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Sample records for pharmacokinetics tissue distribution

  1. Effects of charge on antibody tissue distribution and pharmacokinetics.

    PubMed

    Boswell, C Andrew; Tesar, Devin B; Mukhyala, Kiran; Theil, Frank-Peter; Fielder, Paul J; Khawli, Leslie A

    2010-12-15

    Antibody pharmacokinetics and pharmacodynamics are often governed by biological processes such as binding to antigens and other cognate receptors. Emphasis must also be placed, however, on fundamental physicochemical properties that define antibodies as complex macromolecules, including shape, size, hydrophobicity, and charge. Electrostatic interactions between anionic cell membranes and the predominantly positive surface charge of most antibodies can influence blood concentration and tissue disposition kinetics in a manner that is independent of antigen recognition. In this context, the deliberate modification of antibodies by chemical means has been exploited as a valuable preclinical research tool to investigate the relationship between net molecular charge and biological disposition. Findings from these exploratory investigations may be summarized as follows: (I) shifts in isoelectric point of approximately one pI unit or more can produce measurable changes in tissue distribution and kinetics, (II) increases in net positive charge generally result in increased tissue retention and increased blood clearance, and (III) decreases in net positive charge generally result in decreased tissue retention and increased whole body clearance. Understanding electrostatic interactions between antibodies and biological matrices holds relevance in biotechnology, especially with regard to the development of immunoconjugates. The guiding principles and knowledge gained from preclinical evaluation of chemically modified antibodies will be discussed and placed in the context of therapeutic antibodies that are currently marketed or under development, with a particular emphasis on pharmacokinetic and disposition properties.

  2. Pharmacokinetics, tissue distribution and safety of cinnarizine delivered in lipid emulsion.

    PubMed

    Shi, Shuai; Chen, Hao; Lin, Xia; Tang, Xing

    2010-01-04

    The aim of this study was to assess the potential of cinnarizine loaded in lipid emulsion to modify the pharmacokinetics, tissue distribution and safety of cinnarizine. The cinnarizine-loaded emulsion (CLE) which can remain stable over 18-month storage at 4+/-2 degrees C was prepared by high-pressure homogenization. Nicomp 380 particle sizing system and HPLC were used to evaluate CLE in vitro, while UPLC/MS/MS for pharmacokinetic and tissue distribution study. The pharmacokinetics and tissue distributions of CLE were assessed by comparing with the solution form after intravenous administration to rats at a dose of 2mg/kg. The CLE showed significant higher AUC and lower clearance and distribution volume than those of solution form. This helped cinnarizine to reach higher level in vessel, and circulate in the blood stream for a longer time resulting in better therapeutic effect. The tissue distribution exhibited significant lower uptake of CLE emulsion in lung and brain, indicating the advantage of CLE over the solution form in reducing drug precipitation in vivo and toxicity in CNS. Drug safety assessment studies including hemolysis test, intravenous stimulation and injection anaphylaxis revealed that the CLE was safe for intravenous injection.

  3. 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.

  4. 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.

  5. Pharmacokinetics, Tissue Distribution and Protein Binding Studies of Chrysocauloflavone I in Rats.

    PubMed

    Yang, Sufang; Shi, Peiying; Huang, Xiaomei; Zhao, Meifeng; Li, Shaoguang; Wu, Youjia; Lin, Xinhua; Yao, Hong

    2016-02-01

    Chrysocauloflavone I, an unfrequent biflavonoid, was purified from Selaginella doederleinii in this study. It showed cytotoxic effects on three human cancer cells, NCI-H1975, A549, and HepG-2, in vitro. In silico assessment of the physicochemical properties was performed for predicting the permeability and intestinal absorption of the tested compound. Subsequently, a rapid, sensitive, and specific high-performance liquid chromatography method was developed for determination of the compound in different biological samples to ascertain the pharmacokinetics, tissue distribution, and protein binding profiles of this active ingredient in rats. After intravenous dosing of chrysocauloflavone I at different levels (10 and 20 mg/kg), the elimination half-life was approximately 85 min, and the AUC0-∞ increased with the dose from 148.52 mg/L × min for 10 mg/kg to 399.01 mg/L × min for 20 mg/kg. After single intravenous dosing (20 mg/kg), chrysocauloflavone I was detected in all tissues studied with higher levels in the heart, blood, and lungs. The results of equilibrium dialysis indicated a very high protein binding degree (over 97%) for chrysocauloflavone I. After intragastric administration of 100 mg/kg chrysocauloflavone I to rats, no parent drug was detected in the rat plasma. This is the first report of the favorable bioactivities, plasma pharmacokinetics, tissue distribution, and protein binding profiles of the rare biflavone chrysocauloflavone I.

  6. Pharmacokinetics, tissue distribution and excretion of a new photodynamic drug deuxemether.

    PubMed

    Wang, Rui; Hao, Haiping; Wang, Guangji; Xie, Haitang; Xu, Meijuan; Wang, Wei; He, Hui; Li, Xiaoyu

    2008-03-28

    Deuxemether was a new photodynamic drug effective for many kinds of solid tumor therapy, which was mainly composed of 3-(or 8-)-(1-methoxyethyl)-8-(or 3-)-(1-hydroxyethyl)-deutero-porphyrin IX (MHD) and 3,8-di(1-methoxyethyl)-deuteroporphyrin IX (DMD). The aims of this study were to elucidate its pharmacokinetic characteristics, tissue distribution, plasma protein binding and excretion properties and underlying mechanisms of deuxemether in rats based on the simultaneous determination of MHD and DMD. The pharmacokinetic profiles of both MHD and DMD in rats after intravenous doses were linear and best fitted to a two compartment model, characterized with a rapid distribution phase (MHD: t(1/2)alpha, 0.09-0.14 h; DMD: t 1/2 alpha, 0.07-0.11h) and a relatively slow elimination phase (MHD: t 1/2 beta, 2.03-3.20 h; DMD: t 1/2 beta, 2.51-3.20 h). The tissue distributions of MHD and DMD in rats were rather limited as evidenced from their low distribution volume (0.75-1.70 L/kg) and the results of tissue distribution study. Protein binding of MHD and DMD were moderate (65.36-89.99% for MHD; 45.43-76.23% for DMD), independent of drug concentrations and similar between human and rat plasma over a concentration range of 0.50-50.0 microg/mL. Both MHD and DMD were predominantly (>74.1%) eliminated from rats as the parent drugs through the hepatobiliary systems and finally excreted into the feces. The multidrug resistance-associated proteins 2 (MRP2) inhibitors, bromosulfophthalein and probenecid, substantially inhibited the hepatobiliary elimination of MHD and DMD while the P-gp inhibitor digoxin had little effect, suggesting that MRP2 may contribute to the rapid and extensive hepatobiliary excretion of deuxemether. There were no significant differences between MHD and DMD for all pharmacokinetic characteristics studied. In conclusion, this study provided firstly the full pharmacokinetic characteristics and mechanisms of deuxemether, which would be helpful for its clinical

  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. Cinnamaldehyde in a Novel Intravenous Submicrometer Emulsion: Pharmacokinetics, Tissue Distribution, Antitumor Efficacy, and Toxicity.

