabetic rats. The animals were divided into five groups: control, sham, melatonin-treated, diabetic and melatonin-treated diabetic. Kidney sections were prepared and stained with hematoxylin and eosin, and Crossman's triple staining for histological examination. The immunohistochemical localization of leptin in the kidney tissue was determined using the streptavidin-biotin-peroxidase method. We determined that on days 7 and 14, the leptin immunoreactivity of the diabetic and melatonin-treated diabetic groups was weaker than for the other groups. Weak immunoreactivity was found in the proximal and distal tubules of the kidney in the diabetic and melatonin-treated diabetic groups on days 7 and 14, and strong immunoreactivity was found in the control, sham and melatonin groups. Melatonin application had no significant effect on leptin production in the kidney tissues of diabetic rats. PMID:25539049

  3. mRNA distribution analysis of human TRPC family in CNS and peripheral tissues.

    PubMed

    Riccio, Antonio; Medhurst, Andrew D; Mattei, Cesar; Kelsell, Rosemary E; Calver, Andrew R; Randall, Andrew D; Benham, Christopher D; Pangalos, Menelas N

    2002-12-30

    The mammalian homologues of the Drosophila transient receptor potential (TRP) channel are plasma membrane proteins involved in the regulation of cellular Ca(2+) influx. These ion channels can be activated subsequent to either depletion of Ca(2+) from internal stores or through receptor-mediated processes. The mRNA expression patterns of several individual mammalian short transient receptor potential channels (TRPCs) have been described. Cross-comparisons between these data, however, are at best difficult predominantly due to the non-quantitative methods used. Furthermore there is limited data on the expression of TRPC family members in human tissues. In the present study we used a single technique, namely TaqMan real-time quantitative RT-PCR, to investigate the mRNA distribution of human TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7 (hTRPCs) in discrete human brain areas, peripheral tissues as well as a panel of cell-lines. All hTRPCs studied were widely expressed within CNS and significant peripheral expression was often observed. Despite this, each channel exhibited a distinctive hallmark distribution profile. hTRPC1 was widely expressed in CNS and peripheral tissues, whereas hTRPC3 and hTRPC5 were predominantly expressed in tissues of CNS. hTRPC4 mRNA was detected in CNS and certain peripheral tissues such as bone, heart and prostate. hTRPC6 was homogeneously expressed throughout the CNS and peripheral tissues with the highest levels in placenta and lung. hTRPC7 mRNA was also broadly expressed in CNS as well as some peripheral tissues. The pattern of expression of the TRPCs was quite different in the various cell lines examined. TRPC3 and TRPC6 were selectively present in HEK-293 cells whilst TRPC1 was broadly distributed in the cell lines analyzed. In contrast TRPC4 and TRPC5 mRNAs were predominantly expressed in HK-2 and HEK-293 cell lines respectively. TRPC7 was selectively expressed in COS-1, COS-7 and HK-2 cell lines. These results show tissue- and cell

  4. Dynamic distribution and tissue tropism of classical swine fever virus in experimentally infected pigs

    PubMed Central

    2011-01-01

    Background Classical swine fever (CSF), caused by the Classical swine fever virus (CSFV), is an Office International des Epizooties (OIE) notifiable disease. However, we are far from fully understand the distribution, tissue tropism, pathogenesis, replication and excretion of CSFV in pigs. In this report, we investigated the dynamic distribution and tissue tropism of the virus in internal organs of the experimentally infected pigs using real-time RT-PCR and immunohistochemistry (IHC). Results A relative quantification real-time PCR was established and used to detect the virus load in internal organs of the experimentally infected pigs. The study revealed that the virus was detected in all 21 of the internal organs and blood collected from pigs at day 1 to day 8 post infections, and had an increasing virus load from day 1 to day 8 post infections. However, there was irregular distribution virus load in most internal organs over the first 2 days post infection. Blood, lymphoid tissue, pancreas and ileum usually contain the highest viral loads, while heart, duodenum and brain show relatively low viral loads. Conclusions All the data suggest that CSFV had an increasing virus load from day 1 to day 8 post infections in experimentally infected pigs detected by real-time RT-PCR, which was in consistent with the result of the IHC staining. The data also show that CSFV was likely to reproduce in blood, lymphoid tissue, pancreas and the ileum, while unlikely to replicate in the heart, duodenum and brain. The results provide a foundation for further clarification of the pathogenic mechanism of CSFV in internal organs, and indicate that blood, lymphoid tissue, pancreas and ileum may be preferred sites of acute infection. PMID:21535885

  5. Hemorrhagic Shock and Resuscitation-Mediated Tissue Water Distribution is Normalized by Adjunctive Peritoneal Resuscitation

    PubMed Central

    Zakaria, El Rasheid; Matheson, Paul J; Flessner, Michael F; Garrison, R Neal

    2008-01-01

    BACKGROUND Adjunctive direct peritoneal resuscitation (DPR) from hemorrhagic shock (HS) improves intestinal blood flow and abrogates postresuscitation edema. HS causes water shifts as a result of sodium redistribution and changes in transcapillary Starling forces. Conventional resuscitation (CR) with crystalloid aggravates water sequestration. We examined the compartment pattern of organ tissue water after HS and CR, and modulation of tissue edema by adjunctive DPR. STUDY DESIGN Rats were hemorrhaged (40% mean arterial pressure for 60 minutes) and assigned to four groups (n = 7): sham, no HS; HS no resuscitation; HS+CR (shed blood plus 2 volumes Ringer’s lactate); and HS+CR+DPR (20 mL clinical intraperitoneal (IP) dialysis fluid). Isotopic markers determined equilibrium distribution volumes [VD] in gut, liver, lung, and muscle by quantitative autoradiography (2-hour postresuscitation). Total tissue water (TTW) was determined by wet-dry weights. Extracellular water was measured from 14C-mannitol VD, and intravascular volume (IVV) from 131I-labeled IgG VD. Cellular and interstitial water volumes were calculated. RESULTS HS alone decreased IVV in all tissues and TTW in gut, lung, and muscle, but not liver, compared with shams. IVV remained decreased with all resuscitations despite restoration of central hemodynamics. CR caused interstitial edema in gut, liver, and muscle, and cellular edema in lung. DPR reduced (liver, muscle) or prevented (gut, lung) these volume shifts. CONCLUSIONS HS decreases IVV. HS-induced water shifts are organ-specific and prominent in gut, lung, and muscle. CR restores central hemodynamics, does not restore IVV, and alters organ-specific TTW distribution. Adjunctive DPR with IP dialysis fluid normalizes TTW and water compartment distribution and prevents edema. Combined effect of DPR and intravascular fluid replacement appears to prevent global tissue edema and improve outcomes from HS. PMID:18471737

  6. Analysis of bacopaside I in biomatrices using liquid chromatography-tandem mass spectrometry: Pharmacokinetics and brain distribution in Swiss-albino mice.

    PubMed

    Bhateria, Manisha; Ramakrishna, Rachumallu; Puttrevu, Santosh Kumar; Singh, Rajbir; Bhatta, Rabi Sankar

    2016-06-01

    Bacopaside I (BP-I) is the major pseudojujubogenin glycoside of Bacopa monniera (BM) extract which has been widely used as a nerve tonic to improve the memory and intellect of human beings from ancient times. A selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of BP-I in mouse plasma and brain homogenate has been developed and validated. All biosamples were processed by liquid-liquid extraction and chromatographed on C18- reversed phase column using mobile phase consisting of ammonium acetate (10mM, pH 4) - acetonitrile (10:90, v/v) at a flow rate of 0.5mL/min. The detection was performed in negative electrospray ionization mode and the precursor/product ion transitions of BP-I and internal standard (IS) hydrochlorothiazide were quantified in multiple reaction monitoring (MRM) using QTRAP-5500 MS/MS. The linearity was established over the concentration range of 0.5-2000ng/mL (r(2)>0.990), with lower limit of quantification (LLOQ) of 0.5ng/mL in both plasma and brain matrix. Within- and between-run precision and accuracy were well within the acceptable limits of variation. Consistent and reproducible recovery (>70%) was obtained with insignificant matrix effect for BP-I and IS. The method fulfilled US Food and Drug Administration (USFDA) guidelines for bioanalytical method validation in terms of selectivity, sensitivity, linearity, accuracy, precision, matrix effect, dilution integrity, carry-over effect and stability. Further, the method was successfully applied to execute the plasma pharmacokinetics and brain distribution of BP-I in Swiss-albino mice following intravenous administration at a dose of 5mg/kg. PMID:27017568

  7. Whole-body imaging of the distribution of mercury released from dental fillings into monkey tissues

    SciTech Connect

    Hahn, L.J.; Kloiber, R.; Leininger, R.W.; Vimy, M.J.; Lorscheider, F.L. )

    1990-11-01

    The fate of mercury (Hg) released from dental silver amalgam tooth fillings into human mouth air is uncertain. A previous report about sheep revealed uptake routes and distribution of amalgam Hg among body tissues. The present investigation demonstrates the bodily distribution of amalgam Hg in a monkey whose dentition, diet, feeding regimen, and chewing pattern closely resemble those of humans. When amalgam fillings, which normally contain 50% Hg, are made with a tracer of radioactive {sup 203}Hg and then placed into monkey teeth, the isotope appears in high concentration in various organs and tissues within 4 wk. Whole-body images of the monkey revealed that the highest levels of Hg were located in the kidney, gastrointestinal tract, and jaw. The dental profession's advocacy of silver amalgam as a stable tooth restorative material is not supported by these findings.

  8. Tissue-Specific Distribution of Secondary Metabolites in Rapeseed (Brassica napus L.)

    PubMed Central

    Fang, Jingjing; Reichelt, Michael; Hidalgo, William; Agnolet, Sara; Schneider, Bernd

    2012-01-01

    Four different parts, hypocotyl and radicle (HR), inner cotyledon (IC), outer cotyledon (OC), seed coat and endosperm (SE), were sampled from mature rapeseed (Brassica napus L.) by laser microdissection. Subsequently, major secondary metabolites, glucosinolates and sinapine, as well as three minor ones, a cyclic spermidine conjugate and two flavonoids, representing different compound categories, were qualified and quantified in dissected samples by high-performance liquid chromatography with diode array detection and mass spectrometry. No qualitative and quantitative difference of glucosinolates and sinapine was detected in embryo tissues (HR, IC and OC). On the other hand, the three minor compounds were observed to be distributed unevenly in different rapeseed tissues. The hypothetic biological functions of the distribution patterns of different secondary metabolites in rapeseed are discussed. PMID:23133539

  9. Orientational tomography of optical axes directions distributions of multilayer biological tissues birefringent polycrystalline networks

    NASA Astrophysics Data System (ADS)

    Zabolotna, Natalia I.; Dovhaliuk, Rostyslav Y.

    2013-09-01

    We present a novel measurement method of optic axes orientation distribution which uses a relatively simple measurement setup. The principal difference of our method from other well-known methods lies in direct approach for measuring the orientation of optical axis of polycrystalline networks biological crystals. Our test polarimetry setup consists of HeNe laser, quarter wave plate, two linear polarizers and a CCD camera. We also propose a methodology for processing of measured optic axes orientation distribution which consists of evaluation of statistical, correlational and spectral moments. Such processing of obtained data can be used to classify particular tissue sample as "healthy" or "pathological". For our experiment we use thin layers of histological section of normal and muscular dystrophy tissue sections. It is shown that the difference between mentioned moments` values of normal and pathological samples can be quite noticeable with relative difference up to 6.26.

  10. Motility is Critical for Effective Distribution and Accumulation of Bacteria in Tumor Tissue

    PubMed Central

    Toley, Bhushan J.; Forbes, Neil S.

    2016-01-01

    Motile bacteria can overcome the penetration limitations of cancer chemotherapeutics because they can actively migrate into solid tumors. Although several genera of bacteria have been shown to accumulate preferentially in tumors, the spatiotemporal dynamics of bacterial tumor colonization and their dependence on bacterial motility is not clear. For effective tumor regression, bacteria must penetrate and distribute uniformly throughout tumors. To measure these dynamics, we used an in vitro model of continuously perfused tumor tissue to mimic the delivery and systemic clearance of Salmonella typhimurium strains SL1344 and VNP20009, and Escherichia coli strains K12 and DH5α. Tissues were treated for 1 hour with 105 or 107 CFU/ml suspensions of each strain and the location and extent of bacterial accumulation was observed for 30 hours. Salmonella had 14.5 times greater average swimming speeds than E.coli and colonized tissues at 100 times lower doses than E.coli. Bacterial motility strongly correlated (R2 = 99.3%) with the extent of tissue accumulation. When inoculated at 105 CFU/ml, motile Salmonella formed colonies denser than 1010 CFU/(g-tissue) and less motile E.coli showed no detectable colonization. Based on spatio-temporal profiles and a mathematical model of motility and growth, bacterial dispersion was found to be necessary for deep penetration into tissue. Bacterial colonization caused apoptosis in tumors and apoptosis levels correlated (R2 = 98.6%) with colonization density. These results show that motility is critical for effective distribution of bacteria in tumors and is essential for designing cancer therapies that can overcome the barrier of limited tumor penetration. PMID:22193245

  11. Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872).

    PubMed

    Hajdu, R; Thompson, R; Sundelof, J G; Pelak, B A; Bouffard, F A; Dropinski, J F; Kropp, H

    1997-11-01

    MK-0991 (L-743,872) is a potent antifungal agent featuring long half-life pharmacokinetics. The pharmacokinetics of MK-0991 administered intravenously to mice, rats, rhesus monkeys, and chimpanzees is presented. Unique to MK-0991 is its consistent cross-species performance. The range of values for the pharmacokinetic parameters were as follows: clearance, 0.26 to 0.51 ml/min/kg; half-life, 5.2 to 7.6 h; and distributive volume, 0.11 to 0.27 liters/kg. The level of protein binding of MK-0991 was determined to be 96% in mouse and human serum. The compound exhibited high affinities for human serum albumin and at least two lipid components. The rationale for the selection of MK-0991 as a drug development candidate was based on its two- to threefold superior pharmacokinetic performance in chimpanzees over the performance of an otherwise equivalent analog, L-733,560. Once-daily dosing for MK-0991 is indicated by a graphical comparison of levels in the circulations of chimpanzees and mice. In a study of the pharmacokinetics of MK-0991 in mouse tissue, the organs were assayed following intraperitoneal administration. The area under the concentration-versus-time curves (AUC) segregated the tissues into three exposure categories relative to plasma. The tissues with greater exposure than that for plasma were liver (16 times), kidney (3 times), and large intestine (2 times). The exposure for small intestine, lung, and spleen were equivalent to that for plasma. Organs with lower levels of exposure were the heart (0.3 times that for plasma), thigh (0.2 times), and brain (0.06 times). Kinetically, drug was cleared more slowly from all tissues than from plasma, indicating that terminal-phase equilibrium had not been achieved by 24 h. Thus, some measure of accumulation is predicted for all tissues. Single daily doses of MK-0991 should provide adequate systemic levels of fungicidal activity as a result of its long half-life pharmacokinetics, wide distribution, and slowly

  12. Clinical pharmacokinetics of molsidomine.

    PubMed

    Rosenkranz, B; Winkelmann, B R; Parnham, M J

    1996-05-01

    Molsidomine is a prodrug for the formation of nitric oxide (NO). Its pharmacokinetics are characterised by rapid absorption and hydrolysis, taking a short time to achieve maximal systemic concentrations of both the parent compound and its active metabolite, SIN-1. The time to peak plasma drug concentration (tmax) is 1 to 2 hours. The bioavailability of the parent compound after oral administration in tablet form is 44 to 59%, but further metabolism to release NO and form polar metabolites is rapid; the half-life (t-1/2) of SIN-1 is 1 to 2 hours. Urinary excretion accounts for more than 90% of the part of the administered dose of molsidomine which is not excreted unchanged. Protein binding of the parent compound is very low (3 to 11%) and its volume of distribution (Vd) corresponds to the range of bodyweight. Single-dose studies (1, 2 and 4 mg) have revealed linear pharmacokinetics, and multiple dose studies in healthy individuals (2 mg 3 times daily for 7 days) and coronary artery disease (CAD) patients (4 mg 4 times daily for 4 weeks) do not show any accumulation of the drug. A study in young and elderly individuals indicated that the first-pass effect is decreased and t-1/2 prolonged with age, resulting in an increased area under the concentration-time curve (AUC) of molsidomine and SIN-1. In patients with liver disease and congestive heart failure similar changes were observed, but much less so in patients with CAD. Clearance was also impaired in patients with liver disease, but the pharmacokinetics of molsidomine were not markedly altered by impaired renal function. In general, due to a large therapeutic dose range, dosage adjustments are not required on the basis of clinical experience. In certain patients a lower starting dose may be recommended, such as in those with impaired liver or kidney function, in congestive heart failure or in the presence of concomitant treatment with other vasoactive compounds. A linear dose-effect relationship is observed with

  13. Inhalation uptake of low level elemental mercury vapor and its tissue distribution in rats

    SciTech Connect

    Oberski, S.P.; Fang, S.C.

    1980-07-01

    Elemental mercury vapor is the major component of mercury found in the atmosphere. Furthermore, if usage of coal is increased to meet the energy demand, then atmospheric levels of mercury are expected to rise. Current atmospheric concentrations of mercury vapor over select urban areas of the United States range from 0.5 to 50 ng m/sup -3/ with a mean of 7 ng m/sup -3/. Mercury concentration in brain tissue following inhalation of elemental mercury is significantly higher than those from intravenous injection or oral administration of either organic or ionic mercurials. Although elemental mercury is rapidly oxidized in the blood to the less diffusable mercuric ion, the transient occurrence of elemental mercury in the blood stream and the increased levels detected in the central nervous system are likely a result of its rapid diffusion into target tissues. This study reports the inhalation uptake and consequent tissue distribution of radioactive elemental mercury vapor in rats over a concentration range of 15 to 916 ng m/sup -3/, with particular emphasis on measurement below 50 ng m/sup -3/, in an effort to determine if the tissue distribution of mercury after a low level exposure is similar to those reported using higher concentrations.

  14. Absorption, tissue distribution, and excretion of tritium-labeled ivermectin in cattle, sheep, and rat

    SciTech Connect

    Chiu, Shuething Lee; Green, M.L.; Baylis, F.P.; Eline, D.; Rosegay, A.; Meriwether, H.; Jacob, T.A. )

    1990-11-01

    Tritium-labeled ivermectin was studied in cattle, sheep, and rat for absorption, tissue residue distribution, and excretion at doses of 0.3 mg/kg of body weight. The drug was absorbed by various dosing routes. By intraruminal and subcutaneous dosing routes, highest tissue residues were present in fat and liver of cattle, with half-lives of 6-8 and 4-5 days, respectively. Shorter half-lives (1-2 days) were observed in sheep and rat. The tissue residue distribution pattern was essentially the same for all species studied and similar in male and female rats. With doses of tritium-labeled avermectin B{sub 1a} ranging from 0.06 to 7.5 mg/kg of body weight, plasma and tissue residue concentrations increased proportionally with the dose. When ivermectin was administered by various routes (ip, sc, iv, oral, and intraruminal), blood residue levels converged to 20-50 ppb 4 h after dosing and then depleted at similar rate regardless of the dosing route. Ivermectin was excreted primarily in the feces, with only less than 2% of the doses being eliminated in the urine in all three species studied.

  15. A lead isotope distribution study in swine tissue using ICP-MS

    USGS Publications Warehouse

    May, T.W.; Wiedmeyer, R.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.

  16. 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.

  17. Tissue distribution study of columbianadin and its active metabolite columbianetin in rats.

    PubMed

    Zhang, You-Bo; Yang, Xiu-Wei

    2016-02-01

    Columbianadin, one of the main bioactive constituents of the roots of Angelica pubescens Maxim. f. biserrata Shan et Yuan, has been found to possess obvious pharmacological effects in previous studies. In this study, a valid and sensitive reverse-phase high-performance liquid chromatography (RP-HPLC) method was established and validated for the determination of columbianadin (CBN) and its active metabolite columbianetin (CBT) in rat tissue samples. Sample separation was performed on an RP-HPLC column using a mobile phase of MeOH-H2 O (75:25, v/v) at a flow rate of 1.0 mL/min. The UV absorbance of the samples was measured at the wavelength 325 nm. The calibration curves for CBN were linear over the ranges of 0.5-20 µg/g for brain, testes and muscle, 1.0-10.0 µg/g for stomach and intestine, and 0.2-20.0 µg/g for heart, liver, spleen, lung and kidney. The calibration curves for CBT were linear over the ranges of 0.5-25 µg/g for stomach and intestine, and 0.1-10.0 µg/g for heart, liver, spleen, lung and kidney. The analysis method was successfully applied to a tissue distribution study of CBN and CBT after intravenous administration of CBN to rats. The results of this study indicated that CBN could be detected in all of the selected tissues after i.v. administration. CBN was distributed to rat tissues rapidly and could be metabolized to CBT in most detected tissues. Of the detected tissues, heart had the highest uptake of CBN, which suggested that heart might be one of the main target tissues of CBN. Concentrations of CBT were obviously higher in the digestive system than in other assayed tissues. The information provided by this research is very useful for gaining knowledge of the capacities of CBN and CBT to access different tissues. PMID:26115176

  18. Determination of the magnetic particle distribution in tumour tissue by means of x-ray tomography

    NASA Astrophysics Data System (ADS)

    Brunke, O.; Odenbach, S.; Jurgons, R.; Alexiou, C.; Hilger, I.; Beckmann, F.

    2006-09-01

    In biomedical applications of ferrofluids, the resulting distribution of the magnetic nanoparticles is a crucial parameter for the effect of the therapeutic approach. In order to increase the efficacy of local cancer treatments incorporating ferrofluids like magnetic drug targeting and hyperthermia, the bio-distribution of theses fluids in the respective tissue has to be optimized. Usually, the distribution of particles is determined by histological cuts of the investigated specimen, a technique which provides only local information about the overall distribution of the magnetic material, e.g. in a tumour. Radioscopic techniques based on gamma or x-rays are well established, suitable for in vivo examination and non-destructive, but only provide two-dimensional integral information in the direction of the beam. Here we have used micro-tomography—incorporating a conventional x-ray tube as well as monochromatic synchrotron radiation—as a tool for a three-dimensional analysis of the distribution of magnetic nanoparticles in biological applications. Compared to biological matter, the iron-based magnetic nanoparticles provide sufficiently high absorption for x-rays and thus serve as an intrinsic contrast agent for the examinations. The results show the principle feasibility of the method for a quantitative determination of the agglomeration behaviour of the nanoparticles within carcinogenic tissue after intravascular or intratumoural injection.

  19. Anisotropy of Fibrous Tissues in Relation to the Distribution of Tensed and Buckled Fibers

    PubMed Central

    Ateshian, Gerard A.