    PubMed

    Zhao, Hang; Yuan, Jiani; Yang, Qian; Xie, Yanhua; Cao, Wei; Wang, Siwang

    2015-07-22

    The purpose of our research is to find a new lipid emulsion to deliver a low water-soluble compound, cinnamaldehyde (CA). Its characteristics, pharmacokinetics, antitumor efficacy, and toxicity were evaluated. The mean particle size, zeta potential, and encapsulation efficiency of the submicromemter emulsion of CA (SME-CA) were 130 ± 5.92 nm, -25.7 ± 6.00 mV, and 99.5 ± 0.25%, respectively. The area under the curve from 0 h to termination time (AUC(0-t)) of SME-CA showed a significantly higher value than that of CA (589 ± 59.2 vs 375 ± 83.5 ng h/L, P < 0.01). Tissue distribution study showed various changes; among them, a 27% higher concentration was found in brain tissue when using SME-CA at 15 min after administration. For the efficacy evaluation, SME-CA exhibited 8- and 11-fold antitumor activity in the depression of HeLa and A549 cell lines with the IC50 decreasing to 0.003 and 0.001 mmol/L, respectively. The LD50 values of CA and SME-CA in mice were 74.8 and 125 mg/kg, suggesting increased safety from the new formulation. The new formulation exhibited lower toxicity, higher antitumor activity, and a more satisfactory pharmacokinetic property, which displayed great potential for future pharmacological application.

  9. Galactosylated bovine serum albumin nanoparticles for parenteral delivery of oridonin: tissue distribution and pharmacokinetic studies.

    PubMed

    Li, Caiyun; Zhang, Dianrui; Guo, Yuanyuan; Guo, Hejian; Li, Tingting; Hao, Leilei; Zheng, Dandan; Liu, Guangpu; Zhang, Qiang

    2014-01-01

    Bovine serum albumin (BSA) nanoparticle is a promising drug carrier system. Oridonin (ORI)-loaded galactosylated BSA nanoparticle (ORI-GB-NP) was prepared for liver targeting delivery of ORI. This work was designed to investigate the in vitro release, in vivo pharmacokinetics and tissue distribution of ORI-GB-NP. ORI-GB-NP was prepared by the desolvation method. The particle size of ORI-GB-NP was 172.0 ± 8.3 nm with narrow size distribution. The in vitro release of ORI-GB-NP exhibited biphasic drug release pattern with an initial burst release and consequently sustained release. Pharmacokinetic analysis displayed that ORI-GB-NP and ORI-loaded BSA nanoparticle (ORI-BSA-NP) could enhance the drug plasma level and prolong the circulation time in contrast with ORI solution. Meanwhile, compared with ORI-BSA-NP, ORI-GB-NP could deliver more ORI to liver and simultaneously reduce the toxicity of ORI to heart, lung and kidney. In conclusion, ORI-GB-NP could be a promising drug delivery system for liver cancer therapy.

  10. Pharmacokinetics and tissue distribution of gentiopicroside following oral and intravenous administration in mice.

    PubMed

    Wang, Chang-Hong; Wang, Zheng-Tao; Bligh, S W Annie; White, Kenneth N; White, Christopher J Branford

    2004-01-01

    The pharmacokinetics and tissue distribution of Gentiopicroside (GPS), one of the major active components of the Gentiana species of medicinal plants, was studied following oral and intravenous administration in mice. The distribution of GPS in mice after oral and intravenous doses could be fitted to a two-compartments open model. The serum half-life of GPS was 6.1 h and 2.8 h for intravenous and oral administration, respectively. The Tmax of GPS after oral administration was 0.50 h, and the bioavailability was 39.6%. The AUC gradient in individual tissues following intravenous administration was kidney >serum >liver >spleen >lung >thymus >fat >heart >muscle >stomach >intestinal >brain. The MRT gradient was muscle >serum >lung >spleen >lung >intestinal>heart >stomach >brain >liver >thymus >kidney >fat. Overall the data show that GPS could be absorbed rapidly in mice, but with a low bioavailability, and could distribute to tissues extensively, but was generally cleared quickly with short MRTs. The study demonstrates the need for repeated dosage, or better, a slow release formulation as an ideal means of administering GPS.

  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.

  12. Docetaxel-loaded liposomes: preparation, pH sensitivity, pharmacokinetics, and tissue distribution*

    PubMed Central

    Zhang, Hong; Li, Rui-ying; Lu, Xia; Mou, Zhen-zhen; Lin, Gui-mei

    2012-01-01

    Docetaxel (DTX), as a member of taxoid family, has been widely used in the treatment of cancers. The present study prepared pH-sensitive DTX-loaded liposomes (DTX-Lips) by thin-film dispersion method and various physico-chemical and morphological properties were examined. The pH sensitivity of in vitro DTX release and the in vivo pharmacokinetics and tissue distribution using Kunming mice were also investigated. The mean particle size and zeta potential of DTX liposomes were (277±2) nm and (−32.60±0.26) mV, respectively. Additionally, in vitro drug release study showed that the cumulative release rate was 1.3 times more at pH 5.0 than at pH 7.4, suggesting a pH-dependent release ability of DTX-Lips. Pharmacokinetic and pharmaceutical studies in comparison with Duopafei® showed that the half-time period (t 1/2) and area under the curve (AUC) of DTX-Lips in mouse plasma were 1.8 times longer and 2.6 times higher, respectively, and that DTX-Lips selectively accumulated in macrophage-rich organs such as liver and spleen. These results together suggest that the DTX-Lips could be a promising formulation for the clinical administration of DTX. PMID:23225853

  13. Pharmacokinetics of spiramycin in the rhesus monkey: transplacental passage and distribution in tissue in the fetus.

    PubMed Central

    Schoondermark-Van de Ven, E; Galama, J; Camps, W; Vree, T; Russel, F; Meuwissen, J; Melchers, W

    1994-01-01

    Transplacental transfer of spiramycin was investigated in a rhesus monkey model to study whether the antibiotic reaches therapeutic levels in the fetus. Spiramycin concentrations were measured by bioassay and high-performance liquid chromatography. Pharmacokinetic parameters were determined for bioactive spiramycin as measured by the bioassay. Pharmacokinetic pilot studies showed that spiramycin distribution follows a two-compartment model in rhesus monkeys. Following a single intravenous dose of 50 or 250 mg, dose-dependent kinetics were observed. At a dose of 50 mg, 10% of the dose was excreted unchanged in the urine. At the higher dose of 250 mg, an oliguric effect was observed. Spiramycin concentrations in fetal serum were measured over time while the maternal concentration was maintained at a constant level. During a 5-h experiment, a maximum fetal-maternal serum ratio of 0.27 was found. In three fetuses, concentrations in serum and tissue were measured following intravenous administration of 50 mg of spiramycin twice daily to the mother for at least 7 days. The fetal-maternal serum ratios were found to be 0.4 to 0.58 after intravenous administration of the final dose of 50 mg to the mother. It appeared that spiramycin accumulated in the soft tissues, especially in the liver and spleen, of both the mother and the fetus. The concentration in placental tissue appeared to be 10 to 20 times that of the concentration in fetal serum. The concentration of spiramycin in amniotic fluid was about five times higher than the concentration in fetal serum. Another important observation was that absolutely no spiramycin was found in the brain. PMID:7810999

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

    DTIC Science & Technology

    2008-03-01

    COMPARATIVE KINETICS AND DISTRIBUTION TO TARGET TISSUES OF ORGANOPHOSPHATES USING PHYSIOLOGICALLY...Department of Defense, or the U.S. Government. AFIT/GEM/ENV/08-M20 COMPARATIVE KINETICS AND DISTRIBUTION TO TARGET TISSUES OF ORGANOPHOSPHATES...APPROVED FOR PUBLIC RELEASE; DISTRIBUTION UNLIMITED AFIT/GEM/ENV/08-M20 COMPARATIVE KINETICS AND DISTRIBUTION TO TARGET TISSUES OF ORGANOPHOSPHATES

  15. 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.

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

    PubMed

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

    2015-05-01

    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.

  17. 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

  18. 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

  19. Pharmacokinetics, tissue distribution, and excretion studies of l-isocorypalmine using ultra high performance liquid chromatography with tandem mass spectrometry.

    PubMed

    Wang, Weihui; Liu, Jing; Zhao, Xiaoning; Peng, Yan; Wang, Nannan; Lee, David Y W; Dai, Ronghua

    2017-03-01

    l-Isocorypalmine is a newly identified metabolite of l-tetrahydropalmatine with a unique dual pharmacological profile as a partial dopamine receptor 1 agonist and dopamine receptor 2 antagonist properties for treating cocaine use disorder. The purpose of this study was to explore the pharmacokinetic profiles, tissue distribution, and excretion of l-isocorypalmine in Sprague-Dawley rats. A sensitive and reliable ultra high performance liquid chromatography with tandem mass spectrometry method was developed and validated for determination of l-isocorypalmine in biological samples. The biological samples were extracted by liquid-liquid extraction and separated on a Bonshell ASB C18 column (2.1 × 100 mm, 2.7 μm, Agela) with gradient mobile phase at the flow rate of 0.2 mL/min. The detection was performed by positive electrospray ionization with multiple reaction monitoring mode. Satisfactory linearity, precision, accuracy, extraction recovery, and acceptable matrix effect were achieved. The quantitative method was successfully applied to the pharmacokinetics, tissue distribution, and excretion study of l-isocorypalmine. The results showed that l-isocorypalmine was rapidly distributed, and eliminated from rat plasma and manifested linear dynamics in a dose range of 7.5-15 mg/kg. In addition, the results would be helpful for further clinical reference of l-isocorypalmine as a potential candidate drug for the treatment of cocaine addiction.

  20. 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

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

    PubMed

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

    1998-06-01

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

  2. Grepafloxacin: pharmacokinetics and tissue penetration.

    PubMed

    Wise, Richard

    1998-03-01

    Pharmacokinetic and tissue penetration studies of grepafloxacin, a new broad-spectrum fluoroquinolone, show that it has useful properties for the treatment of respiratory tract infections. Grepafloxacin has a volume of distribution that is larger than those of many of the other fluoroquinolones and is concentrated in alveolar macrophages, bronchial mucosa and epithelial lining fluid to a greater extent than are certain other fluoroquinolones. Grepafloxacin concentrations achieved in plasma after a 400-mg oral dose are well in excess of those required to inhibit the respiratory pathogens Staphylococcus aureus, Haemophilus influenzae and Moraxella catarrhalis. Streptococcus pneumoniae is also covered for most of the dosing interval, but at normal dose levels grepafloxacin might not inhibit Enterococcus faecalis. The maximum plasma concentrations and area under the concentration---time curve achieved with grepafloxacin suggest that it will be effective for the treatment of community-acquired pneumonia and acute exacerbations of chronic bronchitis. The pharmacokinetics of fluoroquinolones are among their most useful properties. The aim of this paper is to demonstrate whether the differences between grepafloxacin and the other fluoroquinolones are of therapeutic significance.

  3. 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.

  4. 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.

  5. Preclinical pharmacokinetics and distribution to tissue of AG1343, an inhibitor of human immunodeficiency virus type 1 protease.

    PubMed

    Shetty, B V; Kosa, M B; Khalil, D A; Webber, S

    1996-01-01

    AG1343, a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) protease (Ki = 2 nM), was designed by protein structure-based drug design techniques. AG1343 has potent antiviral activity (95% effective dose = 0.04 microgram/ml) against a number of HIV-1 strains in acute and chronic models of infection. As part of its preclinical development, the oral bioavailability of AG1343 in rats, dogs, monkeys, and marmosets was determined and its tissue distribution in rats was evaluated. There were no major interspecies differences in AG1343 pharmacokinetics. Following intravenous administration, the elimination half-life of AG1343 ranged from 1 to 1.4 hr. The total volume of distribution (2 to 7 liters/kg) exceeded the volume of total body water, indicating extensive tissue distribution. Systemic clearance of AG1343 (1 to 4 liters/kg) in the different species corresponded to hepatic blood flow, suggesting possible hepatic involvement in the elimination of AG1343. Following oral administration, peak levels in plasma ranged from 0.34 microgram/ml after treatment with 10 mg/kg of body weight in the dog to 1.7 micrograms/ml after dosing with 50 mg/kg in the rat. Because of the slow absorption of AG1343, plasma concentrations of AG1343 exceeding that required for 95% inhibition of HIV-1 replication were maintained for up to 7 h after a single oral dose in all species evaluated. Average oral bioavailability of AG1343 ranged from 17% in the marmoset to 47% in the dog. Studies of distribution to tissue in the rat after oral administration of 14C-AG1343 established extensive distribution with concentrations in most tissues exceeding that found in plasma. Of particular significance were high levels of AG1343 equivalent in mesenteric lymph nodes (32.05 micrograms/g) and spleen tissue (9.33 micrograms/g). The major excretory route for AG1343 was via feces, with 100% of the dose recovered by 48 h. Results from these studies demonstrate that AG1343 is orally bioavailable and

  6. Preclinical pharmacokinetics and distribution to tissue of AG1343, an inhibitor of human immunodeficiency virus type 1 protease.