    2009-01-01

    Fibrous tissues are characterized by a much higher stiffness in tension than compression. This study uses microstructural modeling to analyze the material symmetry of fibrous tissues undergoing tension and compression, to better understand how material symmetry relates to the distribution of tensed and buckled fibers. The analysis is also used to determine whether the behavior predicted from a microstructural model can be identically described by phenomenological continuum models. The analysis confirms that in the case when all the fibers are in tension in the current configuration, the material symmetry of a fibrous the tissue in the corresponding reference configuration is dictated by the symmetry of its fiber angular distribution in that configuration. However, if the strain field exhibits a mix of tensile and compressive principal normal strains, the fibrous tissue is represented by a material body which consists only of those fibers which are in tension; the material symmetry of this body may be deduced from the superposition of the planes of symmetry of the strain and the planes of symmetry of the angular fiber distribution. Thus the material symmetry is dictated by the symmetry of the angular distribution of only those fibers which are in tension. Examples are provided for various fiber angular distribution symmetries. In particular, it is found that a fibrous tissue with isotropic fiber angular distribution exhibits orthotropic symmetry when subjected to a mix of tensile and compressive principal normal strains, with the planes of symmetry normal to the principal directions of the strain. This anisotropy occurs even under infinitesimal strains and is distinct from the anisotropy induced from the finite rotation of fibers. It is also noted that fibrous materials are not stable under all strain states due to the inability of fibers to sustain compression along their axis; this instability can be overcome by the incorporation of a ground matrix. It is

  20. Pharmacokinetics of mitragynine in man

    PubMed Central

    Trakulsrichai, Satariya; Sathirakul, Korbtham; Auparakkitanon, Saranya; Krongvorakul, Jatupon; Sueajai, Jetjamnong; Noumjad, Nantida; Sukasem, Chonlaphat; Wananukul, Winai

    2015-01-01

    Background Kratom, known botanically as Mitragyna speciosa (Korth.), is an indigenous tree in Southeast Asia. Kratom is currently easily available worldwide via special shops and the Internet to use as a drug of abuse, opioid alternative, or pain killer. So far, the pharmacokinetics of this plant has been studied only in animals, and there is no such study in humans. The major abundant active alkaloid in Kratom, mitragynine, is one of the promising new chemical substances to be developed as a new drug. The aim of this study was to examine the pharmacokinetics of mitragynine and assess the linearity in pharmacokinetics in chronic users. Methods Since Kratom is illegal in Thailand, studies in healthy subjects would be unethical. We therefore conducted a prospective study by enrolling ten chronic, regular, healthy users. We adjusted the steady state in each subject by giving a known amount of Kratom tea for 7 days before commencement of the experiment. We admitted and gave different oral doses to subjects to confirm linearity in pharmacokinetics. The mitragynine blood concentrations at 17 times points and the urine concentrations during the 24-hour period were collected and measured by liquid chromatography-tandem mass spectrometry method. Results Ten male subjects completed the study without adverse reactions. The median duration of abuse was 1.75 years. We analyzed one subject separately due to the abnormal behavior of blood concentration. From data of nine subjects, the pharmacokinetic parameters established were time to reach the maximum plasma concentration (0.83±0.35 hour), terminal half-life (23.24±16.07 hours), and the apparent volume of distribution (38.04±24.32 L/kg). The urine excretion of unchanged form was 0.14%. The pharmacokinetics were observed to be oral two-compartment model. Conclusion This was the first pharmacokinetic study in humans, which demonstrated linearity and was consistent with the oral two-compartment model with a terminal half

  1. 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...

  2. Distribution of porfiromycin in EMT6 solid tumors and normal tissues of BALB/c mice.

    PubMed

    Keyes, S R; Rockwell, S; Kennedy, K A; Sartorelli, A C

    1991-05-01

    The distribution of porfiromycin was studied in BALB/c mice bearing EMT6 mammary tumors. The levels of 3H in blood and most tissues peaked approximately 15 minutes after intraperitoneal injection of [3H]porfiromycin. The levels of radioactivity present in most of the tissues and in the tumors were similar at 4 hours and 24 hours after administration. Most of the normal tissues showed uniform, low grain densities when analyzed by autoradiography; the liver and the small intestine had the highest labeling densities. Only kidney, bladder, and tumor showed differential distributions of grains from [3H]porfiromycin. In the kidney, higher grain counts were found in cortex than in medullary regions; grains were uniformly distributed within each region. In the bladder, the highest labeling densities were found in regions near the lumen. Tumor regions that had some necrotic features or regions of necrosis that included some viable cells showed higher labeling intensities than healthy-looking tumor regions, probably because the abnormal microenvironments in these regions led to increased rates of activation of porfiromycin to electrophilic species. These findings show that porfiromycin can reach and be activated in tumor regions containing cells resistant to many chemotherapeutic agents and to x rays. The results also support the concept that agents such as porfiromycin can target cells in specific microenvironmental subpopulations of solid tumors. PMID:2023281

  3. Effects of an implant on temperature distribution in tissue during ultrasound diathermy.

    PubMed

    Sun, Ming-Kuan; Shieh, Jay; Chen, Chuin-Shan; Chiang, Hongsen; Huang, Chang-Wei; Chen, Wen-Shiang

    2016-09-01

    The effects of an implant on temperature distribution in a tissue-mimicking hydrogel phantom during the application of therapeutic ultrasound were investigated. In vitro experiments were conducted to compare the influences of plastic and metal implants on ultrasound diathermy and to calibrate parameters in finite element simulation models. The temperature histories and characteristics of the opaque (denatured) areas in the hydrogel phantoms predicted by the numerical simulations show good correlation with those observed in the in vitro experiments. This study provides an insight into the temperature profile in the vicinity of an implant by therapeutic ultrasound heating typically used for physiotherapy. A parametric study was conducted through numerical simulations to investigate the effects of several factors, such as implant material type, ultrasound operation frequency, implant thickness and tissue thickness on the temperature distribution in the hydrogel phantom. The results indicate that the implant material type and implant thickness are the main parameters influencing the temperature distribution. In addition, once the implant material and ultrasound operation frequency are chosen, an optimal implant thickness can be obtained so as to avoid overheating injuries in tissue. PMID:27150744

  4. Tissue distribution of amyloid deposits in Abyssinian cats with familial amyloidosis.

    PubMed

    DiBartola, S P; Tarr, M J; Benson, M D

    1986-07-01

    The tissue distribution of amyloid deposits was studied in 15 related Abyssinian cats with familial amyloidosis. There was interstitial medullary amyloidosis in the kidneys of all 15 cats but only 11 had detectable glomerular involvement. The thyroid glands, stomach and colon were affected in all cats examined. Most of the cats also had amyloid deposits in the small intestine, spleen, heart, adrenals, pancreas, liver, lymph nodes and bladder. In 50 per cent or fewer of the cats examined, there was involvement of the parathyroids, lung and gonads. The central nervous system was not involved in any of the 3 cats evaluated. In 8 of the cats, no concurrent inflammatory disease could be detected. The tissue distribution of amyloid deposits resembled that found in other breeds of domestic cats with systemic amyloidosis. Despite the wide tissue distribution of amyloid deposits, clinical signs were related to renal amyloidosis. Familial amyloidosis in the Abyssinian cat may represent a valuable spontaneous animal model for the study of Familial Mediterranean Fever in man and the pathogenesis of reactive amyloidosis in general. PMID:3734172

  5. Dynamic distribution and tissue tropism of infectious laryngotracheitis virus in experimentally infected chickens.

    PubMed

    Wang, Lin-Guo; Ma, Jun; Xue, Chun-Yi; Wang, Wei; Guo, Chao; Chen, Feng; Qin, Jian-Ping; Huang, Ning-Hai; Bi, Ying-Zuo; Cao, Yong-Chang

    2013-03-01

    Infectious laryngotracheitis (ILT), caused by infectious laryngotracheitis virus (ILTV), is an Office International des Epizooties (OIE) notifiable disease. However, we have not clearly understood the dynamic distribution, tissue tropism, pathogenesis, and replication of ILTV in chickens. In this report, we investigated the dynamic distribution and tissue tropism of the virus in internal organs of experimentally infected chickens using quantitative real-time polymerase chain reaction (qPCR) and a histopathological test. The study showed that ILTV could be clearly detected in eight internal organs (throat, trachea, lung, cecum, kidney, pancreas, thymus and esophagus) of infected chickens, whereas the virus was difficult to detect in heart, spleen, proventriculus, liver, brain and bursa. Meanwhile, the thymidine kinase (TK) gene levels in eight internal organs increased from 3 days to 5 days postinfection, and then decreased from 6 days to 8 days postinfection. The log copy number of ILTV progressively increased over 3 days, which corresponds to the clinical score and the result of the histopathological test. The results provide a foundation for further clarification of the pathogenic mechanism of ILTV in internal organs and indicate that throat, lung, trachea, cecum, kidney, pancreas and esophagus may be preferred sites of acute infection, suggesting that the tissue tropism and distribution of ILTV is very broad. PMID:23392630

  6. Uptake, tissue distribution and depuration of triclosan in the guppy Poecilia vivipara acclimated to freshwater.

    PubMed

    Escarrone, Ana Laura Venquiaruti; Caldas, Sergiane Souza; Primel, Ednei Gilberto; Martins, Samantha Eslava; Nery, Luiz Eduardo Maia

    2016-08-01

    The agent triclosan has been extensively used in different personal care products as a broad-spectrum antimicrobial and preservative agent. Due to its continuous release into the environment, including discharge via wastewater treatment plants, triclosan has been widely detected in aquatic environments. There is growing interest in improving the knowledge about the environmental fate of triclosan due to its possible bioaccumulation and the toxicity it may pose to organisms, such as fish and other non-target species. To investigate the distribution and bioconcentration of triclosan in fish, Poecilia vivipara was exposed to 0.2mgL(-1). Contents of triclosan in whole fish, brain, gonads, liver, muscle and gills were quantified by LC-MS/MS. When lipid normalised concentration was used, the liver exhibited the highest concentration followed by the gills, gonads, brain and muscle tissues. Bioconcentration was increased with time reaching a steady-state around 7-14days for most all tissues. After 24h depuration, triclosan concentrations declined >80% in all tissues except liver, in which triclosan takes longer to be depurated. These results not only clearly indicate that triclosan accumulated in P. vivipara, with tissue-specific bioconcentration factors (BCF) that ranged from 40.2 to 1025.4, but also show that the elimination of triclosan after transferring the fish to triclosan-free freshwater is rapid in all tissues. PMID:27101458

  7. 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. PMID:24733631

  8. Tissue distribution of cloxacillin after intramammary administration in the isolated perfused bovine udder

    PubMed Central

    2010-01-01

    Background Various intramammary suspensions containing cloxacillin benzathine are registered for use in cattle as antibiotics for intramammary use at drying off. To ensure antibacterial efficacy, the glandular tissue concentration of an antimicrobial agent must be sufficient. Since the possibilities to measure concentrations in the different areas of the glandular tissue in vivo are very limited, it was the aim of the present study to examine the distribution of cloxacillin in vitro using the isolated perfused bovine udder. Methods Mammary glands taken at slaughter from healthy lactating cows were perfused in vitro with warmed and gassed Tyrode solution. 600 mg cloxacillin benzathine were administered as Orbenin Extra Dry Cow by the intramammary route to six front and rear quarters each. Samples of glandular tissue - at different distances from and vertical to the teat right up to the udder base - were gathered from the treated quarters after 6 h. Perfusate was also sampled before and hourly after treatment for 6 h. The cloxacillin content of the tissue samples and perfusate samples was analysed by high performance liquid chromatography. Results The concentration of cloxacillin in the glandular tissue of front quarters measured 6 h after administration tended to decrease with increasing vertical distance from the teat. The decrease pattern of the concentration was not quite clear in rear quarters. A considerable variation in the tissue concentrations of cloxacillin was obvious, which reflects in vivo conditions. The concentrations measured in the perfusate samples were below the limit of quantification at all time points, indicating limited absorption of the antibiotic from the glandular tissue. Conclusion After intramammary administration of the dry off product containing cloxacillin benzathine concentrations of more than 0.5 μg/g (MIC) were reached in all regions of the front and rear quarters. PMID:20925913

  9. Tissue distribution and elimination after oral and intravenous administration of different titanium dioxide nanoparticles in rats

    PubMed Central

    2014-01-01

    Objective The aim of this study was to obtain kinetic data that can be used in human risk assessment of titanium dioxide nanomaterials. Methods Tissue distribution and blood kinetics of various titanium dioxide nanoparticles (NM-100, NM-101, NM-102, NM-103, and NM-104), which differ with respect to primary particle size, crystalline form and hydrophobicity, were investigated in rats up to 90 days post-exposure after oral and intravenous administration of a single or five repeated doses. Results For the oral study, liver, spleen and mesenteric lymph nodes were selected as target tissues for titanium (Ti) analysis. Ti-levels in liver and spleen were above the detection limit only in some rats. Titanium could be detected at low levels in mesenteric lymph nodes. These results indicate that some minor absorption occurs in the gastrointestinal tract, but to a very limited extent. Both after single and repeated intravenous (IV) exposure, titanium rapidly distributed from the systemic circulation to all tissues evaluated (i.e. liver, spleen, kidney, lung, heart, brain, thymus, reproductive organs). Liver was identified as the main target tissue, followed by spleen and lung. Total recovery (expressed as % of nominal dose) for all four tested nanomaterials measured 24 h after single or repeated exposure ranged from 64-95% or 59-108% for male or female animals, respectively. During the 90 days post-exposure period, some decrease in Ti-levels was observed (mainly for NM-100 and NM-102) with a maximum relative decrease of 26%. This was also confirmed by the results of the kinetic analysis which revealed that for each of the investigated tissues the half-lifes were considerable (range 28–650 days, depending on the TiO2-particle and tissue investigated). Minor differences in kinetic profile were observed between the various particles, though these could not be clearly related to differences in primary particle size or hydrophobicity. Some indications were observed for an

  10. Noninvasive imaging of the distribution in oxygen in tissue in vivo using near-infrared phosphors.

    PubMed Central

    Vinogradov, S A; Lo, L W; Jenkins, W T; Evans, S M; Koch, C; Wilson, D F

    1996-01-01

    A newly developed water-soluble phosphor suitable for measuring oxygen pressure in the blood (Green 2W) was used for noninvasive, in vivo imaging of oxygen distribution in the vascular systems of mice. Oxygen quenches the phosphorescence of Green 2W, measured in the presence of 2% albumin, according to the Stern-volmer relationship. This oxygen-dependent quenching of phosphorescence has been used to obtain digital maps of the oxygen distribution in the tissue vasculature. EMT-6 mammary carcinoma tumors were grown by injecting 1 x 10(6) cells in 0.1-ml carrier into the subcutaneous space over the muscle on the hindquarter. When the tumors were approximately 8 mm in diameter, 300 micrograms of phosphorescence probe (Green 2W; absorption maximum 636 nm) was injected into the tail vein. The mice were immobilized with intraperotoneal Ketamine (133 mg/kg) and Xylazine (10 mg/kg) and illuminated with flashes (< 4-microseconds t1/2) of light of 630 +/- 12 nm. The emitted phosphorescence (790-nm maximum) was imaged an intensified CCD camera. Images were collected beginning at 30, 50, 80, 120, 180, 240, 420, and 2500 microseconds after the flash and used to calculate digital maps of the phosphorescence lifetimes and oxygen pressure. Both the illumination light and the phosphorescence were in the near-infrared region of the spectrum, where tissue has greatly decreased absorbance. The light therefore readily passed through the skin and centimeter thicknesses of tissue. The oxygen maps could be obtained by illuminating from the side of the mouse opposite the camera (and tumor). The tumors were readily observed as regions with oxygen pressures substantially below those of the surrounding tissue. Thus, phosphorescence measurements can noninvasively detect volumes of tissue with below-normal oxygen pressure in the presence of much larger volumes of tissue with normal oxygen pressures. In addition, tissue oxygen pressures can be monitored in real time, even through centimeter

  11. Physiologically based modeling of the pharmacokinetics of acetaminophen and its major metabolites in humans using a Bayesian population approach.

    PubMed

    Zurlinden, Todd J; Reisfeld, Brad

    2016-06-01

    The principal aim of this study was to develop, validate, and demonstrate a physiologically based pharmacokinetic (PBPK) model to predict and characterize the absorption, distribution, metabolism, and excretion of acetaminophen (APAP) in humans. A PBPK model was created that included pharmacologically and toxicologically relevant tissue compartments and incorporated mechanistic descriptions of the absorption and metabolism of APAP, such as gastric emptying time, cofactor kinetics, and transporter-mediated movement of conjugated metabolites in the liver. Through the use of a hierarchical Bayesian framework, unknown model parameters were estimated using a large training set of data from human pharmacokinetic studies, resulting in parameter distributions that account for data uncertainty and inter-study variability. Predictions from the model showed good agreement to a diverse test set of data across several measures, including plasma concentrations over time, renal clearance, APAP absorption, and pharmacokinetic and exposure metrics. The utility of the model was then demonstrated through predictions of cofactor depletion, dose response of several pharmacokinetic endpoints, and the relationship between APAP biomarker levels in the plasma and those in the liver. The model addressed several limitations in previous PBPK models for APAP, and it is anticipated that it will be useful in predicting the pharmacokinetics of APAP in a number of contexts, such as extrapolating across doses, estimating internal concentrations, quantifying population variability, assessing possible impacts of drug coadministration, and, when coupled with a suitable pharmacodynamic model, predicting toxicity. PMID:25636597

  12. Pharmacokinetics of leptin in female mice.

    PubMed

    Hart, R A; Dobos, R C; Agnew, L L; Tellam, R L; McFarlane, J R

    2016-06-20

    Pharmacokinetics of leptin in mammals has received limited attention and only one study has examined more than two time points and this was in ob/ob mice. This study is the first to observe the distribution of leptin over a time course in female mice. A physiologic dose (12 ng) of radiolabelled leptin was injected in adult female mice via the lateral tail vein and tissues were dissected out and measured for radioactivity over a time course up to two hours. Major targets for administered leptin included the liver, kidneys, gastrointestinal tract and the skin while the lungs had high concentrations of administered leptin per gram of tissue. Leptin was also found to enter the lumen of the digestive tract intact from the plasma. Very little of the dose (<1 %) was recovered from the brain at any time. Consequently we confirm that the brain is not a major target for leptin from the periphery, although it may be very sensitive to leptin that does get to the hypothalamus. Several of the major targets (GI tract, skin and lungs) for leptin form the interface for the body with the environment, and given the ability of leptin to modulate immune function, this may represent a priming effect for tissues to respond to damage and infection. PMID:26447522

  13. 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. PMID:24392664

  14. 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...

  15. Interspecies mixed-effect pharmacokinetic modeling of penicillin G in cattle and swine.

    PubMed

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

    2014-08-01

    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

  16. Target tissue distribution of the proenkephalin peptides F, E, and B

    SciTech Connect

    Katzenstein, G.E.; Lund, D.; Schultz, P.; Lewis, R.V.

    1987-08-14

    The adrenal medulla is a rich source of endogenous opioid peptides. These peptides exist predominantly in the form of larger (25-34 amino acid long) enkephalin containing peptides, whose biological roles have yet to be elucidated. We report here the tissue binding distribution of three iodinated enkephalin containing peptides, Peptides F, E, and B, in rats, rabbits, and guinea pigs following intravenous injection. Each (/sup 125/I)peptide has a unique distribution profile but all three are found to bind to the pituitary in each species of animal examined. A number of lines of evidence point toward the enkephalin containing peptides, Peptides F, E, and B, having physiological roles distinct from the enkephalins. The distribution profile of these (/sup 125/I)peptides reported here gives insight into their potential effector sites.

  17. Distribution and accumulation of mercury in tissues of captive-reared common loon (Gavia immer) chicks

    USGS Publications Warehouse

    Kenow, K.P.; Meyer, M.W.; Hines, R.K.; Karasov, W.H.

    2007-01-01

    We determined the distribution and accumulation of Hg in tissues of common loon (Gavia immer) chicks maintained for up to 15 weeks on either a control diet with no added methylmercury chloride (MeHgCl) or one containing either 0.4 or 1.2 ??g Hg (as MeHgCl)/g wet-weight food. Total Hg and MeHg tissue concentrations were strongly positively correlated (r2 > 0.95) with the amount of Hg delivered to individual chicks throughout the course of the experiment. The pattern of differential Hg concentration in internal tissues was consistent within each treatment: Liver > kidney > muscle > carcass > brain. Feather Hg concentrations were consistently higher than those of internal tissues and represented an important route of Hg elimination. Feather mass accounted for 4.3% ?? 0.1% (average ?? standard error) of body mass, yet 27.3% ?? 2.6% of total Hg intake was excreted into feathers. Our calculations indicate that 26.7% ?? 4.9% of ingested Hg was not accounted for and, thus, either was never absorbed or was absorbed and subsequently eliminated in feces. With the additional excretion into feathers, 54% of ingested Hg was excreted. Demethylation was evident in the liver at all treatment levels and in the kidneys of chicks dosed at 1.2 ??g Hg/g. Mercury concentrations were strongly positively correlated (r2 ??? 0.95) among internal tissues and with blood Hg concentration. Mercury concentrations of secondary feathers were moderately correlated (r2 = 0.82-0.93) with internal tissues. We supply regression models that may be used to provide perspective and a useful means of interpreting the variety of measures of Hg exposure reported in the literature. ?? 2007 SETAC.

  18. Determination of doxorubicin in rabbit ocular tissues and pharmacokinetics after intravitreal injection of a single dose of doxorubicin-loaded poly-beta-hydroxybutyrate microspheres.