    PubMed Central

    Shetty, B V; Kosa, M B; Khalil, D A; Webber, S

    1996-01-01

    AG1343, a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) protease (Ki = 2 nM), was designed by protein structure-based drug design techniques. AG1343 has potent antiviral activity (95% effective dose = 0.04 microgram/ml) against a number of HIV-1 strains in acute and chronic models of infection. As part of its preclinical development, the oral bioavailability of AG1343 in rats, dogs, monkeys, and marmosets was determined and its tissue distribution in rats was evaluated. There were no major interspecies differences in AG1343 pharmacokinetics. Following intravenous administration, the elimination half-life of AG1343 ranged from 1 to 1.4 hr. The total volume of distribution (2 to 7 liters/kg) exceeded the volume of total body water, indicating extensive tissue distribution. Systemic clearance of AG1343 (1 to 4 liters/kg) in the different species corresponded to hepatic blood flow, suggesting possible hepatic involvement in the elimination of AG1343. Following oral administration, peak levels in plasma ranged from 0.34 microgram/ml after treatment with 10 mg/kg of body weight in the dog to 1.7 micrograms/ml after dosing with 50 mg/kg in the rat. Because of the slow absorption of AG1343, plasma concentrations of AG1343 exceeding that required for 95% inhibition of HIV-1 replication were maintained for up to 7 h after a single oral dose in all species evaluated. Average oral bioavailability of AG1343 ranged from 17% in the marmoset to 47% in the dog. Studies of distribution to tissue in the rat after oral administration of 14C-AG1343 established extensive distribution with concentrations in most tissues exceeding that found in plasma. Of particular significance were high levels of AG1343 equivalent in mesenteric lymph nodes (32.05 micrograms/g) and spleen tissue (9.33 micrograms/g). The major excretory route for AG1343 was via feces, with 100% of the dose recovered by 48 h. Results from these studies demonstrate that AG1343 is orally bioavailable and

  7. Dihydroartemisinin loaded nanostructured lipid carriers (DHA-NLC): evaluation of pharmacokinetics and tissue distribution after intravenous administration to rats.

    PubMed

    Zhang, Xiaoyun; Qiao, Hua; Liu, Jianping; Dong, Haijun; Shen, Chenlin; Ni, Jingman; Shi, Yanbin; Xu, Ying

    2010-09-01

    A simple and rapid LC-MS/MS method was established for the determination of dihydroartemisinin (DHA) in plasma and tissues of rats. Sample preparation was achieved by liquid-liquid extraction with aether and analysis was performed on LC-MS/MS in positive ion mode using electrospray ionization (ESI) as an interface. Target compounds were quantified in a single ion-monitoring (SIM) mode. DHA was monitored at m/z 267.1 and the internal standard finasteride at m/z 305.2. Chromatography was carried out using a Synergi fusion RP 80 column with a mixture of ethanol and 0.1% formic acid mixture (75:25) as the mobile phase. The pharmacokinetics and tissue distribution after intravenous administration of DHA in nanostructured lipid carrier (NLC) and in solution were then compared. The mean residence times (MRT) of the DHA-NLC was much longer than that of the DHA solution. In the tested organs, the AUC values of the DHA-NLC were higher than that of the DHA solution in liver, spleen, lung, brain and muscle, and lower than the DHA solution in heart and kidney. DHA-NLC prepared in this study is a promising sustained-release and drug-targeting system for antitumor drugs. It may also allow a reduction in dosage and a decrease in systemic toxicity.

  8. 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

  9. Comparative pharmacokinetics and tissue distribution of schisandrin, deoxyschisandrin and schisandrin B in rats after combining acupuncture and herb medicine (schisandra chinensis).

    PubMed

    Wu, Xiaoyan; Zhou, Yuan; Yin, Fangzhou; Dai, Guoliang; Li, Lin; Xu, Bin; Ji, De; Sun, Yong; Mao, Chunqin; Lu, Tulin

    2014-08-01

    Recently, combination therapy with acupuncture and medicine as a practical strategy to treat diseases has gained increasing attention. The present study aimed to investigate whether acupuncture stimulation at ST.36 had a potential impact on the pharmacokinetics and tissue distribution of lignans. An HPLC-ESI/MS analytical method was established and successfully applied to a comparative study of drug concentration in plasma and tissues of three lignans. The parameters area under the plasma concentration-time curve from time zero to the final measurable point and from time zero to infinity, and peak concentration were significantly increased, with a prolonged mean residence time and a corresponding decrease in clearance in comparision with the Schisandra-alone group. Additionally, tissue concentrations of three lignans were improved in the group with acupuncture, especially in liver. The results indicated that acupuncture has a synergistic effect on the pharmacokinetics and tissue distribution of the three lignans, which could postpone their elimination, resulting in a longer blood circulating time in rat plasma and prolonged residence time in target tissues, leading to higher tissue concentration. The findings provide some scientific evidence for the mechanism of the combined use of acupuncture and herbal medicine. Furthermore, we suggest that acupuncture and its combination with herbal medicine should be investigated further as a possible adjuvant therapy in clinical treatment for liver injury.

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

    PubMed

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

    2014-12-03

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

  11. [Comparative study on pharmacokinetics and tissue distribution of a novel microemulsion based on the paclitaxel/L-OH lipid complex and paclitaxel injection in cremophor].

    PubMed

    Ma, Yan-li; Ye, Jun; Zhang, Peng-xiao; Xia, Xue-jun; Liu, Yu-ling

    2013-11-01

    The pharmacokinetics and tissue distributions of the novel paclitaxel microemulsion based on the L-OH lipid complex made in our laboratory were studied in this article with the commercial paclitaxel injection in cremophor as reference preparation by injected intravenously with single dose of 5 mg x kg(-1) in rats. LC-MS/MS method was used to determine the drug concentration in plasma and calculate the pharmacokinetic parameters. [3H]-paclitaxel was used to reveal the tissue distributions of different organs in 0.5 h, 3 h, 24 h and 120 h. The results indicated that the AUC of the emulsion group descended to 42.55%, with the CLz and Vz increased by 2.27 times and 3.81 times respectively. Tissue distribution results revealed that the emulsion showed a significantly increase in liver and spleen with a peak concentration up to 5 times; a slightly increase was observed in lung with no statistical differences; a significantly decrease in heart, kidney, gastrointestinal tract, bone marrow, aorta, thymus, pancreas, fat, muscle, skin, seminal vesicle, reproductive organs and brain with a drop of 40%-80%. These results indicated that paclitaxel microemulsion based on L-OH lipid complexes can remarkably reduced the blood exposure, accelerate plasma clearance rate and increase distribution volume. The fact that paclitaxel microemulsion tended to be uptake by reticuloendothelial system (RES) contributed to the target in liver, spleen and lung, and help to reduce the toxicity in blood, heart, kidney and gastrointestinal tract.

  12. Pharmacokinetics and tissue distribution of ginsenoside Rh2 and Rg3 epimers after oral administration of BST204, a purified ginseng dry extract, in rats.

    PubMed

    Bae, Soo Hyeon; Park, Jung Bae; Zheng, Yu Fen; Jang, Min Jung; Kim, Sun Ok; Kim, Jeom Yong; Yoo, Young Hyo; Yoon, Kee Dong; Oh, Euichaul; Bae, Soo Kyung

    2014-12-01

    1. BST204, a purified ginseng dry extract containing a high concentration of racemic Rh2 and Rg3 mixtures, is being developed for supportive care use in cancer patients in Korea. This study investigates the pharmacokinetics and tissue distribution of BST204 in rats. 2. After oral administration of BST204, only the S epimers, S-Rh2 and S-Rg3, could be determined in rat plasma. The poor absorption of the R-epimers, R-Rh2 and R-Rg3, may be attributed to lower membrane permeability and extensive intestinal oxygenation and/or deglycosylation into metabolites. The AUC and Cmax values of both S-Rh2 and S-Rg3 after BST204 oral administration were proportional to the administered BST204 doses ranged from 400 mg/kg to 2000 mg/kg, which suggested linear pharmacokinetic properties. 3. There were no statistically significant differences in the pharmacokinetics of S-Rh2 and S-Rg3 after oral administration of pure S-Rh2 (31.5 mg/kg) and S-Rg3 (68 mg/kg) compared with oral administration of BST204, 1000 mg/kg. These indicated that the presence of other components of BST204 extract did not influence the pharmacokinetic behavior of S-Rh2 and S-Rg3. 4. After oral dosing of BST204, S-Rh2 and S-Rg3 were distributed mainly to the liver and gastrointestinal tract in rats. 5. Our finding may help to understand pharmacokinetic characteristics of S-Rh2, R-Rh2, S-Rg3, and R-Rg3, comprehensively, and provide useful information in clinical application of BST204.

  13. Pharmacokinetics and tissue distribution of the new non-imidazole histamine H3 receptor antagonist 1-[3-(4-tert-butylphenoxy) propyl]piperidine in rats.

    PubMed

    Szafarz, Malgorzata; Kryczyk, Agata; Lazewska, Dorota; Kiec-Kononowicz, Katarzyna; Wyska, Elzbieta

    2015-01-01

    1. The aim of this study was to evaluate pharmacokinetics and tissue distribution of novel histamine H3 receptor antagonist 1-[3-(4-tert-butylphenoxy)propyl]piperidine (compound DL76). 2. Following intravenous administration of DL76 at the dose of 3 mg/kg, pharmacokinetic parameters were calculated using non-compartmental analysis. The systemic serum clearance was 10.08 L/h/kg and the estimated blood clearance was 5.64 L/h/kg. The volume of distribution at steady state was 16.1 L/kg which was greater than total body water, terminal half-life and MRT equalled 1.41 h and 1.6 h, respectively. The two-compartment pharmacokinetic model with enterohepatic circulation was also successfully fitted to the experimental data. 3. After systemic administration, DL76 was rapidly distributed into all organs studied (liver, kidney, brain, and lung). The highest AUC of DL76 was observed in lungs followed by brain, where the exposure to the investigated compound expressed as AUC was almost 30 times higher than in serum. 4. Bioavailability, calculated based on the area-under-the-concentration-time curve extrapolated to infinity after intravenous and intragastric administration of the dose 3 mg/kg, equalled 60.9%.

  14. 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

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

    PubMed

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

    2014-07-15

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

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

    PubMed

    Navolotskii, Denis V; Ivanenko, Natalya B; Solovyev, Nikolay D; Fedoros, Elena I; Panchenko, Andrey V

    2015-09-01

    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.

  17. Pharmacokinetics and tissue distribution of 14C-labeled grape polyphenols in the periphery and the central nervous system following oral administration.

    PubMed

    Janle, Elsa M; Lila, Mary Ann; Grannan, Michael; Wood, Lauren; Higgins, Aine; Yousef, Gad G; Rogers, Randy B; Kim, Helen; Jackson, George S; Ho, Lap; Weaver, Connie M

    2010-08-01

    Grape polyphenols confer potential health benefits, including prevention of neurodegenerative diseases. To determine the absorption and tissue distribution of the complex grape polyphenol mixture, (14)C-labeled polyphenols were biosynthesized by grape cell suspension cultures, during co-incubation with radioisotopically labeled sucrose, and fractionated into polyphenolic subfractions. The pharmacokinetics and distribution of grape polyphenols into blood, brain, and peripheral interstitial fluid were determined by tracking the (14)C label. The blood peak (14)C concentration of the fractions ranged from 15 minutes to 4 hours. Absorption and tissue distribution varied greatly between fractions. Concentrations in interstitial fluid were lower than in blood. The amount of residual label in the brain at 24 hours ranged from 0.1% to 1.7% of the dose, depending on the fraction. (14)C label found in the brain tissue and brain microdialysate indicated that grape polyphenols or their metabolites are able to cross the blood-brain barrier. Using (14)C-labeled plant polyphenols it is possible to track the compounds or their metabolic products into any tissue and determine distribution patterns in spite of low concentrations. A central question regarding the potential role of dietary polyphenolics in neurodegenerative research is whether they are bioavailable in the brain. Our observations indicate that some grape-derived polyphenolics do reach the brain, which suggests their potential value for applications in neurodegenerative disorders.

  18. Pharmacokinetics and tissue distribution after intravenous administration of a single dose of amphotericin B cochleates, a new lipid-based delivery system.

    PubMed

    Segarra, Ignacio; Movshin, Diane A; Zarif, Leila

    2002-08-01

    Model independent pharmacokinetic analysis of intravenous (iv) amphotericin B cochleates (CAMB), a new lipid-based drug delivery system, in mice (0.625 mg/kg) shows a two-phase disposition profile in blood [area under the curve of concentration versus time from time zero to infinity (AUC(0-infinity)) = 1.01 microg. h/mL, half-life (t((1/2))) = 11.68 h, volume of distribution at steady state (V(ss)) = 9.59 L/kg, clearance (CL) = 10.36 mL/min/kg and mean residence time from time 0 to infinity (MRT(0-infinity)) = 15.41 h). In target tissues, maximum time (t(max)) ranged from 2 min (spleen and lung) to 10 min (liver) and lungs presented the highest AMB concentration (16.4 microg. h/g) followed by liver (8.56 microg/g), and spleen (6.63 microg/g). In addition, liver and spleen presented the longest elution half-life (75.03 and 66.71 h, respectively), MRT(0-infinity) (98.4 and 86.3 h, respectively), and AMB exposure:liver AUC(0-infinity) = 474 and 116.4 microg. h/g for the spleen. The large V(ss) and the extensive tissue AUC indicate large and efficient ability of cochleates to penetrate and deliver AMB. Differences in tissue uptake mechanism and pharmacokinetic data suggest a crucial role of macrophages in CAMB clearance from blood as well as an essential role of the liver and the spleen in AMB distribution to target tissues.

  19. Pharmacokinetics, tissue distribution and excretion study of dl-praeruptorin A of Peucedanum praeruptorum in rats by liquid chromatography tandem mass spectrometry.