    PubMed

    Hu, Tao; Le, Qihua; Wu, Zhiyi; Wu, Wei

    2007-01-01

    A validated HPLC method was developed for the quantification of doxorubicin in rabbit ocular tissues using solid phase extraction and ultraviolet detection. Chromatographic separation of doxorubicin in various ocular tissues was performed on a C18 column. The mobile phase was composed of 0.2 M KH2PO4 buffer solution, acetonitrile and triethylamine in volumetric ratio of 70/30/0.2, adjusted to pH 4.0 with orthophosphoric acid. The calibration curve was linear over the range of 0.03-10, 0.03-10, 0.05-10 and 0.05-10 microg/ml in vitreous body, iris, retina/choroids and sclera, respectively. The intra-day and inter-day precisions in all ocular tissues were smaller than 4.95% and 5.73%, and the accuracies were about 100%. The extraction recoveries of doxorubicin in all of the ocular tissues were between 83.47% and 96.33%. After intravitreal administration of doxorubicin-loaded poly-beta-hydroxybutyrate microspheres, doxorubicin level in ocular tissues was much lower than that for administration of free doxorubicin, which was helpful to reduce the associated toxicity to surrounding tissues. Doxorubicin was detectable even after tens of days in the studied ocular tissues. PMID:16884884

  19. Estimating oxygen distribution from vasculature in three-dimensional tumour tissue.

    PubMed

    Grimes, David Robert; Kannan, Pavitra; Warren, Daniel R; Markelc, Bostjan; Bates, Russell; Muschel, Ruth; Partridge, Mike

    2016-03-01

    Regions of tissue which are well oxygenated respond better to radiotherapy than hypoxic regions by up to a factor of three. If these volumes could be accurately estimated, then it might be possible to selectively boost dose to radio-resistant regions, a concept known as dose-painting. While imaging modalities such as 18F-fluoromisonidazole positron emission tomography (PET) allow identification of hypoxic regions, they are intrinsically limited by the physics of such systems to the millimetre domain, whereas tumour oxygenation is known to vary over a micrometre scale. Mathematical modelling of microscopic tumour oxygen distribution therefore has the potential to complement and enhance macroscopic information derived from PET. In this work, we develop a general method of estimating oxygen distribution in three dimensions from a source vessel map. The method is applied analytically to line sources and quasi-linear idealized line source maps, and also applied to full three-dimensional vessel distributions through a kernel method and compared with oxygen distribution in tumour sections. The model outlined is flexible and stable, and can readily be applied to estimating likely microscopic oxygen distribution from any source geometry. We also investigate the problem of reconstructing three-dimensional oxygen maps from histological and confocal two-dimensional sections, concluding that two-dimensional histological sections are generally inadequate representations of the three-dimensional oxygen distribution. PMID:26935806

  20. Estimating oxygen distribution from vasculature in three-dimensional tumour tissue

    PubMed Central

    Kannan, Pavitra; Warren, Daniel R.; Markelc, Bostjan; Bates, Russell; Muschel, Ruth; Partridge, Mike

    2016-01-01

    Regions of tissue which are well oxygenated respond better to radiotherapy than hypoxic regions by up to a factor of three. If these volumes could be accurately estimated, then it might be possible to selectively boost dose to radio-resistant regions, a concept known as dose-painting. While imaging modalities such as 18F-fluoromisonidazole positron emission tomography (PET) allow identification of hypoxic regions, they are intrinsically limited by the physics of such systems to the millimetre domain, whereas tumour oxygenation is known to vary over a micrometre scale. Mathematical modelling of microscopic tumour oxygen distribution therefore has the potential to complement and enhance macroscopic information derived from PET. In this work, we develop a general method of estimating oxygen distribution in three dimensions from a source vessel map. The method is applied analytically to line sources and quasi-linear idealized line source maps, and also applied to full three-dimensional vessel distributions through a kernel method and compared with oxygen distribution in tumour sections. The model outlined is flexible and stable, and can readily be applied to estimating likely microscopic oxygen distribution from any source geometry. We also investigate the problem of reconstructing three-dimensional oxygen maps from histological and confocal two-dimensional sections, concluding that two-dimensional histological sections are generally inadequate representations of the three-dimensional oxygen distribution. PMID:26935806

  1. Analogous reserve distribution and tissue characteristics in quinoa and grass seeds suggest convergent evolution.

    PubMed

    Burrieza, Hernán P; López-Fernández, María P; Maldonado, Sara

    2014-01-01

    Quinoa seeds are highly nutritious due to the quality of their proteins and lipids and the wide range of minerals and vitamins they store. Three compartments can be distinguished within the mature seed: embryo, endosperm, and perisperm. The distribution of main storage reserves is clearly different in those areas: the embryo and endosperm store proteins, lipids, and minerals, and the perisperm stores starch. Tissues equivalent (but not homologous) to those found in grasses can be identified in quinoa, suggesting the effectiveness of this seed reserve distribution strategy; as in cells of grass starchy endosperm, the cells of the quinoa perisperm endoreduplicate, increase in size, synthesize starch, and die during development. In addition, both systems present an extra-embryonic tissue that stores proteins, lipids and minerals: in gramineae, the aleurone layer(s) of the endosperm; in quinoa, the micropylar endosperm; in both cases, the tissues are living. Moreover, the quinoa micropylar endosperm and the coleorhiza in grasses play similar roles, protecting the root in the quiescent seed and controlling dormancy during germination. This investigation is just the beginning of a broader and comparative study of the development of quinoa and grass seeds. Several questions arise from this study, such as: how are synthesis and activation of seed proteins and enzymes regulated during development and germination, what are the genes involved in these processes, and lastly, what is the genetic foundation justifying the analogy to grasses. PMID:25360139

  2. Cloning and tissue distribution of appetite-regulating peptides in pirapitinga (Piaractus brachypomus).

    PubMed

    Volkoff, H

    2015-10-01

    Pirapitinga (or red-bellied pacu, Piaractus brachypomus, Characiforme, Serrasalmidae) is an economically important South American fish for which the endocrine mechanism of the regulation of feeding has never been examined. To better understand these mechanisms, cDNAs encoding the appetite-regulating peptides orexin, cocaine- and amphetamine-regulated transcript (CART), apelin, cholecystokinin (CCK), peptide YY (PYY), leptin and ghrelin were isolated in pirapitinga and their mRNA distributions examined in peripheral tissues and brain. When compared to other fish, the sequences obtained for all peptides were most similar to those of other Characiforme fish (i.e. Mexican cavefish) and Siluriformes (catfish) as well as Cypriniformes (i.e. goldfish, zebrafish). All peptides were widely expressed within the brain. With the exception of CART, which was only expressed in brain, the mRNAs of all peptides were present in several peripheral tissues, including gastrointestinal tract, kidneys and gills. The widespread and peptide-specific distributions suggest that each peptide might have distinct physiological actions in the brain and on peripheral tissues, in particular on the gastrointestinal tract, which include feeding regulation. This preliminary study opens new avenues for further functional studies on the endocrine regulation of feeding in Serrasalmidae fish, including pirapitinga. PMID:25846408

  3. Toxicokinetics and tissue distribution of cadmium-based Quantum Dots in the marine mussel Mytilus galloprovincialis.

    PubMed

    Rocha, Thiago Lopes; Gomes, Tânia; Pinheiro, José Paulo; Sousa, Vânia Serrão; Nunes, Luís Miguel; Teixeira, Margarida Ribau; Bebianno, Maria João

    2015-09-01

    Environmental health hazards of Quantum Dots (QDs) are of emergent concern, but limited data is available about their toxicokinetics (TK) and tissue distribution in marine bivalves. This study investigated the QDs behavior in seawater, their TK and tissue distribution in Mytilus galloprovincialis, in comparison with soluble Cd. Mussels were exposed to CdTe QDs and soluble Cd for 21 days at 10 μgCd L(-1) followed by a 50 days depuration. TK of QDs in mussels is related to the homo-aggregate uptake, surface charge, aggregation and precipitation as key factors. There were tissue- and time-dependent differences in the TK of both Cd forms, and soluble Cd is the most bioavailable form. Digestive gland is a preferential site for QDs storage and both Cd forms are not eliminated by mussels (t1/2>50 days). Results indicate that the TK model of CdTe QDs in marine mussels is distinct from their soluble counterparts. PMID:25982546

  4. Analogous reserve distribution and tissue characteristics in quinoa and grass seeds suggest convergent evolution

    PubMed Central

    Burrieza, Hernán P.; López-Fernández, María P.; Maldonado, Sara

    2014-01-01

    Quinoa seeds are highly nutritious due to the quality of their proteins and lipids and the wide range of minerals and vitamins they store. Three compartments can be distinguished within the mature seed: embryo, endosperm, and perisperm. The distribution of main storage reserves is clearly different in those areas: the embryo and endosperm store proteins, lipids, and minerals, and the perisperm stores starch. Tissues equivalent (but not homologous) to those found in grasses can be identified in quinoa, suggesting the effectiveness of this seed reserve distribution strategy; as in cells of grass starchy endosperm, the cells of the quinoa perisperm endoreduplicate, increase in size, synthesize starch, and die during development. In addition, both systems present an extra-embryonic tissue that stores proteins, lipids and minerals: in gramineae, the aleurone layer(s) of the endosperm; in quinoa, the micropylar endosperm; in both cases, the tissues are living. Moreover, the quinoa micropylar endosperm and the coleorhiza in grasses play similar roles, protecting the root in the quiescent seed and controlling dormancy during germination. This investigation is just the beginning of a broader and comparative study of the development of quinoa and grass seeds. Several questions arise from this study, such as: how are synthesis and activation of seed proteins and enzymes regulated during development and germination, what are the genes involved in these processes, and lastly, what is the genetic foundation justifying the analogy to grasses. PMID:25360139

  5. 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. PMID:27082931

  6. 3H-delta9-tetrahydrocannabinol tissue and subcellular distribution in the central nervous system and tissue distribution in peripheral organs of tolerant and nontolerant dogs.

    PubMed

    Martin, B R; Dewey, W L; Harris, L S; Beckner, J S

    1976-01-01

    Tolerant and nontolerant dogs received one i.v. administration of 0.5 mg/kg of 3H-delta9-tetrahydrocannabinol 30 minutes before they were sacrificed. Plasma, peripheral and brain tissues, as well as subcellular fractions of brain tissues from both treatment groups, were analyzed for radioactivity. Throughout the time period before sacrifice, the plasma concentrations of radioactivity in the tolerant and nontolerant dogs were not significantly different. The percentage of radioactivity in brain and plasma that was due to either unchanged delta9-tetrahydrocannabinol or a major metabolite was the same in each group. Of the radioactivity in brain, 46% was identified as delta9-tetrahydrocannabinol. Regardless of treatment, there was a specific accumulation of radioactivity in adrenals, liver, kidney, heart and pancreas. The only significant differences in radioactivity between tolerant and nontolerant peripheral tissues were found in liver, kidney cortex, heart and lymph nodes. Although all brain areas from tolerant dogs contained less radioactivity than the comparable brain areas from nontolerant animals, only pituitary and putamen were significantly less. There was a specific accumulation of radioactivity in some brain areas that could be associated with behavioral effects. The concentration in cerebellar and cerebral gray was significantly greater than that in white, and there was a marked reduction in the concentration in gray after tolerance developed. The mean percentage of radioactivity in each subcellular fraction was as follows: 23% crude nuclei, 44% mitochondria, 8% cholinergic nerve endings, 7% noncholinergic nerve endings, 2% free mitochondria and 6% synaptic vesicles. The quantity of radioactivity in homogenates of brains from tolerant dogs was 17% less than brains of nontolerant animals, which was merely a reflection of the respective plasma concentrations. The distribution of radioactivity was similar in both groups, although most of the subcellular

  7. Heterotopic ossification: review of histologic findings and tissue distribution in a 10-year experience.

    PubMed

    Liu, Katharine; Tripp, Sheryl; Layfield, Lester J

    2007-01-01

    Heterotopic ossification (HO) within tissues involved by a pathologic process is a well-recognized phenomenon. It is most frequently observed in atherosclerotic plaques, in soft tissue around joints, and in the central nervous system. Less frequently, carcinomas and some benign neoplasms will undergo heterotopic ossification. We performed a retrospective review of our experience with HO over a 10-year period to determine the frequency and tissue site distribution of heterotopic ossification. A computerized review of surgical pathology records of approximately 126,000 reports revealed 85 cases in which heterotopic ossification, ectopic bone or metaplastic bone was specifically mentioned in the surgical pathology diagnosis. Twenty-two cases were neoplasms of non-osseous tissues, and 63 cases were non-neoplastic lesions. Immunohistochemical staining for bone morphogenic proteins (BMP) 1, 4, and 6 was performed. Fourteen cases showed staining for BMP-1, 22 cases showed staining for BMP-4, and five cases showed weak staining for BMP-6. HO is a relatively infrequent finding and is more commonly seen in degenerative and reparative conditions than in neoplasms. PMID:17728073

  8. Imaging the Tissue Distribution of Glucose in Livers Using A PARACEST Sensor

    PubMed Central

    Ren, Jimin; Trokowski, Robert; Zhang, Shanrong; Malloy, Craig R.; Sherry, A. Dean

    2009-01-01

    Noninvasive imaging of glucose in tissues could provide important insights about glucose gradients in tissue, the origins of gluconeogenesis, or perhaps differences in tissue glucose utilization in vivo. Direct spectral detection of glucose in vivo by 1H NMR is complicated by interfering signals from other metabolites and the much larger water signal. One potential way to overcome these problems is to use an exogenous glucose sensor that reports glucose concentrations indirectly through the water signal by chemical exchange saturation transfer (CEST). Such a method is demonstrated here in mouse liver perfused with a Eu3+-based glucose sensor containing two phenylboronate moieties as the recognition site. Activation of the sensor by applying a frequency-selective presaturation pulse at 42 ppm resulted in a 17% decrease in water signal in livers perfused with 10 mM sensor and 10 mM glucose compared with livers with the same amount of sensor but without glucose. It was shown that livers perfused with 5 mM sensor but no glucose can detect glucose exported from hepatocytes after hormonal stimulation of glycogenolysis. CEST images of livers perfused in the magnet responded to changes in glucose concentrations demonstrating that the method has potential for imaging the tissue distribution of glucose in vivo. PMID:18958853

  9. Tissue Distribution of Acetyl-Coenzyme A Carboxylase in Leaves 1

    PubMed Central

    Nikolau, Basil J.; Wurtele, Eve Syrkin; Stumpf, Paul K.

    1984-01-01

    Acetyl-CoA carboxylase [acetyl-CoA—carbon dioxide ligase (ADP forming), EC 6.4.1.2] is a biotin-containing enzyme catalyzing the formation of malonyl-CoA. The tissue distribution of this enzyme was determined for leaves of C3- and C4-plants. The mesophyll tissues of the C3-plants Pisum sativum and Allium porrum contained 90% of the leaf acetyl-CoA carboxylase activity, with the epidermal tissues containing the remainder. Western blotting of proteins fractionated by sodium dodecyl sulfate polyacrylamide gel electrophoresis, using 125I-streptavidin as a probe, revealed biotinyl proteins of molecular weights 62,000, 51,000, and 32,000 in P. sativum and 62,000, 34,000, and 32,000 in A. porrum. In the C4-plant sorghum, epidermal protoplasts, mesophyll protoplasts and strands of bundle sheath cells contained 35, 47, and 17%, respectively, of the total leaf acetyl-CoA carboxylase activity. In Zea mays leaves the respective figures were 10% for epidermal protoplasts, 56% for mesophyll protoplasts, and 32% for bundle sheath strands. Biotinyl proteins of molecular weights 62,000 and 51,000 were identified in leaves of sorghum and Z. mays. The results are discussed with respect to each tissue's requirements for malonyl-CoA for various metabolic pathways. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:16663756

  10. Drug-induced modulation of Tc-99m pyrophosphate tissue distribution: what is involved

    SciTech Connect

    Wahner, H.W.; Dewanjee, M.K.

    1981-06-01

    More than ten years after their introduction, Tc-99m-labeled phosphates and phosphonates (TcP) continue to be of interest to the investigator and to hold promise for new clinical applications in the future. Initially, TcP compounds were valued because of their bone-seeking properties. Emphasis shifted from bone to soft tissue when Bonte et al. introduced Tc-99m-labeled pyrophosphate (TcPPi) for myocardial infarct scanning. Detailed information about TcPPi uptake in ischemic and necrotic myocardial tissue at the subcellular level has accumulated. Therefore, understanding of the mechanism of TcPPi uptake in infarcted myocardium is more detailed than understanding of uptake by bone. A new, and potentially powerful, approach to the use of TcP is being proposed by Carr et al. The authors attempt to modulate favorably the tissue distribution of TcPPi by prior administration of drugs in pharmacological quantities. The authors demonstrate that uptake of TcPPi can be enhanced in the necrotic myocardium, uptake by bone can be reduced, and the lesion-to-blood ratio can be altered favorably when vitamin D/sub 3/ or desoxycorticosterone acetate (DOCA) is administered in pharmacological doses before the TcPPi injection. A short review is presented of background information helpful for interpreting the drug effects on TcPPi uptake in bone or necrotic myocardial tissue.

  11. Plasma disappearance, urine excretion, and tissue distribution of ribavirin in rats and rhesus monkeys

    SciTech Connect

    Ferrara, E.A.; Oishi, J.S.; Wannemacher, R.W. Jr.; Stephen, E.L.

    1981-06-01

    Ribavirin has been shown to have broad-spectrum antiviral. To study its tissue distribution and disappearance rate, a single dose of 10 mg/kg which contained 10 microCi of (14C)ribavirin was injected intravenously into rhesus monkeys and intramuscularly into monkeys and rats. Except for peak plasma concentrations and the initial phases of the plasma disappearance and urine excretion curves, no significant difference was observed between plasma, tissue, or urine values for intramuscularly or intravenously injected monkeys. Plasma disappearance curves were triphasic; plasma concentrations of ribavirin were similar for both monkeys and rats. Rats excreted ribavirin in the urine more rapidly and to a greater extent (82% excreted in 24 h) than did monkeys (60% excreted in 72 h). In the rat, only 3% of the injected (14C)ribavirin was detected in expired CO2. Therefore, for both species, urine was the major route for the elimination of labeled ribavirin and its metabolites from the body. In monkeys, the amount of parent drug in blood cells increased through 48 h and remained stable for 72 h, whereas in rats, ribavirin decreased at a rate similar to the plasma disappearance curve. Concentrations of ribavirin at 8 h were consistently higher in monkeys than in rats for all tissues except the brain. Thus, these differences in blood cellular components and organ content and in urine excretion suggested that there was greater tissue retention of ribavirin in monkeys than in rats.

  12. [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. PMID:26427296

  13. The Application of Physiologically Based Pharmacokinetic Modeling to Determine Route-Specific Contributions to Tissue Dosimetry of Trihalomethanes in Drinking Water

    EPA Science Inventory

    This project summary describes an improved approach for estimating route-specific exposures and tissue doses for trihalomethane (THM) compounds found in drinking water.

  1. Tissue distribution of concentrative and equilibrative nucleoside transporters in male and female rats and mice.

    PubMed

    Lu, Hong; Chen, Chuan; Klaassen, Curtis

    2004-12-01

    Concentrative nucleoside transporters (Cnts) and equilibrative nucleoside transporters (Ents) have essential physiological functions and are important in disposition of anticancer and antiviral nucleoside analogs. Information on tissue distribution of Cnts and Ents in rodents is sparse. Thus, the present study aimed to determine the distribution of Cnt1-3 and Ent1-3 transcripts in 19 tissues of Sprague-Dawley rats and C57BL/6 mice of both genders. These six transcripts were quantified using the branched DNA signal amplification assay. Cnt1 transcripts were highest in small intestine, followed by kidney and testes, with similar expression in both species. Cnt2 mRNA was expressed highest in the small intestine of both rats and mice, intermediate in liver of rats but not in mice, and lower in thymus and spleen of both species. Cnt3 mRNA has marked species differences, with the highest expression in lung of rats but uterus of mice. Ent1 mRNA was most highly expressed in testes and lung of both species. Ent1 mRNA was highly expressed in liver and pituitary of mice, but not in rats. Ent2 mRNA was highly expressed in testes and brain of both species. Ent3 mRNA was highest in kidney, followed by testes, in both species. Significant gender differences were observed in kidney (mouse) and heart (rat). These studies demonstrate that in general, tissue distribution of Cnt and Ent is similar in rats and mice. However, a few important species and gender differences do exist, which could be responsible for related differences in efficacy and toxicity of substrates for these transporters. PMID:15371301

  2. Automated anatomical interpretation of ion distributions in tissue: linking imaging mass spectrometry to curated atlases.

    PubMed

    Verbeeck, Nico; Yang, Junhai; De Moor, Bart; Caprioli, Richard M; Waelkens, Etienne; Van de Plas, Raf

    2014-09-16

    Imaging mass spectrometry (IMS) has become a prime tool for studying the distribution of biomolecules in tissue. Although IMS data sets can become very large, computational methods have made it practically feasible to search these experiments for relevant findings. However, these methods lack access to an important source of information that many human interpretations rely upon: anatomical insight. In this work, we address this need by (1) integrating a curated anatomical data source with an empirically acquired IMS data source, establishing an algorithm-accessible link between them and (2) demonstrating the potential of such an IMS-anatomical atlas link by applying it toward automated anatomical interpretation of ion distributions in tissue. The concept is demonstrated in mouse brain tissue, using the Allen Mouse Brain Atlas as the curated anatomical data source that is linked to MALDI-based IMS experiments. We first develop a method to spatially map the anatomical atlas to the IMS data sets using nonrigid registration techniques. Once a mapping is established, a second computational method, called correlation-based querying, gives an elementary demonstration of the link by delivering basic insight into relationships between ion images and anatomical structures. Finally, a third algorithm moves further beyond both registration and correlation by providing automated anatomical interpretation of ion images. This task is approached as an optimization problem that deconstructs ion distributions as combinations of known anatomical structures. We demonstrate that establishing a link between an IMS experiment and an anatomical atlas enables automated anatomical annotation, which can serve as an important accelerator both for human and machine-guided exploration of IMS experiments. PMID:25153352

  3. Tissue structure-specific distribution of glycosaminoglycans in the human penis.

    PubMed

    Goulas, A; Papakonstantinou, E; Karakiulakis, G; Mirtsou-Fidani, V; Kalinderis, A; Hatzichristou, D G

    2000-09-01

    The aim of this work was to isolate and characterise the glycosaminoglycans present in the different tissue structures of the human penis in view of their potentially significant role in the physiology of erection. Penile tissue samples were obtained from patients who underwent penectomy and were subsequently dissected into individual tissue structures. Total glycosaminoglycans were isolated and purified from tunica albuginea, corpora cavernosa and corpus spongiosum, following tissue mincing, ultrasonication, lipid extraction, extensive digestion with pronase and DNase, treatment with alkali-borohydride and ethanol precipitation. Isolated glycosaminoglycans were separated by cellulose acetate electrophoresis and fractionated by anion exchange chromatography on DEAE Sephacel columns. Different glycosaminoglycan fractions were identified using glycosaminoglycan-degrading enzymes of known specificity. Gradient polyacrylamide gel electrophoresis was used to determine the average molecular mass of the glycosaminoglycans. The corpus cavernosum and the corpus spongiosum extracts contained almost twice the amount of glycosaminoglycan-associated uronic acids as compared to the tunical extracts (1.47+/-0.09, and 1.49+/-0.15 as opposed to 0.75+/-0.15 microg/mg dry defatted tissue, respectively; S.E.M., n=5). With the exception of hyaluronic acid, the relative amount of individual glycosaminoglycan types varied significantly among extracts of different origin. Heparan sulphate was more abundant in cavernosal, dermatan sulphate in tunical, and chondroitin-6-sulphate in corpus spongiosum extracts. No structure-specific differences were detected with respect to the molecular mass distribution of each glycosaminoglycan type. Our study shows that the different structures of the human penis produce distinct profiles of glycosaminoglycans, which are well suited to the individual functional characteristics of these structures. PMID:11084377

  4. Sex differences in adipose tissue: It is not only a question of quantity and distribution.

    PubMed

    Fuente-Martín, Esther; Argente-Arizón, Pilar; Ros, Purificación; Argente, Jesús; Chowen, Julie A

    2013-07-01

    Obesity and its associated secondary complications are active areas of investigation in search of effective treatments. As a result of this intensified research numerous differences between males and females at all levels of metabolic control have come to the forefront. These differences include not only the amount and distribution of adipose tissue, but also differences in its metabolic capacity and functions between the sexes. Here, we review some of the recent advances in our understanding of these dimorphisms and emphasize the fact that these differences between males and females must be taken into consideration in hopes of obtaining successful treatments for both sexes. PMID:23991358

  5. Alternative strategies to manipulate fibrocyte involvement in the fibrotic tissue response: pharmacokinetic inhibition and the feasibility of directed-adipogenic differentiation

    PubMed Central

    Baker, David W; Tsai, Yi-Ting; Weng, Hong; Tang, Liping

    2014-01-01

    Fibrocytes have previously been identified as important mediators in several inflammatory and fibrotic diseases. However, there is no effective treatment thus far to reduce fibrotic tissue responses without affecting wound healing reactions. Here we investigate two strategies to alleviate fibrocyte interactions at the biomaterial interface reducing collagen production and scar tissue formation. First, in an indirect approach, TGF-β inhibitor-SB431542 and IL-1β/TNF-α inhibitor SB203580 were locally released from scaffold implants to block their respective signaling pathways. We show that inhibition of IL-1β/TNF-α has no influence on overall fibrotic tissue reactions to the implants. However, the reduction of localized TGF-β significantly decreases the fibrocyte accumulation and myofibroblast activation while reducing the fibrotic tissue formation. Since fibrocytes can be differentiated into non-fibrotic cell types, such as adipocytes, we further sought a more direct approach to reduce fibrocyte responses by directing fibrocyte differentiation into adipocytes. Interestingly, by initiating fibrocyte-to-adipocyte differentiation through sustained differentiation cocktail release, we find that adipogentic differentiation forces incoming fibrocytes away from the traditional myofibroblast lineage leading to a substantial reduction in the collagen formation and fibrotic response. Our results support a novel and effective strategy to improve implant safety by reducing implant-associated fibrotic tissue reactions via directing non-fibrotic differentiation of fibrocytes. PMID:24657674

  6. Alternative strategies to manipulate fibrocyte involvement in the fibrotic tissue response: pharmacokinetic inhibition and the feasibility of directed-adipogenic differentiation.