    PubMed

    Zhang, Z; Liu, Y Y; Su, M Q; Liang, X F; Wang, W F; Zhu, X

    2011-04-15

    dl-Praeruptorin A (Pd-Ia), isolated from Chinese traditional herbal medicine Peucedanum praeruptorum Dunn, has been proved to be a novel Ca²+-influx blocker and K+-channel opener, and displayed bright prospects in prevention and therapy of cardiac diseases. The aim of this study was to investigate the pharmacokinetics, tissue distribution and excretion of Pd-Ia in rats following a single intravenous (i.v.) administration. The levels of Pd-Ia in plasma, tissues, bile, urine and feces were measured by a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The results showed that Pd-Ia was rapidly distributed and then eliminated from rat plasma and manifested linear dynamics in dose range of 5-20 mg/kg. The mean elimination half-life (t(½) of Pd-Ia for 5, 10 and 20 mg/kg dose were 57.46, 60.87 and 59.01 min, respectively. The major distribution tissues of Pd-Ia in rats were spleen, heart and lung, and low polarity enabled Pd-Ia to cross the blood-brain barrier. There was no long-term accumulation of Pd-Ia in rat tissues. Total recoveries of Pd-Ia within 24 h were low (0.097% in bile, 0.120% in urine and 0.009% in feces), which might be resulted from liver first pass effect.

  20. 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

  1. A validated LC-MS/MS method for quantitative analysis of curcumin in mouse plasma and brain tissue and its application in pharmacokinetic and brain distribution studies.

    PubMed

    Ramalingam, Prakash; Ko, Young Tag

    2014-10-15

    Curcumin is a well-known multitherapeutic agent widely employed in neurodegenerative disorders and cancer. A selective, fast, and sensitive method employing liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was developed and validated for the simultaneous determination of curcumin in mouse plasma and brain tissue, by using salbutamol as an internal standard. Triple quadrupole mass detection with multiple reaction monitoring (MRM) mode was used to monitor the ion transitions, m/z of 369>285 for curcumin, and m/z of 240>148 for salbutamol. The method was validated for recovery, accuracy, precision, linearity, and applicability. The lower limits of quantification (LLOQ) in both matrices were 2.5ng/mL. The inter-day and intra-day precisions and accuracy values were within the Food and Drug Administration (FDA) acceptance criteria, for both matrixes. The method was successfully applied in pharmacokinetics and brain distribution studies of curcumin after intravenous administration of free curcumin and curcumin-loaded solid lipid nanoparticles to mice. Furthermore, the application of this method along with serial blood sampling in mice has led to significant reduction in animal use and dosage and drastic improvement in speed, throughput, and quality of pharmacokinetic parameters.

  2. Investigation on pharmacokinetics, tissue distribution and excretion of a novel platinum anticancer agent in rats by inductively coupled plasma mass spectrometry (ICP-MS).

    PubMed

    Zhao, Jie; Wen, Yanli; Zhang, Wei; Zhao, Di; Fan, Ali; Zhang, Yongjie; Deng, Shuhua; Wang, Xin; Liu, Qingwang; Lu, Yang; Wang, Zhimei; Gou, Shaohua; Chen, Xijing

    2014-08-01

    1. DN604 is a new platinum agent with encouraging anticancer activity. The present study was to explore the pharmacokinetic profiles, distribution and excretion of platinum in Sprague-Dawley rats after intravenous administration of DN604. A sensitive and selective inductively coupled plasma mass spectrometry (ICP-MS) method was established for determination of platinum in biological specimens. The pharmacokinetic parameters were calculated by a non-compartmental method. 2. The area under concentration-time curve AUC0-t and AUC0-∞ for platinum originating from DN604 at 10 mg/kg were 25.15 ± 1.29 and 28.72 ± 1.04 μg/hml, respectively. The mean residence time MRT was 36.59 ± 6.65 h. The volume of distribution Vz was 11.42 ± 2.49 l/kg and clearance CL was 0.18 ± 0.01 l/h/kg. In addition, the elimination half-life T1/2z was 44.83 ± 9.75 h. After intravenous administration of DN604, platinum was extensively distributed in most of tested tissues except brain. The majority of platinum excreted via urine, and its accumulative excretion ratio during the period of 120 h was 63.5% ± 7.7% for urine, but only 6.94% ± 0.11% for feces. 3. The satisfactory half-life, wide distribution and high excretion made this novel platinum agent worthy of further research and development.

  3. 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.

  4. A Bottom-Up Whole-Body Physiologically Based Pharmacokinetic Model to Mechanistically Predict Tissue Distribution and the Rate of Subcutaneous Absorption of Therapeutic Proteins.

    PubMed

    Gill, Katherine L; Gardner, Iain; Li, Linzhong; Jamei, Masoud

    2016-01-01

    The ability to predict subcutaneous (SC) absorption rate and tissue distribution of therapeutic proteins (TPs) using a bottom-up approach is highly desirable early in the drug development process prior to clinical data being available. A whole-body physiologically based pharmacokinetic (PBPK) model, requiring only a few drug parameters, to predict plasma and interstitial fluid concentrations of TPs in humans after intravenous and subcutaneous dosing has been developed. Movement of TPs between vascular and interstitial spaces was described by considering both convection and diffusion processes using a 2-pore framework. The model was optimised using a variety of literature sources, such as tissue lymph/plasma concentration ratios in humans and animals, information on the percentage of dose absorbed following SC dosing via lymph in animals and data showing loss of radiolabelled IgG from the SC dosing site in humans. The resultant model was used to predict t max and plasma concentration profiles for 12 TPs (molecular weight 8-150 kDa) following SC dosing. The predicted plasma concentration profiles were generally comparable to observed data. t max was predicted within 3-fold of reported values, with one third of the predictions within 0.8-1.25-fold. There was no systematic bias in simulated C max values, although a general trend for underprediction of t max was observed. No clear trend between prediction accuracy of t max and TP isoelectric point or molecular size was apparent. The mechanistic whole-body PBPK model described here can be applied to predict absorption rate of TPs into blood and movement into target tissues following SC dosing.

  5. The influence of distributional kinetics into a peripheral compartment on the pharmacokinetics of substrate partitioning between blood and brain tissue.

    PubMed

    Padowski, Jeannie M; Pollack, Gary M

    2011-12-01

    Development of CNS-targeted agents often focuses on identifying compounds with "good" CNS exposure (brain-to-blood partitioning >1). Some compounds undergoing enterohepatic recycling (ER) evidence a partition coefficient, K (p,brain) (expressed as C (brain) /C (plasma)), that exceeds and then decreases to (i.e., overshoots) a plateau (distribution equilibrium) value, rather than increasing monotonically to this value. This study tested the hypothesis that overshoot in K (p,brain) is due to substrate residence in a peripheral compartment. Simulations were based on a 3-compartment model with distributional clearances between central and brain (CL (br)) and central and peripheral (CL (d)) compartments and irreversible clearance from the central compartment (CL). Parameters were varied to investigate the relationship between overshoot and peripheral compartment volume (V (p)), and how this relationship was modulated by other model parameters. Overshoot magnitude and duration were characterized as peak C (brain)/C (plasma) relative to the plateau value (%OS) and time to reach plateau (TRP). Except for systems with high CL (d), increasing V (p) increased TRP and %OS. Increasing brain (V (br)) or central (V (c)) distribution volumes eliminated V (p)-related OS. Parallel increases in all clearances shortened TRP, but did not alter %OS. Increasing either CL or CL (d) individually increased %OS related to V (p), while increasing CL (br) decreased %OS. Under realistic peripheral distribution scenarios, C (brain)/C (plasma) may overshoot substantially K (p,brain) at distribution equilibrium. This observation suggests potential for erroneous assessment of brain disposition, particularly for compounds which exhibit a large apparent V (p), and emphasizes the need for complete understanding of distributional kinetics when evaluating brain uptake.

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

    PubMed

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

    2015-08-01

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

  7. Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue.

    PubMed

    Kuiper, Caroline; Vissers, Margreet C M; Hicks, Kevin O

    2014-12-01

    Ascorbate is delivered to cells via the vasculature, but its ability to penetrate into tissues remote from blood vessels is unknown. This is particularly relevant to solid tumors, which often contain regions with dysfunctional vasculature, with impaired oxygen and nutrient delivery, resulting in upregulation of the hypoxic response and also the likely depletion of essential plasma-derived biomolecules, such as ascorbate. In this study, we have utilized a well-established multicell-layered, three-dimensional pharmacokinetic model to measure ascorbate diffusion and transport parameters through dense tissue in vitro. Ascorbate was found to penetrate the tissue at a slightly lower rate than mannitol and to travel via the paracellular route. Uptake parameters into the cells were also determined. These data were fitted to the diffusion model, and simulations of ascorbate pharmacokinetics in normal tissue and in hypoxic tumor tissue were performed with varying input concentrations, ranging from normal dietary plasma levels (10-100 μM) to pharmacological levels (>1 mM) as seen with intravenous infusion. The data and simulations demonstrate heterogeneous distribution of ascorbate in tumor tissue at physiological blood levels and provide insight into the range of plasma ascorbate concentrations and exposure times needed to saturate all regions of a tumor. The predictions suggest that supraphysiological plasma ascorbate concentrations (>100 μM) are required to achieve effective delivery of ascorbate to poorly vascularized tumor tissue.

  8. 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.

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

    SciTech Connect

    Averbook, B.J.; Jeffes, E.B.; Yamamoto, R.S.; Masunaka, I.; Kobayashi, M.; Granger, G.A. )

    1989-08-01

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

  10. Pharmacokinetics and tissue distribution of docetaxel liposome mediated by a novel galactosylated cholesterol derivatives synthesized by lipase-catalyzed esterification in non-aqueous phase.

    PubMed

    Luo, Li-Hua; Zheng, Pin-Jing; Nie, Hua; Chen, Yu-Chao; Tong, Dan; Chen, Jin; Cheng, Yi

    2016-05-01

    The purpose of this study is to synthesize a novel galactosylated cholesterol derivative, cholesterol-diethenyl decanedioate-lactitol (CHS-DD-LA) through lipase-catalyzed esterification in non-aqueous and to evaluate the preparation, pharmacokinetics and biodistribution of docetaxel (DOC) liposomes modified with CHS-DD-LA (G-DOC-L), which may actively gather at the liver compared with the conventional DOC liposomes (DOC-L) and commercial dosage form of DOC injection (DOC-i). A rapid and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed for the determination of the DOC concentration in plasma and tissues with Taxol as the internal standard (IS). To measure the liver-targeting effect of the G-DOC-L, relative uptake rate (Re), peak concentration ratio (Ce), targeting efficiency (Te) and relative targeting efficiency (RTe) were reduced as the evaluation parameters. The results showed that the entrapment efficiency, particle size and Zeta potential of G-DOC-L was 76.8 ± 3.5%, 95.6 nm and 27.19 mV, respectively. After i.v. administration at the dose of 2.5 mg/kg in rats, a decrease in the AUC, MRT and an increase in CL (p < 0.05) were observed in the G-DOC-L group compared with DOC-L. All these results suggested that galactose-anchored liposomes could rapidly be removed from the circulation in vivo. The tissue distribution of G-DOC-L was widely different from that of DOC-L. The Re of G-DOC-L, DOC-L on liver was 4.011, 0.102; Ce was 3.391, 0.111; Te was 55.01, 3.08, respectively, demonstrating that G-DOC-L had an excellent effect on liver-targeting, which may help to improve the therapeutic effect of hepatic diseases.

  11. Nitro-fatty acid pharmacokinetics in the adipose tissue compartment.

    PubMed

    Fazzari, Marco; Khoo, Nicholas K H; Woodcock, Steven R; Jorkasky, Diane K; Li, Lihua; Schopfer, Francisco J; Freeman, Bruce A

    2017-02-01

    Electrophilic nitro-FAs (NO2-FAs) promote adaptive and anti-inflammatory cell signaling responses as a result of an electrophilic character that supports posttranslational protein modifications. A unique pharmacokinetic profile is expected for NO2-FAs because of an ability to undergo reversible reactions including Michael addition with cysteine-containing proteins and esterification into complex lipids. Herein, we report via quantitative whole-body autoradiography analysis of rats gavaged with radiolabeled 10-nitro-[(14)C]oleic acid, preferential accumulation in adipose tissue over 2 weeks. To better define the metabolism and incorporation of NO2-FAs and their metabolites in adipose tissue lipids, adipocyte cultures were supplemented with 10-nitro-oleic acid (10-NO2-OA), nitro-stearic acid, nitro-conjugated linoleic acid, and nitro-linolenic acid. Then, quantitative HPLC-MS/MS analysis was performed on adipocyte neutral and polar lipid fractions, both before and after acid hydrolysis of esterified FAs. NO2-FAs preferentially incorporated in monoacyl- and diacylglycerides, while reduced metabolites were highly enriched in triacylglycerides. This differential distribution profile was confirmed in vivo in the adipose tissue of NO2-OA-treated mice. This pattern of NO2-FA deposition lends new insight into the unique pharmacokinetics and pharmacologic actions that could be expected for this chemically-reactive class of endogenous signaling mediators and synthetic drug candidates.

  12. Utility of Oatp1a/1b-knockout and OATP1B1/3-humanized mice in the study of OATP-mediated pharmacokinetics and tissue distribution: case studies with pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein.