    PubMed

    Baker, David W; Tsai, Yi-Ting; Weng, Hong; Tang, Liping

    2014-07-01

    Fibrocytes have previously been identified as important mediators in several inflammatory and fibrotic diseases. However, there is no effective treatment thus far to reduce fibrotic tissue responses without affecting wound healing reactions. Here we investigate two strategies to alleviate fibrocyte interactions at the biomaterial interface, reducing collagen production and scar tissue formation. First, in an indirect approach, TGF-β inhibitor-SB431542 and IL-1β/TNF-α inhibitor SB203580 were locally released from scaffold implants to block their respective signaling pathways. We show that the inhibition of IL-1β/TNF-α has no influence on overall fibrotic tissue reactions to the implants. However, the reduction of localized TGF-β significantly decreases the fibrocyte accumulation and myofibroblast activation while reducing the fibrotic tissue formation. Since fibrocytes can be differentiated into non-fibrotic cell types, such as adipocytes, we further sought a more direct approach to reduce fibrocyte responses by directing fibrocyte differentiation into adipocytes. Interestingly, by initiating fibrocyte-to-adipocyte differentiation through sustained differentiation cocktail release, we find that adipogenic differentiation forces incoming fibrocytes away from the traditional myofibroblast lineage, leading to a substantial reduction in the collagen formation and fibrotic response. Our results support a novel and effective strategy to improve implant safety by reducing implant-associated fibrotic tissue reactions via directing non-fibrotic differentiation of fibrocytes. PMID:24657674

  7. Distribution and elimination of [14C] sarafloxacin hydrochloride from tissues of juvenile channel catfish (Ictalurus punctatus)

    USGS Publications Warehouse

    Gingerich, W.H.; Meinertz, J.R.; Dawson, V.K.; Gofus, J.E.; Delaney, L.J.; Bunnell, P.R.

    1995-01-01

    The distribution and loss of radioactivity from tissues were determined in 60 juvenile channel catfish (Ictalurus punctatus) following oral dosing with the candidate fish therapeutant Sarafin® ([14C] sarafloxacin hydrochloride) at 10 mg/kg for 5 consecutive days. Twelve groups of 5 fish each were sampled at selected times ranging from 3 to 240 h after the last dose was administered, The concentration and content of sarafloxacin-equivalent activity was determined in liver, gallbladder, kidney, skin, and skinless fillet by sample oxidation and liquid scintillation counting; content of sarafloxacin-equivalent activity was determined in stomach and anterior and posterior intestines, Skinless fillet tissues were also analyzed for sarafloxacin and for potential metabolites by gradient-elution high-performance liquid chromatography (HPLC) with in-line radiometric and fluorescence detection, Loss of radioactivity from the whole body conformed to a bimodal elimination pattern with a rapid initial phase (t1/2=11 h) and a slower secondary phase (t1/2=222 h). Tissue and contents of the gastrointestinal tract (i.e. stomach and anterior and posterior intestines) were a principal depot of activity during the first four sample times (3, 6, 12, and 24 h); the combined head, skeleton, and fins (i.e. residual carcass) were the principal depot of activity in samples taken after 24 h. Of those tissues sampled 3 h after the last dose, relative sarafloxacin concentration was greatest in the liver (4.06 μg equivalents/g) and least in the residual carcass (1.13 μg equivalents/g), Intermediate concentrations were found in the kidney (2.04 μg equivalents/g), skinless fillet (1.71 μg equivalents/ g), and the skin (1.51 μg equivalents/g). Concentrations of sarafloxacin-equivalent residues in edible skinless fillet were consistently among the lowest of all tissues examined. The highest mean concentration of parent-equivalent material in the fillet tissue was found 12 h after

  8. Modulation of the pharmacokinetics of zinc oxide nanoparticles and their fates in vivo

    NASA Astrophysics Data System (ADS)

    Paek, Hee-Jeong; Lee, Youn-Joung; Chung, Hea-Eun; Yoo, Nan-Hui; Lee, Jeong-A.; Kim, Mi-Kyung; Lee, Jong Kwon; Jeong, Jayoung; Choi, Soo-Jin

    2013-11-01

    In the present study, the effects of particle size (20 nm or 70 nm) and surface charge (negative or positive) on the pharmacokinetics, tissue distributions, and excretion of ZnO nanoparticles were examined following the administration of a single oral dose to rats. Pharmacokinetic profiles and biodistributions were not affected by particle size or gender. However, ZnO (-) particles were markedly more absorbed by the systemic circulation than ZnO (+) particles. Furthermore, the kinetic behaviors of ZnO nanoparticles differed from those of zinc ions, as evidenced by the low dissolution (13-14%) of ZnO nanoparticles under gastric conditions. The kidneys, liver, and lungs were found to be target organs. However, the major biological fate of ZnO nanoparticles in tissues was the ionic form, not the particulate form, and this was independent of exposure routes (oral and intravenous). Particle size was only found to affect excretion kinetics, and 20 nm particles were more rapidly eliminated. Most nanoparticles were excreted via the biliary and fecal routes, but a small amount of the nanoparticles was excreted via urine. The study shows that surface charge, rather than particle size or gender, is the critical modulator of the pharmacokinetic behavior of ZnO nanoparticles.In the present study, the effects of particle size (20 nm or 70 nm) and surface charge (negative or positive) on the pharmacokinetics, tissue distributions, and excretion of ZnO nanoparticles were examined following the administration of a single oral dose to rats. Pharmacokinetic profiles and biodistributions were not affected by particle size or gender. However, ZnO (-) particles were markedly more absorbed by the systemic circulation than ZnO (+) particles. Furthermore, the kinetic behaviors of ZnO nanoparticles differed from those of zinc ions, as evidenced by the low dissolution (13-14%) of ZnO nanoparticles under gastric conditions. The kidneys, liver, and lungs were found to be target organs. However

  9. Distribution of proteoglycans in the trabecular tissue of eyes with neovascular glaucoma.

    PubMed

    Kubota, T; Tawara, A; Khalil, A; Honda, M; Inomata, H

    1996-11-01

    We investigated histo-chemically the composition and distribution of proteoglycans in the trabecular tissue of eyes with neovascular glaucoma. Cupromeronic blue in combination with a series of enzyme digestions and nitrous acid treatment were used. The spaces between the trabecular beams were lined by a single layer of vascular endothelium and were filled with red blood cells. A basal lamina and microfibrils were detected just beneath the newly formed vascular endothelial cells. Chondroitin-sulfate- and dermatan-sulfate-type proteoglycans were present in association with collagen fibrils in the extracellular matrix. Heparan-sulfate-type proteoglycans were present in association with the basal lamina of both the vascular endothelial cells and the trabecular cells. It is unlikely that these abnormalities in the type or distribution of proteoglycans in the trabecular meshwork have a major role in the pathogenesis of glaucoma. PMID:9479524

  10. VISUALIZATION OF TISSUE DISTRIBUTION AND METABOLISM OF BENZO[A]PYRENE IN EARLY EMBRYONIC MEDAKA (ORYZIAS LATIPES)

    EPA Science Inventory

    Fish early life stages are highly sensitive to exposure to persistent bioaccumulative toxicants (PBTs). The factors that contribute to this are unknown, but may include the distribution of PBTs to sensitive tissues during critical stages of development. Multiphoton laser scannin...

  11. Chronic ingestion of Mn/sub 3/O/sub 4/ by young rats: tissue accumulation, distribution, and depletion

    SciTech Connect

    Rehnberg, G.L.; Hein, J.F.; Carter, S.D.; Linko, R.S.; Laskey, J.W.

    1981-02-01

    Mn accumulation, distribution, and disappearance were evaluated in selected tissues of preweanling rats dosed daily with particulate Mn/sub 3/O/sub 4/ for 12 or 27 d postpartum. Significant findings include a high rate of Mn absorption and localization in tissues, especially the cerebrum, hypothalamus, and pituitary. In these tissues, the return of Mn concentrations to control levels was much slower when Mn dosing was continued beyond 18-20 d postpartum.

  12. Label Distribution in Tissues of Wheat Seedlings Cultivated with Tritium-Labeled Leonardite Humic Acid

    PubMed Central

    Kulikova, Natalia A.; Abroskin, Dmitry P.; Badun, Gennady A.; Chernysheva, Maria G.; Korobkov, Viktor I.; Beer, Anton S.; Tsvetkova, Eugenia A.; Senik, Svetlana V.; Klein, Olga I.; Perminova, Irina V.

    2016-01-01

    Humic substances (HS) play important roles in the biotic-abiotic interactions of the root plant and soil contributing to plant adaptation to external environments. However, their mode of action on plants remains largely unknown. In this study the HS distribution in tissues of wheat seedlings was examined using tritium-labeled humic acid (HA) derived from leonardite (a variety of lignites) and microautoradiography (MAR). Preferential accumulation of labeled products from tritiated HA was found in the roots as compared to the shoots, and endodermis was shown to be the major control point for radial transport of label into vascular system of plant. Tritium was also found in the stele and xylem tissues indicating that labeled products from tritiated HA could be transported to shoot tissues via the transpiration stream. Treatment with HA lead to an increase in the content of polar lipids of photosynthetic membranes. The observed accumulation of labeled HA products in root endodermis and positive impact on lipid synthesis are consistent with prior reported observations on physiological effects of HS on plants such as enhanced growth and development of lateral roots and improvement/repairs of the photosynthetic status of plants under stress conditions. PMID:27350412

  13. Maternal transfer of dechloranes and their distribution among tissues in contaminated ducks.

    PubMed

    Wu, Ping-Fan; Yu, Lian-Lian; Li, Long; Zhang, Yun; Li, Xing-Hong

    2016-05-01

    The tissue concentrations of dechlorane plus and its analogues were determined in ducks collected from several e-waste recycling villages of Taizhou, China. Compared with the published literature, the relatively high concentrations of these compounds were detected in ducks, indicating serious DP contamination. Since both the duck meat and eggs were important components for diet, this result reminded us of keeping a watchful eye on human dietary exposure to DP and its analogues in this study area. The wet-weight concentrations of DP and its analogues were significantly related to tissue lipid content (p < 0.05), indicating that the lipid pools predominantly impacted the distribution of DPs in ducks. On the basis of lipid adjustment, the significantly lower levels in brain than those in liver and blood, displayed the occurrence of liver sequestration and blood-brain barrier to DP and its analogues in the duck (p < 0.05). The maternal transfer of DP and Mirex was not obviously limited, and the transferring extent of Dec 602 was over one. The stereo-selected accumulation of two DP isomers occurred among tissues with preference to syn-DP in blood, and to anti-DP in brain. The values of lipid-adjusted monodechlorinated products mainly originated from the exterior environment in ducks. PMID:26651433

  14. Mouse tissue distribution and persistence of the food-born fusariotoxins Enniatin B and Beauvericin.

    PubMed

    Rodríguez-Carrasco, Yelko; Heilos, Daniela; Richter, Lennart; Süssmuth, Roderich D; Heffeter, Petra; Sulyok, Michael; Kenner, Lukas; Berger, Walter; Dornetshuber-Fleiss, Rita

    2016-04-15

    The fusariotoxins Enniatin B (Enn B) and Beauvericin (Bea) have recently aroused interest as food contaminants and as potential anticancer drugs. However, limited data are available about their toxic profile. Aim of this study was to investigate their pharmacological behavior in vivo and their persistence in mice. Therefore, liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to analyze the distribution of Enn B and Bea in selected tissue samples and biological fluids originating from mice treated intraperitoneally with these cyclohexadepsipeptides. Overall, no toxicological signs during life time or pathological changes were observed. Moreover, both fusariotoxins were found in all tissues and serum but not in urine. Highest amounts were measured in liver and fat demonstrating the moleculeś tendency to bioaccumulate in lipophilic tissues. While for Bea no metabolites could be detected, for Enn B three phase I metabolites (dioxygenated-Enn B, mono- and di-demethylated-Enn B) were found in liver and colon, with dioxygenated-Enn B being most prominent. Consequently, contribution of hepatic as well as intestinal metabolism seems to be involved in the overall metabolism of Enn B. Thus, despite their structural similarity, the metabolism of Enn B and Bea shows distinct discrepancies which might affect long-term effects and tolerability in humans. PMID:26892719

  15. Label Distribution in Tissues of Wheat Seedlings Cultivated with Tritium-Labeled Leonardite Humic Acid.

    PubMed

    Kulikova, Natalia A; Abroskin, Dmitry P; Badun, Gennady A; Chernysheva, Maria G; Korobkov, Viktor I; Beer, Anton S; Tsvetkova, Eugenia A; Senik, Svetlana V; Klein, Olga I; Perminova, Irina V

    2016-01-01

    Humic substances (HS) play important roles in the biotic-abiotic interactions of the root plant and soil contributing to plant adaptation to external environments. However, their mode of action on plants remains largely unknown. In this study the HS distribution in tissues of wheat seedlings was examined using tritium-labeled humic acid (HA) derived from leonardite (a variety of lignites) and microautoradiography (MAR). Preferential accumulation of labeled products from tritiated HA was found in the roots as compared to the shoots, and endodermis was shown to be the major control point for radial transport of label into vascular system of plant. Tritium was also found in the stele and xylem tissues indicating that labeled products from tritiated HA could be transported to shoot tissues via the transpiration stream. Treatment with HA lead to an increase in the content of polar lipids of photosynthetic membranes. The observed accumulation of labeled HA products in root endodermis and positive impact on lipid synthesis are consistent with prior reported observations on physiological effects of HS on plants such as enhanced growth and development of lateral roots and improvement/repairs of the photosynthetic status of plants under stress conditions. PMID:27350412

  16. Label Distribution in Tissues of Wheat Seedlings Cultivated with Tritium-Labeled Leonardite Humic Acid

    NASA Astrophysics Data System (ADS)

    Kulikova, Natalia A.; Abroskin, Dmitry P.; Badun, Gennady A.; Chernysheva, Maria G.; Korobkov, Viktor I.; Beer, Anton S.; Tsvetkova, Eugenia A.; Senik, Svetlana V.; Klein, Olga I.; Perminova, Irina V.

    2016-06-01

    Humic substances (HS) play important roles in the biotic-abiotic interactions of the root plant and soil contributing to plant adaptation to external environments. However, their mode of action on plants remains largely unknown. In this study the HS distribution in tissues of wheat seedlings was examined using tritium-labeled humic acid (HA) derived from leonardite (a variety of lignites) and microautoradiography (MAR). Preferential accumulation of labeled products from tritiated HA was found in the roots as compared to the shoots, and endodermis was shown to be the major control point for radial transport of label into vascular system of plant. Tritium was also found in the stele and xylem tissues indicating that labeled products from tritiated HA could be transported to shoot tissues via the transpiration stream. Treatment with HA lead to an increase in the content of polar lipids of photosynthetic membranes. The observed accumulation of labeled HA products in root endodermis and positive impact on lipid synthesis are consistent with prior reported observations on physiological effects of HS on plants such as enhanced growth and development of lateral roots and improvement/repairs of the photosynthetic status of plants under stress conditions.

  17. Correlations of trace elements in breast human tissues: Evaluation of spatial distribution using μ-XRF

    NASA Astrophysics Data System (ADS)

    Silva, Marina Piacenti da; Silva, Deisy Mara da; Ribeiro-Silva, Alfredo; Poletti, Martin Eduardo

    2012-05-01

    The aim of this work is to investigate microscopic correlations between trace elements in breast human tissues. A synchrotron X-ray fluorescence microprobe system (μ-XRF) was used to obtain two-dimensional distribution of trace element Ca, Fe, Cu and Zn in normal (6 samples) and malignant (14 samples) breast tissues. The experiment was performed in X-ray Fluorescence beam line at Laboratório Nacional de Luz Síncrotron (LNLS), Campinas, Brazil. The white microbeam was generated with a fine conical capillary with a 20 μm output diameter. The samples were supported on a XYZ table. An optical microscope with motorized zoom was used for sample positioning and choice the area to be scanned. Automatic two-dimensional scans were programmed and performed with steps of 30 μm in each direction (x, y) on the selected area. The fluorescence signals were recorded using a Si(Li) detector, positioned at 90 degrees with respect to the incident beam, with a collection time of 10 s per point. The elemental maps obtained from each sample were overlap to observe correlation between trace elements. Qualitative results showed that the pairs of elements Ca-Zn and Fe-Cu could to be correlated in malignant breast tissues. Quantitative results, achieved by Spearman correlation tests, indicate that there is a spatial correlation between these pairs of elements (p < 0.001) suggesting the importance of these elements in metabolic processes associated with the development of the tumor.

  18. Correlations of trace elements in breast human tissues: Evaluation of spatial distribution using {mu}-XRF

    SciTech Connect

    Piacenti da Silva, Marina; Silva, Deisy Mara da; Ribeiro-Silva, Alfredo; Poletti, Martin Eduardo

    2012-05-17

    The aim of this work is to investigate microscopic correlations between trace elements in breast human tissues. A synchrotron X-ray fluorescence microprobe system ({mu}-XRF) was used to obtain two-dimensional distribution of trace element Ca, Fe, Cu and Zn in normal (6 samples) and malignant (14 samples) breast tissues. The experiment was performed in X-ray Fluorescence beam line at Laboratorio Nacional de Luz Sincrotron (LNLS), Campinas, Brazil. The white microbeam was generated with a fine conical capillary with a 20 {mu}m output diameter. The samples were supported on a XYZ table. An optical microscope with motorized zoom was used for sample positioning and choice the area to be scanned. Automatic two-dimensional scans were programmed and performed with steps of 30 {mu}m in each direction (x, y) on the selected area. The fluorescence signals were recorded using a Si(Li) detector, positioned at 90 degrees with respect to the incident beam, with a collection time of 10 s per point. The elemental maps obtained from each sample were overlap to observe correlation between trace elements. Qualitative results showed that the pairs of elements Ca-Zn and Fe-Cu could to be correlated in malignant breast tissues. Quantitative results, achieved by Spearman correlation tests, indicate that there is a spatial correlation between these pairs of elements (p < 0.001) suggesting the importance of these elements in metabolic processes associated with the development of the tumor.

  19. Tissue distribution of residual antimony in rats treated with multiple doses of meglumine antimoniate

    PubMed Central

    Coelho, Deise Riba; Miranda, Elaine Silva; Saint’Pierre, Tatiana Dillenburg; Paumgartten, Francisco José Roma

    2014-01-01

    Meglumine antimoniate (MA) and sodium stibogluconate are pentavalent antimony (SbV) drugs used since the mid-1940s. Notwithstanding the fact that they are first-choice drugs for the treatment of leishmaniases, there are gaps in our knowledge of their toxicological profile, mode of action and kinetics. Little is known about the distribution of antimony in tissues after SbV administration. In this study, we evaluated the Sb content of tissues from male rats 24 h and three weeks after a 21-day course of treatment with MA (300 mg SbV/kg body wt/d, subcutaneous). Sb concentrations in the blood and organs were determined by inductively coupled plasma-mass spectrometry. In rats, as with in humans, the Sb blood levels after MA dosing can be described by a two-compartment model with a fast (t1/2 = 0.6 h) and a slow (t1/2 >> 24 h) elimination phase. The spleen was the organ that accumulated the highest amount of Sb, while bone and thyroid ranked second in descending order of tissues according to Sb levels (spleen >> bone, thyroid, kidneys > liver, epididymis, lungs, adrenals > prostate > thymus, pancreas, heart, small intestines > skeletal muscle, testes, stomach > brain). The pathophysiological consequences of Sb accumulation in the thyroid and Sb speciation in the liver, thyroid, spleen and bone warrant further studies. PMID:25075781

  20. Uptake, tissue distribution, and metabolism of malachite green in the channel catfish (Ictalurus punctatus)

    USGS Publications Warehouse

    Plakas, S.M.; El Said, K. R.; Stehly, G.R.; Gingerich, W.H.; Allen, J.L.

    1996-01-01

    The disposition of malachite green was determined in channel catfish (Ictalurus punctatus) after intravascular dosing (0.8 mg . Kg-1) or waterborne exposure (0.8 mg . L-1 for 1 h). After intravascular dosing, mean plasma concentrations of the parent compound exhibited a triphasic decline with a terminal elimination half-life of 6.2 h. Malachite green was rapidly absorbed and concentrated in the tissues during waterborne exposure. The rate of accumulation was directly related to pH of the exposure water. After waterborne exposure, elimination of the parent compound from plasma also was triphasic with a terminal half-life of 4.7 h. In muscle, the half-life of the parent compound was approximately 67 h. Malachite green and its metabolites were widely distributed in all tissues. In fish exposed to C-14-labeled malachite green, total drug equivalent concentrations were highest in abdominal fat and lowest in plasma. Malachite green was rapidly and extensively metabolized to its reduced form, leucomalachite green, which was slowly eliminated from the tissues. Leucomalachite green is an appropriate target analyte for monitoring exposure of channel catfish to this drug.

  1. Molecular Characterization and Tissue Distribution of Estrogen Receptor Genes in Domestic Yak

    PubMed Central

    Fu, Mei; Xiong, Xian-Rong; Lan, Dao-liang; Li, Jian

    2014-01-01

    Estrogen and its receptors are essential hormones for normal reproductive function in males and females during developmental stage. To better understand the effect of estrogen receptor (ER) gene in yak (Bos grunniens), reverse transcription-polymerase chain reaction (PCR) was carried out to clone ERα and ERβ genes. Bioinformatics methods were used to analyze the evolutionary relationship between yaks and other species, and real-time PCR was performed to identify the mRNA expression of ERα and ERβ. Sequence analysis showed that the ER open reading frames (ORFs) encoded 596 and 527 amino acid proteins. The yak ERα and ERβ shared 45.3% to 99.5% and 53.9% to 99.1% protein sequence identities with other species homologs, respectively. Real-time PCR analysis revealed that ERα and ERβ were expressed in a variety of tissues, but the expression level of ERα was higher than that of ERβ in all tissues, except testis. The mRNA expression of ERα was highest in the mammary gland, followed by uterus, oviduct, and ovary, and lowest in the liver, kidney, lung, testis, spleen, and heart. The ERβ mRNA level was highest in the ovary; intermediary in the uterus and oviduct; and lowest in the heart, liver, spleen, lung, kidney, mammary gland, and testis. The identification and tissue distribution of ER genes in yaks provides a foundation for the further study on their biological functions. PMID:25358360

  2. Quantitative Polymerase Chain Reaction Analysis of the Mouse Cyp2j Subfamily: Tissue Distribution and Regulation.

    PubMed

    Graves, Joan P; Gruzdev, Artiom; Bradbury, J Alyce; DeGraff, Laura M; Li, Huiling; House, John S; Hoopes, Samantha L; Edin, Matthew L; Zeldin, Darryl C

    2015-08-01

    Members of the cytochrome P450 CYP2J subfamily are expressed in multiple tissues in mice and humans. These enzymes are active in the metabolism of fatty acids to generate bioactive compounds. Herein we report new methods and results for quantitative polymerase chain reaction (qPCR) analysis for the seven genes (Cyp2j5, Cyp2j6, Cyp2j8, Cyp2j9, Cyp2j11, Cyp2j12, and Cyp2j13) of the mouse Cyp2j subfamily. SYBR Green primer sets were developed and compared with commercially available TaqMan primer/probe assays for specificity toward mouse Cyp2j cDNA, and analysis of tissue distribution and regulation of Cyp2j genes. Each TaqMan primer/probe set and SYBR Green primer set were shown to be specific for their intended mouse Cyp2j cDNA. Tissue distribution of the mouse Cyp2j isoforms confirmed similar patterns of expression between the two qPCR methods. Cyp2j5 and Cyp2j13 were highly expressed in male kidneys, and Cyp2j11 was highly expressed in both male and female kidneys. Cyp2j6 was expressed in multiple tissues, with the highest expression in the small intestine and duodenum. Cyp2j8 was detected in various tissues, with highest expression found in the skin. Cyp2j9 was highly expressed in the brain, liver, and lung. Cyp2j12 was predominately expressed in the brain. We also determined the Cyp2j isoform expression in Cyp2j5 knockout mice to determine whether there was compensatory regulation of other Cyp2j isoforms, and we assessed Cyp2j isoform regulation during various inflammatory models, including influenza A, bacterial lipopolysaccharide, house dust mite allergen, and corn pollen. Both qPCR methods detected similar suppression of Cyp2j6 and Cyp2j9 during inflammation in the lung. PMID:25994032

  3. Tissue Distribution of Glutamate Synthase and Glutamine Synthetase in Rice Leaves 1

    PubMed Central

    Yamaya, Tomoyuki; Hayakawa, Toshihiko; Tanasawa, Keisuke; Kamachi, Kazunari; Mae, Tadahiko; Ojima, Kunihiko

    1992-01-01

    To further explore the function of NADH-dependent glutamate synthase (GOGAT), the tissue distribution of NADH-GOGAT protein and activity was investigated in rice (Oryza sativa L.) leaves. The distributions of ferredoxin (Fd)-dependent GOGAT, plastidic glutamine synthetase, and cytosolic glutamine synthetase proteins were also determined in the same tissues. High levels of NADH-GOGAT protein (33.1 μg protein/g fresh weight) and activity were detected in the 10th leaf blade before emergence. The unexpanded, nongreen portion of the 9th leaf blade contained more than 50% of the NADH-GOGAT protein and activity per gram fresh weight when compared with the 10th leaf. The expanding, green portion of the 9th leaf blade outside of the sheath contained a slightly lower abundance of NADH-GOGAT protein than the nongreen portion of the 9th blade on a fresh weight basis. The fully expanded leaf blades at positions lower than the 9th leaf had decreased NADH-GOGAT levels as a function of increasing age, and the oldest, 5th blade contained only 4% of the NADH-GOGAT protein compared with the youngest 10th leaf blade. Fd-GOGAT protein, on the other hand, was the major form of GOGAT in the green tissues, and the highest amount of Fd-GOGAT protein (111 μg protein/g fresh weight) was detected in the 7th leaf blade. In the nongreen 10th leaf blade, the content of Fd-GOGAT protein was approximately 7% of that found in the 7th leaf blade. In addition, the content of NADH-GOGAT protein in the 10th leaf blade was about 4 times higher than that of Fd-GOGAT protein. The content of plastidic glutamine synthetase polypeptide was also the highest in the 7th leaf blade (429 μg/g fresh weight) and lowest in nongreen blades and sheaths. On the other hand, the relative abundance of the cytosolic glutamine synthetase polypeptide was the highest in the oldest leaf blade, decreasing to 10 to 20% of that value in young, nongreen leaves. These results suggest that NADH-GOGAT is important for the

  4. 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

  5. Effect of tissue inhomogeneity on dose distribution of point sources of low-energy electrons.

    PubMed

    Kwok, C S; Bialobzyski, P J; Yu, S K; Prestwich, W V

    1990-01-01

    Perturbation in dose distributions of point sources of low-energy electrons at planar interfaces of cortical bone (CB) and red marrow (RM) was investigated experimentally and by Monte Carlo codes EGS and the TIGER series. Ultrathin LiF thermoluminescent dosimeters were used to measure the dose distributions of point sources of 204Tl and 147Pm in RM. When the point sources were at 12 mg/cm2 from a planar interface of CB and RM equivalent plastics, dose enhancement ratios in RM averaged over the region 0-12 mg/cm2 from the interface were measured to be 1.08 +/- 0.03 (SE) and 1.03 +/- 0.03 (SE) for 204Tl and 147Pm, respectively. The Monte Carlo codes predicted 1.05 +/- 0.02 and 1.01 +/- 0.02 for the two nuclides, respectively. However, EGS gave consistently 3% higher dose in the dose scoring region than the TIGER series when point sources of monoenergetic electrons up to 0.75 MeV energy were considered in the homogeneous RM situation or in the CB and RM heterogeneous situation. By means of the TIGER series, it was demonstrated that aluminum, which is normally assumed to be equivalent to CB in radiation dosimetry, leads to an overestimation of backscattering of low-energy electrons in soft tissue at a CB-soft-tissue interface by as much as a factor of 2. PMID:2233564

  6. Analysis of adipose tissue distribution using whole-body magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Wald, Diana; Schwarz, Tobias; Dinkel, Julien; Delorme, Stefan; Teucher, Birgit; Kaaks, Rudolf; Meinzer, Hans-Peter; Heimann, Tobias

    2011-03-01

    Obesity is an increasing problem in the western world and triggers diseases like cancer, type two diabetes, and cardiovascular diseases. In recent years, magnetic resonance imaging (MRI) has become a clinically viable method to measure the amount and distribution of adipose tissue (AT) in the body. However, analysis of MRI images by manual segmentation is a tedious and time-consuming process. In this paper, we propose a semi-automatic method to quantify the amount of different AT types from whole-body MRI data with less user interaction. Initially, body fat is extracted by automatic thresholding. A statistical shape model of the abdomen is then used to differentiate between subcutaneous and visceral AT. Finally, fat in the bone marrow is removed using morphological operators. The proposed method was evaluated on 15 whole-body MRI images using manual segmentation as ground truth for adipose tissue. The resulting overlap for total AT was 93.7% +/- 5.5 with a volumetric difference of 7.3% +/- 6.4. Furthermore, we tested the robustness of the segmentation results with regard to the initial, interactively defined position of the shape model. In conclusion, the developed method proved suitable for the analysis of AT distribution from whole-body MRI data. For large studies, a fully automatic version of the segmentation procedure is expected in the near future.

  7. Structure of the human laminin {gamma}2 chain gene (LAMC2): Alternative splicing with different tissue distribution of two transcripts

    SciTech Connect

    Airenne, T.; Haakana, H.; Kallunki, T.

    1996-02-15

    This article discusses the exon-intron structure and tissue distribution of the laminin {gamma}2 chain (LAMC2) gene, which is mutated in some cases of junctional epidermolysis bullosa. The article also discusses the transcription and splicing of this gene, which result in alternative uses of the last two exons of the gene. The different tissue distributions of the transcripts indicate different functions for the gene in vivo. 36 refs., 8 figs., 3 tabs.

  8. Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials.

    PubMed

    Lamp, K C; Freeman, C D; Klutman, N E; Lacy, M K

    1999-05-01

    Metronidazole, the prototype nitroimidazole antimicrobial, was originally introduced to treat Trichomonas vaginalis, but is now used for the treatment of anaerobic and protozoal infections. The nitroimidazoles are bactericidal through toxic metabolites which cause DNA strand breakage. Resistance, both clinical and microbiological, has been described only rarely. Metronidazole given orally is absorbed almost completely, with bioavailability > 90% for tablets; absorption is unaffected by infection. Rectal and intravaginal absorption are 67 to 82%, and 20 to 56%, of the dose, respectively. Metronidazole is distributed widely and has low protein binding (< 20%). The volume of distribution at steady state in adults is 0.51 to 1.1 L/kg. Metronidazole reaches 60 to 100% of plasma concentrations in most tissues studied, including the central nervous system, but does not reach high concentrations in placental tissue. Metronidazole is extensively metabolised by the liver to 5 metabolites. The hydroxy metabolite has biological activity of 30 to 65% and a longer elimination half-life than the parent compound. The majority of metronidazole and its metabolites are excreted in urine and faeces, with less than 12% excreted unchanged in urine. The pharmacokinetics of metronidazole are unaffected by acute or chronic renal failure, haemodialysis, continuous ambulatory peritoneal dialysis, age, pregnancy or enteric disease. Renal dysfunction reduces the elimination of metronidazole metabolites; however, no toxicity has been documented and dosage alterations are unnecessary. Liver disease leads to a decreased clearance of metronidazole and dosage reduction is recommended. Recent pharmacodynamic studies of metronidazole have demonstrated activity for 12 to 24 hours after administration of metronidazole 1 g. The post-antibiotic effect of metronidazole extends beyond 3 hours after the concentration falls below the minimum inhibitory concentration (MIC). The concentration

  9. Sequestration, tissue distribution and developmental transmission of cyanogenic glucosides in a specialist insect herbivore.

    PubMed

    Zagrobelny, Mika; Olsen, Carl Erik; Pentzold, Stefan; Fürstenberg-Hägg, Joel; Jørgensen, Kirsten; Bak, Søren; Møller, Birger Lindberg; Motawia, Mohammed Saddik

    2014-01-01

    Considering the staggering diversity of bioactive natural products present in plants, insects are only able to sequester a small number of phytochemicals from their food plants. The mechanisms of how only some phytochemicals are sequestered and how the sequestration process takes place remains largely unknown. In this study the model system of Zygaena filipendulae (Lepidoptera) and their food plant Lotus corniculatus is used to advance the knowledge of insect sequestration. Z. filipendulae larvae are dependent on sequestration of the cyanogenic glucosides linamarin and lotaustralin from their food plant, and have a much lower fitness if reared on plants without these compounds. This study investigates the fate of the cyanogenic glucosides during ingestion, sequestration in the larvae, and in the course of insect ontogeny. To this purpose, double-labeled linamarin and lotaustralin were chemically synthesized carrying two stable isotopes, a (2)H labeled aglucone and a (13)C labeled glucose moiety. In addition, a small amount of (14)C was incorporated into the glucose residue. The isotope-labeled compounds were applied onto cyanogenic L. corniculatus leaves that were subsequently presented to the Z. filipendulae larvae. Following ingestion by the larvae, the destiny of the isotope labeled cyanogenic glucosides was monitored in different tissues of larvae and adults at selected time points, using radio-TLC and LC-MS analyses. It was shown that sequestered compounds are taken up intact, contrary to earlier hypotheses where it was suggested that the compounds would have to be hydrolyzed before transport across the gut. The uptake from the larval gut was highly stereo selective as the β-glucosides were retained while the α-glucosides were excreted and recovered in the frass. Sequestered compounds were rapidly distributed into all analyzed tissues of the larval body, partly retained throughout metamorphosis and transferred into the adult insect where they were

  10. Microfocus study of metal distribution and speciation in tissue extracted from revised metal on metal hip implants

    NASA Astrophysics Data System (ADS)

    Hart, Alister J.; Sandison, Ann; Quinn, Paul; Sampson, Barry; Atkinson, Kirk D.; Skinner, John A.; Goode, Angela; Powell, Jonathan J.; Mosselmans, J. Frederick W.

    2009-11-01

    Unexplained tissue inflammation in metal-on-metal hip replacements is suspected to be caused by implant-derived nanoparticles. The aim of this study was to investigate the nature of the metal particles in tissue surrounding metal-on-metal (MOM) hips that has been extracted during revision. Mapping of tissue surrounding the failed MOM hips was performed using microfocus X-ray Fluorescence (XRF). This revealed mainly Cr which was localized to the cellular regions. There was co-localisation of Co, were present, to areas of high Cr abundance. XANES of the tissue and appropriate standards revealed that the most common species were Cr(III) and Co(II). EXAFS analysis of the tissue and various metal standards revealed that the most abundant implant-related species was Cr(III) phosphate. Different tissue preparation methods, including frozen sectioning, were examined but were found not to affect the distribution or speciation of the metals in the tissue.

  11. Distribution of trace elements in tissues of shrimp species Litopenaeus vannamei (Boone, 1931) from Bahia, Brazil.

    PubMed

    Silva, E; Viana, Z C V; Onofre, C R E; Korn, M G A; Santos, V L C S

    2016-02-01

    In this study, concentrations of trace elements in tissues of shrimp species (Litopenaeus vannamei) from farming and zone natural coastal located in the northeastern Brazil were investigated. The elements determination was performed by optical emission spectrometry with inductively coupled plasma (ICP OES). The following ranges of concentrations in the tissues were obtained in µg g-1 dry weight: Al: 13.4-886.5, Cd: 0.93-1.80; Cu: 24.8-152; Fe: 3.2-410.9; Mn: 0.36-24.4; Se: 0.094-9.81 and Zn: 20.3-109.4. The shrimp muscle can be a good iron source (about 88.9 mg-1g dry weight). The distribution of Se concentration in tissues showed much variation between locations, and the concentration levels found in shrimp muscles of wild samples were high, where its levels in 67% of muscle and 50% of others tissues samples exceeded the ANVISA limit, indicating evidence of selenium bioaccumulation. Significant correlation was observed between the following pairs of elements: Fe-Zn (r= -0.70), Mn-Cu (r= -0.74), Se-Cu (r= -0.68), Se-Mn (r= 0.82) in the muscles; Fe-Al (r= 0.99), Mn-Al (r= 0.62), Mn-Fe (r= 0.62), Se-Al (r = 0.88), Se-Fe (r= 0.87), Se-Mn (r= 0.58) in the exoskeleton and Cu-Zn (r = 0.68), Al-Cu (r= 0.88), Fe-Cu (r= 0.95) and Fe-Al (r= 0.97) in the viscera. PMID:26909636

  12. Distribution of particulate matter and tissue remodeling in the human lung.

    PubMed Central

    Pinkerton, K E; Green, F H; Saiki, C; Vallyathan, V; Plopper, C G; Gopal, V; Hung, D; Bahne, E B; Lin, S S; Ménache, M G; Schenker, M B

    2000-01-01

    We examined the relationship between intrapulmonary particle distribution of carbonaceous and mineral dusts and remodeling of the airways along anatomically distinct airway paths in the lungs of Hispanic males from the central valley of California. Lung autopsy specimens from the Fresno County Coroner's Office were prepared by intratracheal instillation of 2% glutaraldehyde at 30 cm H(2)O pressure. Two distinct airway paths into the apico-posterior and apico-anterior portions of the left upper lung lobe were followed. Tissue samples for histologic analysis were generally taken from the intrapulmonary second, fourth, sixth, and ninth airway generations. Parenchymal tissues beyond the 12th airway generation of each airway path were also analyzed. There was little evidence of visible particle accumulation in the larger conducting airways (generations 2-6), except in bronchial-associated lymphoid tissues and within peribronchial connective tissue. In contrast, terminal and respiratory bronchioles arising from each pathway revealed varying degrees of wall thickening and remodeling. Walls with marked thickening contained moderate to heavy amounts of carbonaceous and mineral dusts. Wall thickening was associated with increases in collagen and interstitial inflammatory cells, including dust-laden macrophages. These changes were significantly greater in first-generation respiratory bronchioles compared to second- and third-generation respiratory bronchioles. These findings suggest that accumulation of carbonaceous and mineral dust in the lungs is significantly affected by lung anatomy with the greatest retention in centers of lung acini. Furthermore, there is significant remodeling of this transitional zone in humans exposed to ambient particulate matter. PMID:11102298

  13. 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.

  14. Pharmacokinetics of Cefuroxime in Porcine Cortical and Cancellous Bone Determined by Microdialysis

    PubMed Central

    Hardlei, Tore Forsingdal; Bendtsen, Michael; Bue, Mats; Brock, Birgitte; Fuursted, Kurt; Søballe, Kjeld; Birke-Sørensen, Hanne

    2014-01-01

    Traditionally, the pharmacokinetics of antimicrobials in bone have been investigated using bone biopsy specimens, but this approach suffers from considerable methodological limitations. Consequently, new methods are needed. The objectives of this study were to assess the feasibility of microdialysis (MD) for measuring cefuroxime in bone and to obtain pharmacokinetic profiles for the same drug in porcine cortical and cancellous bone. The measurements were conducted in bone wax sealed and unsealed drill holes in cortical bone and in drill holes in cancellous bone and in subcutaneous tissue. As a reference, the free and total plasma concentrations were also measured. The animals received a bolus of 1,500 mg cefuroxime over 30 min. No significant differences were found between the key pharmacokinetic parameters for sealed and unsealed drill holes in cortical bone. The mean ± standard error of the mean area under the concentration-time curve (AUC) values from 0 to 5 h were 6,013 ± 1,339, 3,222 ± 1086, 2,232 ± 635, and 952 ± 290 min · μg/ml for free plasma, subcutaneous tissue, cancellous bone, and cortical bone, respectively (P < 0.01, analysis of variance). The AUC for cortical bone was also significantly different from that for cancellous bone (P = 0.04). This heterogeneous tissue distribution was also reflected in other key pharmacokinetic parameters. This study validates MD as a suitable method for measuring cefuroxime in bone. Cefuroxime penetration was impaired for all tissues, and bone may not be considered one distinct compartment. PMID:24663019

  15. Development and validation of a LC-MS assay for the quantification of ikh12 a novel anti-tumor candidate in rat plasma and tissues and its application in a pharmacokinetic study.

    PubMed

    Otaegui, Dorleta; Masdeu, Carme; Aldaba, Eneko; Vara, Yosu; Zubia, Aizpea; San Sebastian, Eider; Alcalá, Maria; Villafruela, Sergio; Cossío, Fernando P; Rodriguez-Gascón, Alicia

    2015-08-01

    IKH12 is a novel histone deacetylase 6 selective inhibitor. A rapid and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for the quantification of IKH12 in rat plasma and tissue with kendine 91 as internal standard (IS). The samples were prepared by liquid-liquid extraction with tert-butyl methyl ether. The chromatographic separation was accomplished by using a Zorbax Extend C18 4.6 × 150 mm, 5 µm column, with a mobile phase consisting of methanol and 0.1% formic acid (75:25 v/v). Multiple reaction monitoring, using electrospray ionization in positive ion mode, was employed to quantitatively detect IKH12 and IS. The monitored transitions were set at m/z 418 → 252 and 444 → 169 for IKH12 and kendine 91, respectively. The calibration curve was linear over the concentration range 2-1000 ng mL(-1) . The intra- and inter-assay precision and accuracy of the quality controls and the limit of quantification were satisfactory in all cases (according to European Medicines Agency guidelines). Stability studies showed that plasma samples were stable in the chromatography rack for 24 h and at -80°C for 2 months and also after three freeze-thaw cycles. This method was successfully applied to a pharmacokinetic study of IKH12 in rat. PMID:25616154

  16. Calculation of the positron distribution from 15O nuclei formed in nuclear reactions in human tissue during proton therapy.

    PubMed

    Tuckwell, W; Bezak, E

    2007-05-01

    To measure and verify the dose distribution within a patient during proton therapy, indirect methods must be used. One such method is to use positron emission tomography (PET), which takes advantage of the nuclear reactions that take place between protons and nuclei in the tissue. The dominant nuclear reaction in human muscle tissue involves oxygen nuclei and produces radioactive oxygen-15. Oxygen-15 decays through positron emission, and it is these positrons that go on to annihilate that produce the signal used in the PET technique. Finding the distribution of annihilation points, however, is not analogous to finding the proton dose distribution. The oxygen-15 and positrons travel finite distances within the tissue, blurring the detected PET distribution from the desired proton distribution. Through Monte Carlo modelling, an analysis of the differences between the positron, oxygen-15 and proton distributions has been made. The program SRIM 2003 was used to find the correlation between the three distributions within simulated muscle tissue. Results show that the distal edge of the proton Bragg peak correlates with the detectable positron distribution, which is a section of the dose distribution of interest due to the steep dose gradient and position of adjacent critical structures. PMID:17440247

  17. Pharmacokinetic study of six flavones in rat plasma and tissues after oral administration of 'JiangYaBiFeng' using SPE-HPLC-DAD.

    PubMed

    Zeng, Hua-jin; Yang, Ran; Guo, Cheng; Wang, Qing-wen; Qu, Ling-bo; Li, Jian-jun

    2011-12-01

    In this study, a high performance liquid chromatography (HPLC) coupled with diode array detection (DAD) for simultaneous determination of six flavones including baicalein, sophoricoside, rutin, baicalin, quercetin and genistein in rat plasma and tissues after oral administration of JiangYaBifeng (JYBF) tablets was developed. The investigated analytes in plasma and tissues were extracted and purified with liquid-liquid extraction and solid phase extraction (SPE). Chromatographic separation was accomplished on a DIONEX Acclaim C18 column (250mm×4.6mm, 5.0μm particle size) with a simple linear gradient elution. The calibration curves for all the flavones had good linearity in the measured range with R(2) higher than 0.9983. The relative errors (REs) of the intra- and inter-day accuracy at different flavones levels were all less than ±10%. The proposed method enables unambiguous identification and quantification of investigated flavones in vivo. This is the first report on determination of the major flavones in rat plasma and tissues after oral administration of JYBF tablets. The results provided a meaningful basis for evaluating the clinical application of this medicine. PMID:21831556

  18. Intravenous ampicillin pharmacokinetics in the third trimester of pregnancy.

    PubMed

    Kubacka, R T; Johnstone, H E; Tan, H S; Reeme, P D; Myre, S A

    1983-01-01

    The pharmacokinetics of a single dose of intravenous ampicillin were studied in nine patients during their third trimester of pregnancy. Each volunteer was given either 500 mg (5.7-8.8 mg/kg) or 1 g (15.4-21.4 mg/kg) of sodium ampicillin by rapid infusion. Postinfusion plasma concentration-time curves followed biexponential decay in all subjects. Calculated parameters included a mean plasma distribution volume of 177.1 +/- 97.5 ml/kg, tissue or peripheral distribution volume of 246.2 +/- 143.9 ml/kg, elimination half-life of 1.60 +/- 0.51 h, and total body clearance of 4.59 +/- 1.48 ml/min/kg. Dose-dependent disposition was not observed. Gestation-specific drug therapy research during pregnancy is discussed. PMID:6845399

  19. [Study of distribution of 169Yb, 69Ga and 111In in tumor tissues by macroautoradiography; comparison between viable and necrotic tumor tissues].

    PubMed

    Ando, A; Doishita, K; Sanada, S; Ando, I; Hiraki, T

    1977-01-01

    The localization of 169Yb, 67Ga and 111In in tumor tissues was determined macroautoradiographically. 169Yb-citrate and 111In-citrate were injected intravenously to the rats subcutaneously transplanted Yoshida sarcoma and were injected intraperitoneally to the mice subcutaneously transplanted Ehrlich tumor. These animals were sacrificed 3, 24 and 48 hours after injection. These tumor tissues were frozen in n-hexane (-70 degrees C) cooled with dry ice-acetone. After this, these frozen tumor tissues were cut into serial thin sections (10 micron) in the cryostat (-20 degrees C). One of the slice of these sections was then placed on X-ray film and this film was developed after exposure of several days. On the other hand, next slice of these sections were then stained using the hematoxylin and eosin. From the observations of these autoradiogram and H-E stained slice, the following results were obtained. Concentration of 169Yb, 67Ga and 111In was predominant in viable tumor tissue rather than in necrotic tumor tissue, regardless of time after the administration. 67Ga and 111In were distributed uniformly in viable tumor tissue, but deposition of 169Yb was observed more avidly in viabl tumor tissue neighboring to necrotic tumor. PMID:577017

  20. Evaluation of brachytherapy lung implant dose distributions from photon-emitting sources due to tissue heterogeneities

    SciTech Connect

    Yang Yun; Rivard, Mark J.

    2011-11-15

    Purpose: Photon-emitting brachytherapy sources are used for permanent implantation to treat lung cancer. However, the current brachytherapy dose calculation formalism assumes a homogeneous water medium without considering the influence of radiation scatter or tissue heterogeneities. The purpose of this study was to determine the dosimetric effects of tissue heterogeneities for permanent lung brachytherapy. Methods: The MCNP5 v1.40 radiation transport code was used for Monte Carlo (MC) simulations. Point sources with energies of 0.02, 0.03, 0.05, 0.1, 0.2, and 0.4 MeV were simulated to cover the range of pertinent brachytherapy energies and to glean dosimetric trends independent of specific radionuclide emissions. Source positions from postimplant CT scans of five patient implants were used for source coordinates, with dose normalized to 200 Gy at the center of each implant. With the presence of fibrosis (around the implant), cortical bone, lung, and healthy tissues, dose distributions and {sub PTV}DVH were calculated using the MCNP *FMESH4 tally and the NIST mass-energy absorption coefficients. This process was repeated upon replacing all tissues with water. For all photon energies, 10{sup 9} histories were simulated to achieve statistical errors (k = 1) typically of 1%. Results: The mean PTV doses calculated using tissue heterogeneities for all five patients changed (compared to dose to water) by only a few percent over the examined photon energy range, as did PTV dose at the implant center. The {sub PTV}V{sub 100} values were 81.2%, 90.0% (as normalized), 94.3%, 93.9%, 92.7%, and 92.2% for 0.02, 0.03, 0.05, 0.1, 0.2, and 0.4 MeV source photons, respectively. Relative to water, the maximum bone doses were higher by factors of 3.7, 5.1, 5.2, 2.4, 1.2, and 1.0 The maximum lung doses were about 0.98, 0.94, 0.91, 0.94, 0.97, and 0.99. Relative to water, the maximum healthy tissue doses at the mediastinal position were higher by factors of 9.8, 2.2, 1.3, 1.1, 1.1, and

  1. 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.

  2. Tissue-specific distribution and whole-body burden estimates of persistent organic pollutants in the bottlenose dolphin (Tursiops truncatus).

    PubMed

    Yordy, Jennifer E; Pabst, D Ann; McLellan, William A; Wells, Randall S; Rowles, Teri K; Kucklick, John R

    2010-06-01

    Most exposure assessments for free-ranging cetaceans focus on contaminant concentrations measured in blubber, and few data are available for other tissues or the factors governing contaminant distribution among tissues. The goal of this study was to provide a detailed description of the distribution of persistent organic pollutants (POPs) within the common bottlenose dolphin (Tursiops truncatus) body and assess the role of lipid dynamics in mediating contaminant distribution. Thirteen tissues (brain, blubber, heart, liver, lung, kidney, mammary gland, melon, skeletal muscle, spleen, thyroid, thymus, and testis/uterus) were sampled during necropsy from bottlenose dolphins (n = 4) and analyzed for lipid and 85 POPs, including polychlorinated biphenyls, organochlorine pesticides, and polybrominated diphenyl ethers. Significant correlations between tissue POP concentrations and lipid suggest that distribution of POPs is generally related to tissue lipid content. However, blubber:tissue partition coefficients ranged widely from 0.753 to 6.25, suggesting that contaminant distribution is not entirely lipid-dependent. Tissue-specific and whole-body contaminant burdens confirmed that blubber, the primary site of metabolic lipid storage, is also the primary site for POP accumulation, contributing >90% to the whole-body burdens. Observations also suggest that as lipid mobilizes from blubber, contaminants may redistribute, leading to elevated tissue concentrations. These results suggest that individuals with reduced blubber lipid may be at increased risk for exposure-related health effects. However, this study also provides evidence that the melon, a metabolically inert lipid-rich structure, may serve as an alternate depot for POPs, thus preventing the bulk of blubber contaminants from being directly available to other tissues. This unique physiological adaptation should be taken into consideration when assessing contaminant-related health effects in wild cetacean populations

  3. Absorption and distribution of etoricoxib in plasma, CSF, and wound tissue in patients following hip surgery--a pilot study.

    PubMed

    Renner, Bertold; Zacher, Josef; Buvanendran, Asokumar; Walter, Gerrit; Strauss, Jochen; Brune, Kay

    2010-02-01

    The perioperative administration of selective cyclooxygenase-2 (COX-2)-inhibitors to avoid postoperative pain is an attractive option: they show favorable gastro-intestinal tolerability, lack inhibition of blood coagulation, and carry a low risk of asthmatic attacks. The purpose of this study was to determine the cerebrospinal fluid (CSF), plasma, and tissue pharmacokinetics of orally administered etoricoxib and to compare it with effect data, i.e., COX-2-inhibition in patients after hip surgery. The study was performed in a blinded, randomized, parallel group design. A total of 12 adult patients were included who received 120 mg etoricoxib (n = 8) or placebo (n = 4) on day 1 post-surgery. Samples from plasma, CSF, and tissue exudates were collected over a period of 24 h post-dosing and analyzed for etoricoxib and prostaglandin E(2) (PGE(2)) using liquid chromatography-tandem mass spectrometry and immuno-assay techniques. CSF area under the curve (AUC) [AUCs((O-24h))] for etoricoxib amounted to about 5% of the total AUC in plasma (range: 2-7%). Individual CSF lag times with respect to (50%) peak plasma concentration were tissue was significantly blocked by the COX-2 inhibitor starting with the appearance of etoricoxib in tissue and lasting for the whole observation period of 24 h (P < 0.01). In conclusion, etoricoxib reaches the CSF and site of surgery at effective concentrations and reduces PGE(2) production at the presumed site of action. PMID:20052461

  4. Preclinical Pharmacokinetic Analysis of NOV-002, a Glutathione Disulfide Mimetic

    PubMed Central

    Uys, Joachim D.; Manevich, Yefim; DeVane, Lindsay C.; He, Lin; Garret, Tracy E.; Pazoles, Christopher J.; Tew, Kenneth D.; Townsend, Danyelle M.

    2010-01-01

    Summary NOV-002 is a glutathione disulfide (GSSG) mimetic that is in Phase III clinical trials for the treatment of advanced non-small cell lung cancer and other oncology indications. GSSG is reduced by glutathione reductase (GR) to form glutathione (GSH), thereby maintaining redox homeostasis. The purpose of the study was to report the pharmacokinetic properties of NOV-002 and evaluate the effect that NOV-002 elicits in redox homeostasis. The pharmacokinetic analysis and tissue distribution of NOV-002 and GSH was evaluated in mice following a dose of 250 mg/kg, i.p. The redox potential and total protein thiol status was calculated. Here we show that NOV-002 is a substrate for GR and that GSH is a primary metabolite. Nonlinear pharmacokinetic modeling predicted that the estimated absorption and elimination rate constants correspond to a half-life of ~13 mins with an AUC of 1.18 μg.h/ml, a Cmax of 2.16 μg/ml and a volume of distribution of 42.61 L/kg. In addition, measurement of the redox potential and total protein thiol status indicated the generation of a transient oxidative signal in the plasma compartment after administration of NOV-002. These results indicate that NOV-002 exerts kinetic and dynamic effects in mice consistent with the GSSG component as the active pharmacological constituent of the drug. A longer-lasting decrease in total plasma free thiol content was also seen, suggesting that the oxidative effect of the GSSG from NOV-002 was impacting redox homeostasis. PMID:20359856

  5. Preclinical pharmacokinetic analysis of NOV-002, a glutathione disulfide mimetic.

    PubMed

    Uys, J D; Manevich, Y; Devane, L C; He, L; Garret, T E; Pazoles, C J; Tew, K D; Townsend, D M

    2010-09-01

    NOV-002 is a glutathione disulfide (GSSG) mimetic that is the subject of clinical investigation in oncology indications. GSSG is reduced by glutathione reductase (GR) to form glutathione (GSH), thereby maintaining redox homeostasis. The purpose of the study was to report the pharmacokinetic properties of NOV-002 and evaluate the effect that NOV-002 elicits in redox homeostasis. The pharmacokinetic analysis and tissue distribution of NOV-002 and GSH was evaluated in mice following a dose of 250 mg/kg, i.p. The redox potential and total protein thiol status was calculated. Here we show that NOV-002 is a substrate for GR and that GSH is a primary metabolite. Non-linear pharmacokinetic modeling predicted that the estimated absorption and elimination rate constants correspond to a half-life of approximately 13 min with an AUC of 1.18 μgh/mL, a C(max) of 2.16 μg/ml and a volume of distribution of 42.61 L/kg. In addition, measurement of the redox potential and total protein thiol status indicated the generation of a transient oxidative signal in the plasma compartment after administration of NOV-002. These results indicate that NOV-002 exerts kinetic and dynamic effects in mice consistent with the GSSG component as the active pharmacological constituent of the drug. A longer-lasting decrease in total plasma free thiol content was also seen, suggesting that the oxidative effect of the GSSG from NOV-002 was impacting redox homeostasis. PMID:20359856

  6. Pharmacokinetics and disposition of WR-1065 in the rhesus monkey

    SciTech Connect

    Mangold, D.J.; Huelle, B.K.; Miller, M.A.; Geary, R.S.; Sanchez-Barona, D.O.; Swynnerton, N.F.; Fleckenstein, L.; Ludden, T.M. )

    1990-05-01

    The pharmacokinetics of WR-1065 (S-2-(3-aminopropylamino)ethanethiol) were investigated following iv, intraduodenal, and intraportal administrations in the rhesus monkey. Pharmacokinetic parameters were estimated by compartmental modeling of plasma concentration data from 10-min and 120-min iv infusions. Higher apparent volumes of distribution (Vc and Vss) and higher mean residence time (MRT) were observed at the slower infusion rate but a constant total dose. The values reflect a change in the distribution of WR-1065, possibly due to to saturation of binding in plasma and tissue. However, clearance remained unchanged. For a monkey administered approximately twice the 60 mg/kg dose infused over 120 min, data analysis indicates a disproportional increase in AUC and a substantial decrease in clearance. Low and erratic plasma concentrations of free drug (analytically determined without reductive cleavage) were observed following intraduodenal administration of WR-1065, demonstrating the drug's poor oral bioavailability. Results of intraduodenal administrations of radiolabeled drug indicated than an appreciable amount of the radiolabel in the dose reached the systemic circulation. However, after either intraduodenal or iv administration, only 31% of the AUC (radiolabel) could be accounted for as total (free and disulfide-bound) WR-1065 by specific analysis in separate experiments. Low levels of total cysteamine strongly suggest it to be a minor contributor to the disposition of the drug. Free WR-1065 AUC values following intraportal administration were similar to values obtained after iv administration.

  7. Pharmacokinetics and disposition of WR-1065 in the rhesus monkey.

    PubMed

    Mangold, D J; Huelle, B K; Miller, M A; Geary, R S; Sanchez-Barona, D O; Swynnerton, N F; Fleckenstein, L; Ludden, T M

    1990-01-01

    The pharmacokinetics of WR-1065 [S-2-(3-aminopropylamino)ethanethiol] were investigated following iv, intraduodenal, and intraportal administrations in the rhesus monkey. Pharmacokinetic parameters were estimated by compartmental modeling of plasma concentration data from 10-min and 120-min iv infusions. Higher apparent volumes of distribution (Vc and Vss) and higher mean residence time (MRT) were observed at the slower infusion rate but a constant total dose. The values reflect a change in the distribution of WR-1065, possibly due to to saturation of binding in plasma and tissue. However, clearance remained unchanged. For a monkey administered approximately twice the 60 mg/kg dose infused over 120 min, data analysis indicates a disproportional increase in AUC and a substantial decrease in clearance. Low and erratic plasma concentrations of free drug (analytically determined without reductive cleavage) were observed following intraduodenal administration of WR-1065, demonstrating the drug's poor oral bioavailability. Results of intraduodenal administrations of radiolabeled drug indicated than an appreciable amount of the radiolabel in the dose reached the systemic circulation. However, after either intraduodenal or iv administration, only 31% of the AUC (radiolabel) could be accounted for as total (free and disulfide-bound) WR-1065 by specific analysis in separate experiments. Low levels of total cysteamine strongly suggest it to be a minor contributor to the disposition of the drug. Free WR-1065 AUC values following intraportal administration were similar to values obtained after iv administration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1974187

  8. Distribution of G/sub o. cap alpha. / mRNA and protein in bovine tissues

    SciTech Connect

    Price, S.R.; Tsai, S.C.; Adamik, R.; Angus, C.W.; Van Meurs, K.P.; Czarnecki, S.; Bruckwick, E.C.; Moss, J.; Vaughan, M.

    1987-05-01

    G/sub o..cap alpha../ is a 39 kDa guanyl nucleotide-binding protein similar in structure and function to G/sub s..cap alpha../ and G/sub i..cap alpha../ in the adenylate cyclase complex and transducin (G/sub t..cap alpha../) in the retinal photon receptor system. A bovine retinal cDNA clone, lambdaG09, that encodes the complete amino acid sequence of G/sub o..cap alpha../ has been isolated. Nick-translated lambdaG09 cDNA and a 5' end-labeled oligonucleotide probe complementary to a 24 base sequence unique to G/sub o..cap alpha../ were used as probes for Northern analysis of poly(A)/sup +/ RNA from bovine tissues. A major 4.0 kb mRNA was detected in brain and retina and in lesser amounts in heart. Several smaller mRNAs also hybridized with both probes in these tissues and in liver and lung. G/sub o..cap alpha../ protein was identified using rabbit polyclonal antibodies directed against purified bovine G/sub o..cap alpha../ and pertussis toxin-catalyzed (/sup 32/P)ADP-ribosylation. Soluble and membrane proteins were incubated with toxin and (/sup 32/P)NAD and then separated by gel electrophoresis before transfer to nitrocellulose for immunoreaction and subsequent autoradiography. A radiolabeled and immunoreactive 39 kDa membrane protein was found principally in retina and brain, and to a lesser extent, in heart. Thus, in the tissues examined, distribution of the 4.0 kb mRNA parallels that of the immunoreactive G/sub o..cap alpha../ with relatively small amounts in heart and larger amounts in brain and retina.

  9. Drosophila melanogaster lipins are tissue-regulated and developmentally regulated and present specific subcellular distributions.

    PubMed

    Valente, Valeria; Maia, Rafaela Martins; Vianna, Murilo Carlos Bizam; Paçó-Larson, Maria Luisa

    2010-11-01

    Lipins constitute a novel family of Mg(2+)-dependent phosphatidate phosphatases that catalyze the dephosphorylation of phosphatidic acid to yield diacylglycerol, an important intermediate in lipid metabolism and cell signaling. Whereas a single lipin is detected in less complex organisms, in mammals there are distinct lipin isoforms and paralogs that are differentially expressed among tissues. Compatible with organism tissue complexity, we show that the single Drosophila Lpin1 ortholog (CG8709, here named DmLpin) expresses at least three isoforms (DmLpinA, DmLpinK and DmLpinJ) in a temporal and spatially regulated manner. The highest levels of lipin in the fat body, where DmLpinA and DmLpinK are expressed, correlate with the highest levels of triacylglycerol (TAG) measured in this tissue. DmLpinK is the most abundant isoform in the central nervous system, where TAG levels are significantly lower than in the fat body. In the testis, where TAG levels are even lower, DmLpinJ is the predominant isoform. Together, these data suggest that DmLpinA might be the isoform that is mainly involved in TAG production, and that DmLpinK and DmLpinJ could perform other cellular functions. In addition, we demonstrate by immunofluorescence that lipins are most strongly labeled in the perinuclear region of the fat body and ventral ganglion cells. In visceral muscles of the larval midgut and adult testis, lipins present a sarcomeric distribution. In the ovary chamber, the lipin signal is concentrated in the internal rim of the ring canal. These specific subcellular localizations of the Drosophila lipins provide the basis for future investigations on putative novel cellular functions of this protein family. PMID:20977671

  10. Cloning, characterization, and tissue distribution of prolactin receptor in the sea bream (Sparus aurata).

    PubMed

    Santos, C R; Ingleton, P M; Cavaco, J E; Kelly, P A; Edery, M; Power, D M

    2001-01-01

    The prolactin receptor (PRLR) was cloned and its tissue distribution characterized in adults of the protandrous hermaphrodite marine teleost, the sea bream (Sparus aurata). An homologous cDNA probe for sea bream PRLR (sbPRLR) was obtained by RT-PCR using gill mRNA. This probe was used to screen intestine and kidney cDNA libraries from which two overlapping clones (1100 and 2425 bp, respectively) were obtained. These clones had 100% sequence identity in the overlapping region (893 bp) and were used to deduce the complete amino acid sequence of sbPRLR. The receptor spans 2640 bp and encodes a protein of 537 amino acids. Features characteristic of PRLR, two pairs of cysteines, WS box, hydrophobic transmembrane domain, box 1, and box 2, were identified and showed a high degree of sequence identity to PRLRs from other vertebrate species. SbPRLR is 29 and 32% identical to tilapia (Oreochromis niloticus) and goldfish (Carassius auratus) PRLRs, respectively. In the sea bream two PRLR transcripts of 2.8 and 3.2 kb were detected in the intestine, kidney, and gills and a single transcript of 2.8 kb was detected in skin and pituitary by Northern blot. Spermiating gonads (more than 95% male tissue; gonado-somatic index of 0.6) contained, in addition to the 2.8-kb transcript, three more transcripts of 1.9, 1.3, and 1.1 kb. RT-PCR, which is a far more sensitive method than Northern blot, detected PRLR mRNA in gills, intestine, brain, pituitary, kidney, liver, gonads, spleen, head-kidney, heart, muscle, and bone. Immunohistochemistry using specific polyclonal antibodies raised against an oligopeptide from the extracellular domain of sbPRLR detected PRLR in several epithelial tissues of juvenile sea bream, including the anterior gut, renal tubule, choroid membrane of the third ventricle, saccus vasculosus, branchial chloride cells, and branchial cartilage. PMID:11161768

  11. Pathogenesis, tissue distribution and host response to Rhabdochlamydia porcellionis infection in rough woodlouse Porcellio scaber.

    PubMed

    Kostanjšek, Rok; Pirc Marolt, Tinkara

    2015-02-01

    Rhabdochlamydia porcellionis is a known intracellular pathogen in digestive glands of the terrestrial isopod crustacean Porcellio scaber. To describe the pathogenesis, tissue distribution and host response to R. porcellionis, we conducted microscopic observations and localization of infection in tissues by Fluorescent In Situ Hybridization (FISH). Digestive glands were confirmed as the primary site of infection. From there, R. porcellionis disseminates either through the apical membrane of infected cells into the lumen of digestive glands and further throughout the digestive tract or into the surrounding hemocoel by rupture of the basal membrane and lamina of infected digestive gland cells. Once in the hemocoel, R. porcellionis infects hindgut cells, hemocytes and hemopoetic tissues while the ventral nerve cord and gonads seem to be devoid of infection despite the presence of rhabdochlamydia on the surface of these organs. The host response to R. porcellionis includes aggregation of hemocytes around the infected cells and formation of multilayered melanized nodules exhibiting endogenous fluorescence. The structure of nodules is asymmetric when hemocytes are deposited on the basal side of infected gut and digestive glands cells, or symmetric, when nodules entrapping clusters of rhabdochlamydiae are deposited on other organs in the hemocoel. The study also revealed a high prevalence of infection in P. scaber populations (up to 27%) and confirmed its detrimental effect on the host. Although agility, behavior and molting cycle of infected animals appear unaffected, in the later stages R. porcellionis infection manifests as severe damage to the digestive system and decreased feeding, which eventually lead to the death of the host organism. PMID:25593037

  12. Tetrasulfated disaccharide unit in heparan sulfate: enzymatic formation and tissue distribution.

    PubMed

    Mochizuki, Hideo; Yoshida, Keiichi; Shibata, Yuniko; Kimata, Koji

    2008-11-01

    We previously reported that the heparan sulfate 3-O-sulfotransferase (3OST)-5 produces a novel component of heparan sulfate, i.e. the tetrasulfated disaccharide (Di-tetraS) unit ( Mochizuki, H., Yoshida, K., Gotoh, M., Sugioka, S., Kikuchi, N., Kwon, Y.-D., Tawada, A., Maeyama, K., Inaba, N., Hiruma, T., Kimata, K., and Narimatsu, H. (2003) J. Biol. Chem. 278, 26780-26787 ). In the present study, we investigated the potential of other 3OST isoforms to produce Di-tetraS with heparan sulfate and heparin as acceptor substrates. 3OST-2, 3OST-3, and 3OST-4 produce Di-tetraS units as a major product from both substrates. 3OST-5 showed the same specificity for heparin, but the production from heparan sulfate was very low. Di-tetraS production by 3OST-1 was negligible. We then investigated the presence of Di-tetraS units in heparan sulfates from various rat tissues. Di-tetraS was detected in all of the tissues analyzed. Liver and spleen contain relatively high levels of Di-tetraS, 1.6 and 0.95%, respectively. However, the content of this unit in heart, large intestine, ileum, and lung is low, less than 0.2%. We further determined the expression levels of 3OST transcripts by quantitative real time PCR. The 3OST-3 transcripts are highly expressed in spleen and liver. The 3OST-2 and -4 are specifically expressed in brain. These results indicate that the Di-tetraS unit is widely distributed throughout the body as a rare and unique component of heparan sulfate and is synthesized by tissue-specific 3OST isoforms specific for Di-tetraS production. PMID:18757372

  13. Arsenic-induced biochemical and genotoxic effects and distribution in tissues of Sprague-Dawley rats.

    PubMed

    Patlolla, Anita K; Todorov, Todor I; Tchounwou, Paul B; van der Voet, Gijsbert; Centeno, Jose A

    2012-11-01

    Arsenic (As) is a well documented human carcinogen. However, its mechanisms of toxic action and carcinogenic potential in animals have not been conclusive. In this research, we investigated the biochemical and genotoxic effects of As and studied its distribution in selected tissues of Sprague-Dawley rats. Four groups of six male rats, each weighing approximately 60 ± 2 g, were injected intraperitoneally, once a day for 5 days with doses of 5, 10, 15, 20 mg/kg bw of arsenic trioxide. A control group was also made of 6 animals injected with distilled water. Following anaesthetization, blood was collected and enzyme analysis was performed by spectrophotometry following standard protocols. At the end of experimentation, the animals were sacrificed, and the lung, liver, brain and kidney were collected 24 h after the fifth day treatment. Chromosome and micronuclei preparation was obtained from bone marrow cells. Arsenic exposure significantly increased (p<0.05) the activities of plasma alanine aminotransferase-glutamate pyruvate transaminase (ALT/GPT), and aspartate aminotransferase-glutamate oxaloacetate transaminase (AST/GOT), as well as the number of structural chromosomal aberrations (SCA) and frequency of micronuclei (MN) in the bone marrow cells. In contrast, the mitotic index in these cells was significantly reduced (p<0.05). These findings indicate that aminotransferases are candidate biomarkers for arsenic-induced hepatotoxicity. Our results also demonstrate that As has a strong genotoxic potential, as measured by the bone marrow SCA and MN tests in Sprague-Dawley rats. Total arsenic concentrations in tissues were measured by inductively coupled plasma mass spectrometry (ICP-MS). A dynamic reaction cell (DRC) with hydrogen gas was used to eliminate the ArCl interference at mass 75, in the measurement of total As. Total As doses in tissues tended to correlate with specific exposure levels. PMID:23175155

  14. Distribution of a macaque immunosuppressive type D retrovirus in neural, lymphoid, and salivary tissues.

    PubMed Central

    Lackner, A A; Rodriguez, M H; Bush, C E; Munn, R J; Kwang, H S; Moore, P F; Osborn, K G; Marx, P A; Gardner, M B; Lowenstine, L J

    1988-01-01

    Simian acquired immune deficiency syndrome (SAIDS) in rhesus macaques (Macaca mulatta) at the California Primate Research Center is caused by a type D retrovirus designated SAIDS retrovirus serotype 1 (SRV-1). This syndrome is characterized by profound immunosuppression and death associated with opportunistic infections. Neurologic signs and lesions have not been described as part of this syndrome. The distribution of SRV-1 in the salivary glands, lymph nodes, spleens, thymuses, and brains of eight virus-infected rhesus macaques was examined by immunohistochemistry. Electron microscopy, in situ RNA hybridization, and Southern blot hybridization were also performed on selected tissues to detect viral particles, RNA, and DNA, respectively. In seven of eight SRV-1-infected animals, the transmembrane envelope glycoprotein (gp20) of SRV-1 was present in three or more tissues, but never in the brain. In the remaining animal, no viral antigen was detected in any tissue. In this same group of animals, viral nucleic acid was detected in the lymph nodes of six of six animals by Southern blot hybridization, in the salivary glands of two of five animals by both Southern blot and in situ hybridizations, and, surprisingly, in the brains of three of three animals by Southern blot and of three of five animals by in situ hybridization, including the one animal in which viral gp20 was undetectable. None of these animals had neurologic signs or lesions. The detection of viral nucleic acid in the absence of viral antigen in the brain suggests latent SRV-1 infection of the central nervous system. Images PMID:3285033

  15. Bioaccumulation Efficiency, Tissue Distribution, and Environmental Occurrence of Hepatitis E Virus in Bivalve Shellfish from France

    PubMed Central

    Grodzki, Marco; Schaeffer, Julien; Piquet, Jean-Côme; Le Saux, Jean-Claude; Chevé, Julien; Ollivier, Joanna; Le Pendu, Jacques

    2014-01-01

    Hepatitis E virus (HEV), an enteric pathogen of both humans and animals, is excreted by infected individuals and is therefore present in wastewaters and coastal waters. As bivalve molluscan shellfish are known to concentrate viral particles during the process of filter feeding, they may accumulate this virus. The bioaccumulation efficiencies of oysters (Crassostrea gigas), flat oysters (Ostrea edulis), mussels (Mytilus edulis), and clams (Ruditapes philippinarum) were compared at different time points during the year. Tissue distribution analysis showed that most of the viruses were concentrated in the digestive tissues of the four species. Mussels and clams were found to be more sensitive to sporadic contamination events, as demonstrated by rapid bioaccumulation in less than 1 h compared to species of oysters. For oysters, concentrations increased during the 24-h bioaccumulation period. Additionally, to evaluate environmental occurrence of HEV in shellfish, an environmental investigation was undertaken at sites potentially impacted by pigs, wild boars, and human waste. Of the 286 samples collected, none were contaminated with hepatitis E virus, despite evidence that this virus is circulating in some French areas. It is possible that the number of hepatitis E viral particles discharged into the environment is too low to detect or that the virus may have a very short period of persistence in pig manure and human waste. PMID:24795382

  16. Heterogeneous receptor binding of classical quaternary muscarinic antagonists. I. Bovine tissue distribution.

    PubMed

    Roffel, A F; Ensing, K; in 't Hout, W G; de Zeeuw, R A; Zaagsma, J

    1991-01-01

    In competition experiments with the tertiary radioligand [3H]dexetimide, classical quaternary muscarinic antagonists like ipratropium bromide and N-methylscopolamine bromide distinguished two muscarinic binding sites in bovine brain (total brain minus cerebellum) membranes, in contrast to their tertiary analogues, atropine and scopolamine, which recognized only one binding site. This binding behavior was found to be almost identical in bovine striatal membranes, both in terms of binding affinities and proportions of high (Q1) and low (Q2) affinity binding sites. Both in total brain and in striatal membranes, the Q1/Q2 binding heterogeneity was independent of pirenzepine binding heterogeneity (M1/M2). In peripheral tissues, the binding properties of quaternary muscarinic antagonists varied. Whereas tertiary as well as quaternary compounds showed only high affinity binding towards muscarinic receptors in bovine atrial and left ventricular membranes, heterogeneous binding behavior was observed with quaternary but not with tertiary antagonists in bovine tracheal smooth muscle membranes. The tissue distribution found in the present study suggests that bovine tracheal smooth muscle contraction studies might shed light on the functional significance of the anomalous binding behavior of quaternary muscarinic antagonists. PMID:1824191

  17. Toxicokinetics and tissue distribution of titanium in ionic form after intravenous and oral administration.

    PubMed

    Golasik, Magdalena; Herman, Małgorzata; Olbert, Magdalena; Librowski, Tadeusz; Szklarzewicz, Janusz; Piekoszewski, Wojciech

    2016-04-15

    Titanium is widely used both in food and cosmetics, as well as in surgery and industry. Contrary to most studies, the present work focused on the determination of the toxicokinetic parameters of titanium in ionic form, as well as on its tissue biodistribution in rats. The animals were administered either a single intravenous dose of 6 mg Ti/kg b.w., or received the same dose orally every day for 30 days. The concentration of titanium in the serum and organs was measured by a graphite furnace atomic absorption spectrometry. Metal rapidly distributed from the circulation to the investigated organs after both routes of administration, and kidney was identified as the main target tissue, followed by liver and spleen. One month of oral exposure to Ti led to the increase of its concentration in liver, kidneys, spleen, and heart. In the intravenous study, both the highest area under concentration-time curves and the longest elimination half-life time were recorded in the kidney followed by serum, spleen and liver. The present study contributes to the knowledge of the toxicokinetics of titanium in ionic form, which may be especially useful when assessing the health risks of long-term exposure to titanium alloy implants in patients. PMID:26892718

  18. Tissue Distribution of Porcine FTO and Its Effect on Porcine Intramuscular Preadipocytes Proliferation and Differentiation

    PubMed Central

    Chen, Xiaoling; Zhou, Bo; Luo, Yanliu; Huang, Zhiqing; Jia, Gang; Liu, Guangmang; Zhao, Hua

    2016-01-01

    The fat mass and obesity associated (FTO) gene plays an important role in adipogenesis. However, its function during porcine intramuscular preadipocyte proliferation and differentiation remains poorly understood. In this study, we prepared the antiserum against porcine FTO (pFTO), which was used to determine its subcellular localization and tissue distribution. Our data indicated that pFTO was localized predominantly in the nucleus. Real-time quantitative PCR and western blot analysis showed that pFTO was highly expressed in the lung and subcutaneous adipose tissue. Overexpression of pFTO in porcine intramuscular preadipocytes significantly promoted cell proliferation and lipid deposition. Furthermore, overexpression of pFTO in differentiating porcine intramuscular preadipocytes also significantly increased the mRNA levels of adipocyte differentiation transcription factors peroxisome proliferators-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα), lipoprotein lipase (LPL) and fatty acid synthase (FAS). Our findings provide the first functional evidence to reveal a role of pFTO in porcine intramuscular preadipocyte proliferation and differentiation. PMID:26964098

  19. Distribution and load of elephant endotheliotropic herpesviruses in tissues from associated fatalities of Asian elephants.

    PubMed

    Seilern-Moy, Katharina; Darpel, Karin; Steinbach, Falko; Dastjerdi, Akbar

    2016-07-15

    Elephant Endotheliotropic Herpesviruses (EEHVs) are the cause of a highly fatal haemorrhagic disease in elephants primarily affecting young Asian elephants (Elephas maximus) in both captivity and in the wild. The viruses have emerged as a significant threat to Asian elephant conservation, critically affecting overall sustainability of their population. So far insight into the pathogenesis of EEHV infections has been restricted to examination of EEHV-infected tissues. However, little is known about distribution and burden of the viruses within the organs of fatal cases, crucial elements in the understanding of the virus pathogenesis. This study was therefore undertaken to assess the extent of organ and cell involvement in fatal cases of EEHV-1A, 1B and 5 using a quantitative real-time PCR. EEHV-1 and 5 DNA were detectable in all the tissues examined, albeit with substantial differences in the viral DNA load. The highest EEHV-1A DNA load was observed in the liver, followed by the heart, thymus and tongue. EEHV-1B and 5 showed the highest DNA load in the heart, followed by tongue and liver. This study provides new insights into EEHV pathogenicity and has implications in choice of sample type for disease investigation and virus isolation. PMID:27102836

  20. Tissue Distribution and Associated Toxicological Effects of Decabrominated Diphenyl Ether in Subchronically Exposed Male Rats

    PubMed Central

    Wang, Fuxin; Wang, Jianshe; Hu, Guocheng; Luo, Xiaojun; Mai, Bixian; Dai, Jiayin

    2011-01-01

    Concerns about decabrominated diphenyl ether (BDE-209) have arisen recently due to its increasing concentrations in the environment. We investigated the tissue concentration, distribution, and the debromination of BDE-209 after oral exposure, using rats as a model. Three groups of male rats were administrated by oral gavage with corn oil containing 0, 10, or 50 mg/kg bw/day of BDE-209 over 90 days. After exposure, BDE-209 and its metabolites levels in the liver, kidney, and adipose of the rats were measured. The mRNA expression levels of cytochrome P450 (CYP) enzymes in liver, serum thyroid hormone levels, and open-field tests were also measured. BDE-209 and several octa- and nona-BDE congeners were detected in the tissues of the dosed rats, indicating that BDE-209 was bioavailable and biotransformative in male rats. BDE-209 and its debrominated congeners had no mRNA level effect on selective genes from the CYP family in the liver or on the spontaneous behavior of adult male rats. Conversely, the level of thyroid hormone, total triiodothyronine (T3) in rats from the dosed treatments increased significantly compared to the control group. PMID:23724291

  1. Bioaccumulation efficiency, tissue distribution, and environmental occurrence of hepatitis E virus in bivalve shellfish from France.

    PubMed

    Grodzki, Marco; Schaeffer, Julien; Piquet, Jean-Côme; Le Saux, Jean-Claude; Chevé, Julien; Ollivier, Joanna; Le Pendu, Jacques; Le Guyader, Françoise S

    2014-07-01

    Hepatitis E virus (HEV), an enteric pathogen of both humans and animals, is excreted by infected individuals and is therefore present in wastewaters and coastal waters. As bivalve molluscan shellfish are known to concentrate viral particles during the process of filter feeding, they may accumulate this virus. The bioaccumulation efficiencies of oysters (Crassostrea gigas), flat oysters (Ostrea edulis), mussels (Mytilus edulis), and clams (Ruditapes philippinarum) were compared at different time points during the year. Tissue distribution analysis showed that most of the viruses were concentrated in the digestive tissues of the four species. Mussels and clams were found to be more sensitive to sporadic contamination events, as demonstrated by rapid bioaccumulation in less than 1 h compared to species of oysters. For oysters, concentrations increased during the 24-h bioaccumulation period. Additionally, to evaluate environmental occurrence of HEV in shellfish, an environmental investigation was undertaken at sites potentially impacted by pigs, wild boars, and human waste. Of the 286 samples collected, none were contaminated with hepatitis E virus, despite evidence that this virus is circulating in some French areas. It is possible that the number of hepatitis E viral particles discharged into the environment is too low to detect or that the virus may have a very short period of persistence in pig manure and human waste. PMID:24795382

  2. Intestinal absorption and tissue distribution of ( sup 14 C)pyrroloquinoline quinone in mice

    SciTech Connect

    Smidt, C.R.; Unkefer, C.J.; Houck, D.R.; Rucker, R.B. )

    1991-05-01

    Pyrroloquinoline quinone (PQQ) functions as a cofactor for prokaryotic oxidoreductases, such as methanol dehydrogenase and membrane-bound glucose dehydrogenase. In animals fed chemically defined diets, PQQ improves reproductive outcome and neonatal growth. Consequently, the present study was undertaken to determine the extent to which PQQ is absorbed by the intestine, its tissue distribution, and route of excretion. About 28 micrograms of PQQ (0.42 microCi/mumol), labeled with {sup 14}C derived from L-tyrosine, was administered orally to Swiss-Webster mice (18-20 g) to estimate absorption. PQQ was readily absorbed (62%, range 19-89%) in the lower intestine, and was excreted by the kidneys (81% of the absorbed dose) within 24 hr. The only tissues that retained significant amounts of ({sup 14}C)PQQ at 24 hr were skin and kidney. For kidney, it was assumed that retention of ({sup 14}C)PQQ represented primarily PQQ destined for excretion. For skin, the concentration of ({sup 14}C)PQQ increased from 0.3% of the absorbed dose at 6 hr to 1.3% at 24 hr. Furthermore, most of the ({sup 14}C)PQQ in blood (greater than 95%) was associated with the blood cell fraction, rather than plasma.

  3. Tissue and Stage-Specific Distribution of Wolbachia in Brugia malayi

    PubMed Central

    Fischer, Kerstin; Beatty, Wandy L.; Jiang, Daojun; Weil, Gary J.; Fischer, Peter U.

    2011-01-01

    Background Most filarial parasite species contain Wolbachia, obligatory bacterial endosymbionts that are crucial for filarial development and reproduction. They are targets for alternative chemotherapy, but their role in the biology of filarial nematodes is not well understood. Light microscopy provides important information on morphology, localization and potential function of these bacteria. Surprisingly, immunohistology and in situ hybridization techniques have not been widely used to monitor Wolbachia distribution during the filarial life cycle. Methods/Principal Findings A monoclonal antibody directed against Wolbachia surface protein and in situ hybridization targeting Wolbachia 16S rRNA were used to monitor Wolbachia during the life cycle of B. malayi. In microfilariae and vector stage larvae only a few cells contain Wolbachia. In contrast, large numbers of Wolbachia were detected in the lateral chords of L4 larvae, but no endobacteria were detected in the genital primordium. In young adult worms (5 weeks p.i.), a massive expansion of Wolbachia was observed in the lateral chords adjacent to ovaries or testis, but no endobacteria were detected in the growth zone of the ovaries, uterus, the growth zone of the testis or the vas deferens. Confocal laser scanning and transmission electron microscopy showed that numerous Wolbachia are aligned towards the developing ovaries and single endobacteria were detected in the germline. In inseminated females (8 weeks p.i.) Wolbachia were observed in the ovaries, embryos and in decreasing numbers in the lateral chords. In young males Wolbachia were found in distinct zones of the testis and in large numbers in the lateral chords in the vicinity of testicular tissue but never in mature spermatids or spermatozoa. Conclusions Immunohistology and in situ hybridization show distinct tissue and stage specific distribution patterns for Wolbachia in B. malayi. Extensive multiplication of Wolbachia occurs in the lateral chords of L4

  4. Analysis of elemental concentration censored distributions in breast malignant and breast benign neoplasm tissues

    NASA Astrophysics Data System (ADS)

    Kubala-Kukuś, A.; Banaś, D.; Braziewicz, J.; Góźdź, S.; Majewska, U.; Pajek, M.

    2007-07-01

    The total reflection X-ray fluorescence method was applied to study the trace element concentrations in human breast malignant and breast benign neoplasm tissues taken from the women who were patients of Holycross Cancer Centre in Kielce (Poland). These investigations were mainly focused on the development of new possibilities of cancer diagnosis and therapy monitoring. This systematic comparative study was based on relatively large (˜ 100) population studied, namely 26 samples of breast malignant and 68 samples of breast benign neoplasm tissues. The concentrations, being in the range from a few ppb to 0.1%, were determined for thirteen elements (from P to Pb). The results were carefully analysed to investigate the concentration distribution of trace elements in the studied samples. The measurements of concentration of trace elements by total reflection X-ray fluorescence were limited, however, by the detection limit of the method. It was observed that for more than 50% of elements determined, the concentrations were not measured in all samples. These incomplete measurements were treated within the statistical concept called left-random censoring and for the estimation of the mean value and median of censored concentration distributions, the Kaplan-Meier estimator was used. For comparison of concentrations in two populations, the log-rank test was applied, which allows to compare the censored total reflection X-ray fluorescence data. Found statistically significant differences are discussed in more details. It is noted that described data analysis procedures should be the standard tool to analyze the censored concentrations of trace elements analysed by X-ray fluorescence methods.

  5. Kinetics of Satratoxin G Tissue Distribution and Excretion Following Intranasal Exposure in the Mouse

    PubMed Central

    Amuzie, Chidozie J.; Islam, Zahidul; Kim, Jae Kyung; Seo, Ji-Hyun; Pestka, James J.

    2010-01-01

    Intranasal exposure of mice to satratoxin G (SG), a macrocyclic trichothecene produced by the indoor air mold Stachybotrys chartarum, selectively induces apoptosis in olfactory sensory neurons (OSNs) of the nose and brain. The purpose of this study was to measure the kinetics of distribution and clearance of SG in the mouse. Following intranasal instillation of female C57B16 mice with SG (500 μg/kg bw), the toxin was detectable from 5 to 60 min in blood and plasma, with the highest concentrations, 30 and 19 ng/ml, respectively, being observed at 5 min. SG clearance from plasma was rapid and followed single-compartment kinetics (t1/2 = 20 min) and differed markedly from that of other tissues. SG concentrations were maximal at 15–30 min in nasal turbinates (480 ng/g), kidney (280 ng/g), lung (250 ng/g), spleen (200 ng/g), liver (140 ng/g), thymus (90 ng/g), heart (70 ng/g), olfactory bulb (14 ng/g), and brain (3 ng/g). The half-lives of SG in the nasal turbinate and thymus were 7.6 and 10.1 h, respectively, whereas in other organs, these ranged from 2.3 to 4.4 h. SG was detectable in feces and urine, but cumulative excretion over 5 days via these routes accounted for less than 0.3% of the total dose administered. Taken together, SG was rapidly taken up from the nose, distributed to tissues involved in respiratory, immune, and neuronal function, and subsequently cleared. However, a significant amount of the toxin was retained in the nasal turbinate, which might contribute to SG’s capacity to evoke OSN death. PMID:20466779

  6. Comparative tissue pharmacokinetics and efficacy of moxidectin, abamectin and ivermectin in lambs infected with resistant nematodes: Impact of drug treatments on parasite P-glycoprotein expression☆

    PubMed Central

    Lloberas, Mercedes; Alvarez, Luis; Entrocasso, Carlos; Virkel, Guillermo; Ballent, Mariana; Mate, Laura; Lanusse, Carlos; Lifschitz, Adrian

    2012-01-01

    The high level of resistance to the macrocyclic lactones has encouraged the search for strategies to optimize their potential as antiparasitic agents. There is a need for pharmaco-parasitological studies addressing the kinetic-dynamic differences between various macrocyclic lactones under standardized in vivo conditions. The current work evaluated the relationship among systemic drug exposure, target tissue availabilities and the pattern of drug accumulation within resistant Haemonchus contortus for moxidectin, abamectin and ivermectin. Drug concentrations in plasma, target tissues and parasites were measured by high performance liquid chromatography. Additionally, the efficacy of the three molecules was evaluated in lambs infected with resistant nematodes by classical parasitological methods. Furthermore, the comparative determination of the level of expression of P-glycoprotein (P-gp2) in H. contortus recovered from lambs treated with each drug was performed by real time PCR. A longer persistence of moxidectin (P < 0.05) concentrations in plasma was observed. The concentrations of the three compounds in the mucosal tissue and digestive contents were significant higher than those measured in plasma. Drug concentrations were in a range between 452 ng/g (0.5 day post-treatment) and 32 ng/g (2 days post-treatment) in the gastrointestinal (GI) contents (abomasal and intestinal). Concentrations of the three compounds in H. contortus were in a similar range to those observed in the abomasal contents (positive correlation P = 0.0002). Lower moxidectin concentrations were recovered within adult H. contortus compared to abamectin and ivermectin at day 2 post-treatment. However, the efficacy against H. contortus was 20.1% (ivermectin), 39.7% (abamectin) and 89.6% (moxidectin). Only the ivermectin treatment induced an enhancement on the expression of P-gp2 in the recovered adult H. contortus, reaching higher values at 12 and 24 h post-administration compared to

  7. Comparative tissue pharmacokinetics and efficacy of moxidectin, abamectin and ivermectin in lambs infected with resistant nematodes: Impact of drug treatments on parasite P-glycoprotein expression.

    PubMed

    Lloberas, Mercedes; Alvarez, Luis; Entrocasso, Carlos; Virkel, Guillermo; Ballent, Mariana; Mate, Laura; Lanusse, Carlos; Lifschitz, Adrian

    2013-12-01

    The high level of resistance to the macrocyclic lactones has encouraged the search for strategies to optimize their potential as antiparasitic agents. There is a need for pharmaco-parasitological studies addressing the kinetic-dynamic differences between various macrocyclic lactones under standardized in vivo conditions. The current work evaluated the relationship among systemic drug exposure, target tissue availabilities and the pattern of drug accumulation within resistant Haemonchus contortus for moxidectin, abamectin and ivermectin. Drug concentrations in plasma, target tissues and parasites were measured by high performance liquid chromatography. Additionally, the efficacy of the three molecules was evaluated in lambs infected with resistant nematodes by classical parasitological methods. Furthermore, the comparative determination of the level of expression of P-glycoprotein (P-gp2) in H. contortus recovered from lambs treated with each drug was performed by real time PCR. A longer persistence of moxidectin (P < 0.05) concentrations in plasma was observed. The concentrations of the three compounds in the mucosal tissue and digestive contents were significant higher than those measured in plasma. Drug concentrations were in a range between 452 ng/g (0.5 day post-treatment) and 32 ng/g (2 days post-treatment) in the gastrointestinal (GI) contents (abomasal and intestinal). Concentrations of the three compounds in H. contortus were in a similar range to those observed in the abomasal contents (positive correlation P = 0.0002). Lower moxidectin concentrations were recovered within adult H. contortus compared to abamectin and ivermectin at day 2 post-treatment. However, the efficacy against H. contortus was 20.1% (ivermectin), 39.7% (abamectin) and 89.6% (moxidectin). Only the ivermectin treatment induced an enhancement on the expression of P-gp2 in the recovered adult H. contortus, reaching higher values at 12 and 24 h post-administration compared to

  8. Two-Dimensional N-Glycan Distribution Mapping of Hepatocellular Carcinoma Tissues by MALDI-Imaging Mass Spectrometry.

    PubMed

    Powers, Thomas W; Holst, Stephanie; Wuhrer, Manfred; Mehta, Anand S; Drake, Richard R

    2015-01-01

    A new mass spectrometry imaging approach to simultaneously map the two-dimensional distribution of N-glycans in tissues has been recently developed. The method uses Matrix Assisted Laser Desorption Ionization Imaging Mass Spectrometry (MALDI-IMS) to spatially profile the location and distribution of multiple N-linked glycan species released by peptide N-glycosidase F in frozen or formalin-fixed tissues. Multiple formalin-fixed human hepatocellular carcinoma tissues were evaluated with this method, resulting in a panel of over 30 N-glycans detected. An ethylation reaction of extracted N-glycans released from adjacent slides was done to stabilize sialic acid containing glycans, and these structures were compared to N-glycans detected directly from tissue profiling. In addition, the distribution of singly fucosylated N-glycans detected in tumor tissue microarray cores were compared to the histochemistry staining pattern of a core fucose binding lectin. As this MALDI-IMS workflow has the potential to be applied to any formalin-fixed tissue block or tissue microarray, the advantages and limitations of the technique in context with other glycomic methods are also summarized. PMID:26501333

  9. Gamma Knife 3-D dose distribution near the area of tissue inhomogeneities by normoxic gel dosimetry

    SciTech Connect

    Isbakan, Fatih; Uelgen, Yekta; Bilge, Hatice; Ozen, Zeynep; Agus, Onur; Buyuksarac, Bora

    2007-05-15

    The accuracy of the Leksell GammaPlan registered , the dose planning system of the Gamma Knife Model-B, was evaluated near tissue inhomogeneities, using the gel dosimetry method. The lack of electronic equilibrium around the small-diameter gamma beams can cause dose calculation errors in the neighborhood of an air-tissue interface. An experiment was designed to investigate the effects of inhomogeneity near the paranosal sinuses cavities. The homogeneous phantom was a spherical glass balloon of 16 cm diameter, filled with MAGIC gel; i.e., the normoxic polymer gel. Two hollow PVC balls of 2 cm radius, filled with N{sub 2} gas, represented the air cavities inside the inhomogeneous phantom. For dose calibration purposes, 100 ml gel-containing vials were irradiated at predefined doses, and then scanned in a MR unit. Linearity was observed between the delivered dose and the reciprocal of the T2 relaxation time constant of the gel. Dose distributions are the results of a single shot of irradiation, obtained by collimating all 201 cobalt sources to a known target in the phantom. Both phantoms were irradiated at the same dose level at the same coordinates. Stereotactic frames and fiducial markers were attached to the phantoms prior to MR scanning. The dose distribution predicted by the Gamma Knife planning system was compared with that of the gel dosimetry. As expected, for the homogeneous phantom the isodose diameters measured by the gel dosimetry and the GammaPlan registered differed by 5% at most. However, with the inhomogeneous phantom, the dose maps in the axial, coronal and sagittal planes were spatially different. The diameters of the 50% isodose curves differed 43% in the X axis and 32% in the Y axis for the Z=90 mm axial plane; by 44% in the X axis and 24% in the Z axis for the Y=90 mm coronal plane; and by 32% in the Z axis and 42% in the Y axis for the X=92 mm sagittal plane. The lack of ability of the GammaPlan registered to predict the rapid dose fall off, due

  10. Gamma Knife 3-D dose distribution near the area of tissue inhomogeneities by normoxic gel dosimetry.

    PubMed

    Isbakan, Fatih; Ulgen, Yekta; Bilge, Hatice; Ozen, Zeynep; Agus, Onur; Buyuksarac, Bora

    2007-05-01

    The accuracy of the Leksell GammaPlan, the dose planning system of the Gamma Knife Model-B, was evaluated near tissue inhomogeneities, using the gel dosimetry method. The lack of electronic equilibrium around the small-diameter gamma beams can cause dose calculation errors in the neighborhood of an air-tissue interface. An experiment was designed to investigate the effects of inhomogeneity near the paranosal sinuses cavities. The homogeneous phantom was a spherical glass balloon of 16 cm diameter, filled with MAGIC gel; i.e., the normoxic polymer gel. Two hollow PVC balls of 2 cm radius, filled with N2 gas, represented the air cavities inside the inhomogeneous phantom. For dose calibration purposes, 100 ml gel-containing vials were irradiated at predefined doses, and then scanned in a MR unit. Linearity was observed between the delivered dose and the reciprocal of the T2 relaxation time constant of the gel. Dose distributions are the results of a single shot of irradiation, obtained by collimating all 201 cobalt sources to a known target in the phantom. Both phantoms were irradiated at the same dose level at the same coordinates. Stereotactic frames and fiducial markers were attached to the phantoms prior to MR scanning. The dose distribution predicted by the Gamma Knife planning system was compared with that of the gel dosimetry. As expected, for the homogeneous phantom the isodose diameters measured by the gel dosimetry and the GammaPlan differed by 5% at most. However, with the inhomogeneous phantom, the dose maps in the axial, coronal and sagittal planes were spatially different. The diameters of the 50% isodose curves differed 43% in the X axis and 32% in the Y axis for the Z =90 mm axial plane; by 44% in the X axis and 24% in the Z axis for the Y=90 mm coronal plane; and by 32% in the Z axis and 42% in the Y axis for the X=92 mm sagittal plane. The lack of ability of the GammaPlan to predict the rapid dose fall off, due to the air cavities behind or near the

  11. SU-E-I-44: Some Preliminary Analysis of Angular Distribution of X-Ray Scattered On Soft Tissues

    SciTech Connect

    Ganezer, K; Krmar, M; Cvejic, Z; Rakic, S; Pajic, B

    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 profile 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.

  12. Phylogenetic sequence analysis, recombinant expression, and tissue distribution of a channel catfish estrogen receptor beta

    USGS Publications Warehouse

    Xia, Zhenfang; Gale, William L.; Chang, Xiaotian; Langenau, David; Patino, Reynaldo; Maule, Alec G.; Densmore, Llewellyn D.

    2000-01-01

    An estrogen receptor β (ERβ) cDNA fragment was amplified by RT-PCR of total RNAextracted from liver and ovary of immature channel catfish. This cDNA fragment was used to screen an ovarian cDNA library made from an immature female fish. A clone was obtained that contained an open reading frame encoding a 575-amino-acid protein with a deduced molecular weight of 63.9 kDa. Maximum parsimony and Neighbor Joining analyses were used to generate a phylogenetic classification of channel catfish ERβ on the basis of 25 full-length teleost and tetrapod ER sequences. The consensus tree obtained indicated the existence of two major vertebrate ER subtypes, α and β. Within each subtype, and in accordance with established phylogenetic relationships, teleost and tetrapod ER were monophyletic confirming the results of a previous analysis (Z. Xiaet al., 1999, Gen. Comp. Endocrinol. 113, 360–368). Extracts of COS-7 cells transfectedwith channel catfish ERβ cDNA bound estrogen with high affinity (Kd = 0.21 nM) and specificity. The affinity of channel catfish ERβ for estrogen was higher than previously reported for channel catfish ERα. As determined by qualitative RT-PCR, the tissue distributions of ERα and ERβ were similar but not identical. Both ER subtypes were present in ovary and testis. ERα was found in all other tissues examined from juvenile and mature fish of both sexes. ERβ was also found in most tissues except, in most cases, whole blood and head kidney. Interestingly, the pattern of expression of ER subtypes in head kidney always corresponded to the pattern in whole blood. In conclusion, we isolated a channel catfish ERβ with ligand-binding affinity and tissue expression patterns different from ERα. Also, we confirmed the validity of our previously proposed general classification scheme for vertebrate ER into α and β subtypes and within each subtype, into teleost and tetrapod clades.

  13. VISUALIZING THE STRESS DISTRIBUTION WITHIN VASCULAR TISSUES USING INTRAVASCULAR ULTRASOUND ELASTOGRAPHY: A PRELIMINARY INVESTIGATION

    PubMed Central

    Richards, Michael S.; Perucchio, Renato; Doyley, Marvin M.

    2015-01-01

    A methodology for computing the stress distribution of vascular tissue using finite element-based, intravascular ultrasound (IVUS) reconstruction elastography is described. This information could help cardiologists detect life-threatening atherosclerotic plaques and predict their propensity to rupture. The calculation of vessel stresses requires the measurement of strain from the ultrasound images, a calibrating pressure measurement and additional model assumptions. In this work, we conducted simulation studies to investigate the effect of varying the model assumptions, specifically Poisson’s ratio and the outer boundary conditions, on the resulting stress fields. In both simulation and phantom studies, we created vessel geometries with two fibrous cap thicknesses to determine if we could detect a difference in peak stress (spatially) between the two. The results revealed that (i) Poisson’s ratios had negligible impact on the accuracy of stress elastograms, (ii) the outer boundary condition assumption had the greatest effect on the resulting modulus and stress distributions and (iii) in simulation and in phantom experiments, our stress imaging technique was able to detect an increased peak stress for the vessel geometry with the smaller cap thickness. This work is a first step toward understanding and creating a robust stress measurement technique for evaluating atherosclerotic plaques using IVUS elastography. PMID:25837424

  14. Expression and distribution of acyl-CoA thioesterases in the white adipose tissue of rats.

    PubMed

    Ohtomo, Takayuki; Hoshino, Atsuko; Yajima, Masako; Tsuchiya, Akiharu; Momose, Atsushi; Tanonaka, Kouichi; Toyoda, Hiroo; Kato, Tetsuta; Yamada, Junji

    2013-08-01

    Acyl-CoA thioesterases (Acots) are enzymes that catalyze the hydrolysis of fatty acyl-CoAs to free fatty acids and coenzyme A, and have the potential to regulate the intracellular levels of these molecules. In this study, we show that a cytosolic isoform, Acot1, is expressed and distributed in immature adipocytes located in the perivascular region of the white adipose tissue (WAT) of rats. Immunoblot analyses detected Acot1 in all of the WATs examined, while immunohistochemistry revealed positively stained layered structures surrounding the adventitia of blood vessels in the subcutaneous WAT. When the subcutaneous WAT was digested with collagenase and centrifuged, Acot1 was recovered in the stromal vascular fraction (SVF), and not in the large mature adipocytes. In the SVF, undigested cells attached to short tubular fragments of blood vessels showed positive immunostaining, as well as a proportion of the dispersed cells. These fibroblast-like cells contained fine particulate lipid droplets, stained by oil-red O dye, in their cytoplasm, or expressed fatty acid-binding protein 4, an adipocyte marker. After induction of adipocyte differentiation following a 15-day preculture without insulin, the dedifferentiated cells showed increased Acot1 expression with a diffuse distribution throughout the cytosol. These findings suggest that Acot1 expression is transiently upregulated at an early stage of adipocyte maturation, possibly to maintain cytosolic acyl-CoAs below a certain level until the cells acquire their full capability for fat storage. PMID:23385637

  15. Temperature distribution during RF ablation on ex vivo liver tissue: IR measurements and simulations

    NASA Astrophysics Data System (ADS)

    Macchi, Edoardo Gino; Gallati, Mario; Braschi, Giovanni; Cigada, Alfredo; Comolli, Lorenzo

    2015-05-01

    Radiofrequency thermal ablation is the first therapeutic option for the minimally invasive treatment of liver tumors. This medical procedure employs the Joule heat produced by a RF electromagnetic field to kill tumor cells. The outcome of the procedure is strongly affected by the temperature distribution near the RF applicator, however the measurement of this distribution, even in ex vivo experiments, is not straightforward since most traditional local temperature measurement techniques are not well-suited, due to both electromagnetic interferences and the sensor heat sink effect. Given the importance of the temperature field knowledge, in this paper special care was devoted to its measurement employing both infrared thermal imaging and NTC thermistors. Several RF ablation tests on ex vivo porcine liver tissue were carried out measuring the space-time evolution of temperature during the procedure (with spatial resolution ≤1 mm) and producing useful data for the design and the calibration of a numerical model. Electro-thermal numerical simulations of the experimental tests were performed using a mathematical model suitable for the heating phase of the procedure (up to 95 °C). The simulations results allowed to check the physical consistency of the measured data and suggested that a constant thermal conductivity is satisfactory for modeling the temperature evolution during RF ablation.

  16. Visualizing the stress distribution within vascular tissues using intravascular ultrasound elastography: a preliminary investigation.

    PubMed

    Richards, Michael S; Perucchio, Renato; Doyley, Marvin M

    2015-06-01

    A methodology for computing the stress distribution of vascular tissue using finite element-based, intravascular ultrasound (IVUS) reconstruction elastography is described. This information could help cardiologists detect life-threatening atherosclerotic plaques and predict their propensity to rupture. The calculation of vessel stresses requires the measurement of strain from the ultrasound images, a calibrating pressure measurement and additional model assumptions. In this work, we conducted simulation studies to investigate the effect of varying the model assumptions, specifically Poisson's ratio and the outer boundary conditions, on the resulting stress fields. In both simulation and phantom studies, we created vessel geometries with two fibrous cap thicknesses to determine if we could detect a difference in peak stress (spatially) between the two. The results revealed that (i) Poisson's ratios had negligible impact on the accuracy of stress elastograms, (ii) the outer boundary condition assumption had the greatest effect on the resulting modulus and stress distributions and (iii) in simulation and in phantom experiments, our stress imaging technique was able to detect an increased peak stress for the vessel geometry with the smaller cap thickness. This work is a first step toward understanding and creating a robust stress measurement technique for evaluating atherosclerotic plaques using IVUS elastography. PMID:25837424

  17. Temperature distribution during RF ablation on ex vivo liver tissue: IR measurements and simulations

    NASA Astrophysics Data System (ADS)

    Macchi, Edoardo Gino; Gallati, Mario; Braschi, Giovanni; Cigada, Alfredo; Comolli, Lorenzo

    2014-09-01

    Radiofrequency thermal ablation is the first therapeutic option for the minimally invasive treatment of liver tumors. This medical procedure employs the Joule heat produced by a RF electromagnetic field to kill tumor cells. The outcome of the procedure is strongly affected by the temperature distribution near the RF applicator, however the measurement of this distribution, even in ex vivo experiments, is not straightforward since most traditional local temperature measurement techniques are not well-suited, due to both electromagnetic interferences and the sensor heat sink effect. Given the importance of the temperature field knowledge, in this paper special care was devoted to its measurement employing both infrared thermal imaging and NTC thermistors. Several RF ablation tests on ex vivo porcine liver tissue were carried out measuring the space-time evolution of temperature during the procedure (with spatial resolution ≤1 mm) and producing useful data for the design and the calibration of a numerical model. Electro-thermal numerical simulations of the experimental tests were performed using a mathematical model suitable for the heating phase of the procedure (up to 95 °C). The simulations results allowed to check the physical consistency of the measured data and suggested that a constant thermal conductivity is satisfactory for modeling the temperature evolution during RF ablation.

  18. Biodistribution of etanercept to tissues and sites of inflammation in arthritic rats.

    PubMed

    Chen, Xi; DuBois, Debra C; Almon, Richard R; Jusko, William J

    2015-06-01

    Many monoclonal antibodies (mAbs) and other protein drugs have targets usually residing within tissues, making tissue concentrations of mAbs relevant to their pharmacologic effects. Therefore, knowledge of tissue distribution kinetics is important to better understand their pharmacokinetics and pharmacodynamics. The tissue distribution of mAbs is affected by many physiologic factors that may be altered in disease status. In the present work, we studied the tissue distribution kinetics of the fusion protein etanercept in inflamed joint tissues and examined the impact of inflammation on the tissue distribution of etanercept. Etanercept concentration profiles in plasma, blister fluid, and different tissues were obtained from healthy and collagen-induced arthritic (CIA) rats by use of a fluorescence quantification method via IRDye800CW labeling. Stepwise minimal and full physiologically based pharmacokinetic (PBPK) approaches were applied to characterize the distribution kinetics of etanercept in tissues in healthy and diseased animals. Etanercept exhibited modest tissue access (tissue/plasma area under the concentration curve [AUC] ratios 0.03-0.15 and estimated tissue reflection coefficients [σ] of 0.6-1.0), but with good penetration into arthritic paws (tissue/plasma AUC ratio 0.23 and σ 0.36). Etanercept exposure in the inflamed paws of CIA rats was approximately 3-fold higher than in normal paws taken from either CIA or healthy rats (tissue/plasma AUC ratios 0.23 versus 0.07 and σ 0.36 versus 0.71). The tissue distribution kinetics of etanercept in arthritic paws were well characterized with PBPK modeling approaches. Etanercept shows good penetration to arthritic paws in CIA rats. Our study indicates that inflammation produced increased tissue distribution of etanercept in CIA rats. PMID:25834031

  19. Bioactive Markers Based Pharmacokinetic Evaluation of Extracts of a Traditional Medicinal Plant, Piper sarmentosum

    PubMed Central

    Hussain, Khalid; Ismail, Zhari; Sadikun, Amirin; Ibrahim, Pazillah

    2011-01-01

    In vitro assays are economical and easy to perform but to establish relevance of their results to real clinical outcome in animals or human, pharmacokinetics is prerequisite. Despite various in vitro pharmacological activities of extracts of Piper sarmentosum, there is no report of pharmacokinetics. Therefore, the present study aimed to evaluate ethanol extract of fruit of the plant in dose of 500 mg kg−1 orally for pharmacokinetics. Sprague-Dawley rats were randomly divided into groups 1, 2, and 3 (each n = 6) to study absorption, distribution and excretion, respectively. High performance liquid chromatography (HPLC) with ultraviolet detection was applied to quantify pellitorine, sarmentine and sarmentosine in plasma, tissues, feces and urine to calculate pharmacokinetic parameters. Pellitorine exhibited maximum plasma concentration (Cmax) 34.77 ng mL−1 ± 1.040, time to achieve Cmax (Tmax) 8 h, mean resident time (MRT) 26.00 ± 0.149 h and half life (t1/2) 18.64 ± 1.65 h. Sarmentine showed Cmax 191.50 ± 12.69 ng mL−1, Tmax 6 h, MRT 11.12 ± 0.44 h and t1/2 10.30 ± 1.98 h. Sarmentosine exhibited zero oral bioavailability because it was neither detected in plasma nor in tissues, and in urine. Pellitorine was found to be distributed in intestinal wall, liver, lungs, kidney, and heart, whereas sarmentine was found only in intestinal wall and heart. The cumulative excretion of pellitorine, sarmentine and sarmentosine in feces in 72 h was 0.0773, 0.976, and 0.438 μg, respectively. This study shows that pellitorine and sarmentine have good oral bioavailability while sarmentosine is not absorbed from the gastrointestinal tract. PMID:19770264

  20. Impact of Internal Metallic Ports in Temporary Tissue Expanders on Postmastectomy Radiation Dose Distribution

    SciTech Connect

    Chen, Susie A.; Ogunleye, Tomiwa; Dhabbaan, Anees; Huang, Eugene H.; Losken, Albert; Gabram, Sheryl; Davis, Lawrence; Torres, Mylin A.

    2013-03-01

    Purpose: Temporary tissue expanders (TTE) with an internal magnetic metal port (IMP) have been increasingly used for breast reconstruction in post-mastectomy patients who receive radiation therapy (XRT). We evaluated XRT plans of patients with IMP to determine its effect on XRT dose distribution. Methods and Materials: Original treatment plans with CT simulation scans of 24 consecutive patients who received XRT (ORI), planned without heterogeneity corrections, to a reconstructed breast containing an IMP were used. Two additional treatment plans were then generated: one treatment plan with the IMP assigned the electron density of the rare earth magnet, nickel plated neodymium-iron-boron (HET), and a second treatment plan with the IMP assigned a CT value of 1 to simulate a homogeneous breast without an IMP (BRS). All plans were prescribed 50 Gy to the reconstructed breast (CTV). Results: CTV coverage by 50 Gy was significantly lower in the HET (mean 87.7% CTV) than in either the ORI (mean 99.7% CTV, P<.001) or BRS plans (mean 95.0% CTV, P<.001). The effect of the port was more pronounced on CT slices containing the IMP with prescription dose coverage of the CTV being less in the HET than in either ORI (mean difference 33.6%, P<.01) or BRS plans (mean difference 30.1%, P<.001). HET had a less homogeneous and conformal dose distribution than BRS or ORI. Conclusion: IMPs increase dose heterogeneity and reduce dose to the breast CTV through attenuation of the beam. For optimal XRT treatment, heterogeneity corrections should be used in XRT planning for patients with TTE with IMP, as the IMP impacts dose distribution.

  1. A Gauss-Kronrod-Trapezoidal integration scheme for modeling biological tissues with continuous fiber distributions.

    PubMed

    Hou, Chieh; Ateshian, Gerard A

    2016-01-01

    Fibrous biological tissues may be modeled using a continuous fiber distribution (CFD) to capture tension-compression nonlinearity, anisotropic fiber distributions, and load-induced anisotropy. The CFD framework requires spherical integration of weighted individual fiber responses, with fibers contributing to the stress response only when they are in tension. The common method for performing this integration employs the discretization of the unit sphere into a polyhedron with nearly uniform triangular faces (finite element integration or FEI scheme). Although FEI has proven to be more accurate and efficient than integration using spherical coordinates, it presents three major drawbacks: First, the number of elements on the unit sphere needed to achieve satisfactory accuracy becomes a significant computational cost in a finite element (FE) analysis. Second, fibers may not be in tension in some regions on the unit sphere, where the integration becomes a waste. Third, if tensed fiber bundles span a small region compared to the area of the elements on the sphere, a significant discretization error arises. This study presents an integration scheme specialized to the CFD framework, which significantly mitigates the first drawback of the FEI scheme, while eliminating the second and third completely. Here, integration is performed only over the regions of the unit sphere where fibers are in tension. Gauss-Kronrod quadrature is used across latitudes and the trapezoidal scheme across longitudes. Over a wide range of strain states, fiber material properties, and fiber angular distributions, results demonstrate that this new scheme always outperforms FEI, sometimes by orders of magnitude in the number of computational steps and relative accuracy of the stress calculation. PMID:26291492

  2. Generalized pharmacokinetic modeling for drugs with nonlinear binding: I. Theoretical framework.

    PubMed

    Gillespie, W R

    1993-02-01

    The following integrodifferential equation is proposed as the basis for a generalized treatment of pharmacokinetic systems in which nonlinear binding occurs phi'(cu)c'u = -q(cu)+g * cu+f where cu identical to unbound plasma drug concentration, f identical to drug input rate, ' indicates the derivative of a function, and * indicates the convolution operation: (g * cu) (t) = integral of t0 g(t-u)cu(u) du. Possible physical interpretations of the functions q, g and f are: q(cu) identical to rate at which drug leaves the sampling compartment, g * cu identical to rate at which drug returns to the sampling compartment from the peripheral system (tissues that are kinetically distinct from the sampling compartment), and phi(cu) identical to amount of drug in the sampling compartment. The approach assumes that drug binding is sufficiently rapid that it may be treated as an equilibrium process. It may be applied to systems in which nonlinear binding occurs within the sampling compartment, i.e., in the systemic circulation or in tissues to which drug is rapidly distributed. The proposed relationship is a generalization of most existing models for drugs with nonlinear binding. It can serve as a general theoretical framework for such models or as the basis for "model-independent" methods for analyzing the pharmacokinetics of drugs with nonlinear binding. Computer programs for the numerical solution of the integrodifferential equation are presented. Methods for pharmacokinetic system characterization, prediction and bioavailability are presented and demonstrated. PMID:8410685

  3. Biodistribution, pharmacokinetic, and in-vivo fluorescence spectroscopic studies of photosensitizers

    NASA Astrophysics Data System (ADS)

    Moan, Johan; Peng, Qian; Iani, Vladimir; Ma, Li Wei; Horobin, Richard W.; Berg, Kristian; Kongshaug, Magne; Nesland, Jahn M.

    1996-01-01

    Some key data concerning the pharmacokinetics of PCT photosensitizers are reviewed. The following topics are discussed: The binding of photosensitizers to serum proteins, and the significance of LDL binding for tumor localization, the distribution of sensitizers among different tissue compartments and the significance of extracellular proteins and other stromal elements, such as macrophages, low tumor pH, leaky vasculature and poor lymphatic drainage for tumor selectivity of drugs, the retention and excretion of sensitizers, and intracellular pharmacokinetics. Furthermore, the usefulness of fluorescence measurements in the study of sensitizer pharmacokinetics is briefly discussed. A key observation is that 1O2 has a short radius of action. Since practically all PCT sensitizers act via the 1O2 pathway, only targets with significant sensitizer concentrations can be damaged. A given number of 1O2 entities generated in different organelles (mitochondria, lysosomes, plasma membrane, etc.) may lead to widely different effects with respect to cell inactivation. Similarly, sensitizers localizing in different compartments of tissues may have different photosensitizing efficiencies even under conditions of a similar 1O2 yield.

  4. 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…

  5. 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)

  6. Thrombolytic and pharmacokinetic properties of human tissue-type plasminogen activator variants, obtained by deletion and/or duplication of structural/functional domains, in a hamster pulmonary embolism model.

    PubMed

    Collen, D; Lijnen, H R; Vanlinthout, I; Kieckens, L; Nelles, L; Stassen, J M

    1991-02-12

    A pulmonary embolism model in hamsters was used for the quantitative evaluation of the thrombolytic and pharmacokinetic properties of variants of tissue-type plasminogen activator (t-PA). A 25 microliters 125I-fibrin labeled human plasma clot was made in vitro and injected into the jugular vein of heparinized hamsters. The extent of thrombolysis within 90 min was determined as the difference between the radioactivity injected in the jugular vein and that recovered in the heart and lungs. Recombinant t-PA (home-made rt-PA or Activase) infused intravenously over 60 min caused dose-dependent progressive thrombolysis. The results of throm