    PubMed

    Higgins, J William; Bao, Jing Q; Ke, Alice B; Manro, Jason R; Fallon, John K; Smith, Philip C; Zamek-Gliszczynski, Maciej J

    2014-01-01

    Although organic anion transporting polypeptide (OATP)-mediated hepatic uptake is generally conserved between rodents and humans at a gross pharmacokinetic level, the presence of three major hepatic OATPs with broad overlap in substrate and inhibitor affinity, and absence of rodent-human orthologs preclude clinical translation of single-gene knockout/knockin findings. At present, changes in pharmacokinetics and tissue distribution of pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein were studied in oatp1a/1b-knockout mice lacking the three major hepatic oatp isoforms, and in knockout mice with liver-specific knockin of human OATP1B1 or OATP1B3. Relative to wild-type controls, oatp1a/1b-knockout mice exhibited 1.6- to 19-fold increased intravenous and 2.1- to 115-fold increased oral drug exposure, due to 33%-75% decreased clearance, 14%-60% decreased volume of distribution, and ≤74-fold increased oral bioavailability, with the magnitude of change depending on the contribution of oatp1a/1b to pharmacokinetics. Hepatic drug distribution was 4.2- to 196-fold lower in oatp1a/1b-knockout mice; distributional attenuation was less notable in kidney, brain, cardiac, and skeletal muscle. Knockin of OATP1B1 or OATP1B3 partially restored control clearance, volume, and bioavailability values (24%-142% increase, ≤47% increase, and ≤77% decrease vs. knockout, respectively), such that knockin pharmacokinetic profiles were positioned between knockout and wild-type mice. Consistent with liver-specific humanization, only hepatic drug distribution was partially restored (1.3- to 6.5-fold increase vs. knockout). Exposure and liver distribution changes in OATP1B1-humanized versus knockout mice predicted the clinical impact of OATP1B1 on oral exposure and contribution to human hepatic uptake of statins within 1.7-fold, but only after correcting for human/humanized mouse liver relative protein expression factor (OATP1B1 = 2.2, OATP1B3 = 0.30).

  13. Pharmacokinetics and skin-tissue penetration of daptomycin in rats

    PubMed Central

    Matsumoto, Kazuaki; Kitaoka, Masashi; Kuroda, Yuko; Ikawa, Kazuro; Morikawa, Norifumi; Sasaki, Junichi; Iketani, Osamu; Iwata, Satoshi; Horino, Tetsuya; Hori, Seiji; Kizu, Junko

    2015-01-01

    Background Daptomycin is recommended for complicated skin and skin-structure infections. However, information on the penetration of daptomycin into skin is limited. Therefore, the aim of this in vivo investigation was to determine the pharmacokinetics and skin penetration of daptomycin in rats. Materials and methods Concentrations of daptomycin were determined by high-performance liquid chromatography. A noncompartmental pharmacokinetic analysis was conducted to estimate the rate and extent of daptomycin penetration from the systemic circulation into skin tissue. Since protein binding of daptomycin in rat serum was 89.3%, the free maximum concentration (Cmax) and free area under the curve from time 0 to infinity (AUC0–∞) for plasma were calculated as follows: fCmax, plasma = (1 – 0.893) × Cmax, plasma, fAUC0–∞, plasma = (1 – 0.893) × AUC0–∞, plasma. Results The following values (mean ± standard deviation) were obtained: 0.06±0 L/h/kg for total clearance (CLtotal), 0.44±0.06 hours for elimination-rate constant, 1.58±0.23 hours for half-life, 0.14±0.02 L/kg for steady-state volume distribution, and 2.28±0.33 hours for mean residence time. Time to Cmax was 3.0 hours for plasma and skin tissue. Cmax and AUC0–∞ for plasma were 175.8±5.1 μg/mL and 811.8±31.9 μg × h/mL, respectively. Cmax and AUC0–∞ for skin tissue were 19.1±1.7 μg/mL and 113.9±21.8 μg × h/mL, respectively. Furthermore, fCmax and fAUC0–∞ for plasma were 18.8 μg/mL and 86.9 μg × h/mL, respectively. The degrees of skin-tissue penetration, defined as the Cmax, skin tissue/fCmax, plasma ratio and AUC0–∞, skin tissue/fAUC0–∞, plasma ratio, were 1.0 and 1.3, respectively. Conclusion Daptomycin exhibited good penetration into skin tissue, supporting its use for the treatment of complicated skin and skin-structure infections. However, further studies are needed in infected patients in order to investigate the relationship between the antimicrobial efficacy

  14. Pharmacokinetics of SPECT radiopharmaceuticals for imaging hypoxic tissues.

    PubMed

    Wiebe, L I; Stypinski, D

    1996-09-01

    Although hypoxia has been known for decades to play an important role in the outcome of radiotherapy in oncology, and inspite of the contribution of hypoxia to a myriad of pathologies that involve vascular disease, the selective imaging of hypoxic tissue has attained prominence only within the past decade. Contemporary research in the hypoxia imaging field is based largely on radiosensitizer research of the 1960's and 1970's. Early sensitizer research identified a family of nitro-organic compounds, the N-1 substituted 2-nitroimidazoles as candidate drugs. The early champion, and still the reference standard for therapeutic radiosensitization of hypoxic tumor cells is misonidazole (MISO). Its peripheral neurotoxicity led to failure in clinical studies, but its biological, biophysical and biochemical properties have been investigated in detail and serve as a basis for further design, not only of sensitizers, but of diagnostic radiopharmaceuticals for imaging tissue hypoxia. Pharmacokinetic characterization of radiopharmaceuticals, specifically radiopharmaceuticals for imaging tissue hypoxia, has not been a central theme in their development. The advent of PET, through which quantitative determinations first became possible, opened the field for both descriptive and analytical radiopharmacokinetic studies. In SPECT, however, this approach is still undergoing refinement. This paper addresses some of the underlying issues in radiopharmaceutical pharmacokinetics. There is a paucity of published radiopharmacokinetic data for SPECT hypoxia imaging agents. Consequently, the pharmacokinetic issues for MISO are presented as a basis for development of pharmacokinetics for the chemically-related imaging agents. Properties of an hypoxia marker are described from a pharmacokinetic viewpoint, a theoretical model for descriptive pharmacokinetics is introduced and finally, recent pharmacokinetic studies from our laboratory are described.

  15. A Sensitive Amphotericin B Immunoassay for Pharmacokinetic and Distribution Studies

    PubMed Central

    Machard, Sophie; Theodoro, Frederic; Benech, Henri; Grognet, Jean-Marc; Ezan, Eric

    2000-01-01

    Since currently used assays of amphotericin B (AMB) lack sensitivity or are not easily adaptable in all laboratories, we have developed an enzyme immunoassay for AMB in biological fluids and tissues. Antibodies to AMB were raised in rabbits after administration of an AMB-bovine serum albumin conjugate. The enzymatic tracer was obtained by coupling AMB via its amino group to acetylcholinesterase (EC 3.1.1.7). These reagents were used for the development of a competitive immunoassay performed on microtitration plates. The limit of quantification was 100 pg/ml in plasma and 1 ng/g in tissues. The plasma assay was performed directly without extraction on a minimal volume of 0.1 ml. The intra- and interassay coefficients of variation were in the range of 5 to 17%, and the recoveries were 92 to 111% for AMB added to human plasma. The assay was applied to a pharmacokinetic study with mice given AMB intraperitoneally at the dose of 1 mg/kg. The drug distribution in selected compartments (plasma, liver, spleen, lung, and brain) was monitored until 72 h after administration. In conclusion, our assay is at least 100-fold more sensitive than previously described bioassays or chromatographic determinations of AMB and may be useful in studying the tissue pharmacokinetics of new AMB formulations and in drug monitoring in clinical situations. PMID:10681316

  16. 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)

    NASA Astrophysics Data System (ADS)

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

    2014-11-01

    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.

  17. Nanoparticle accumulation in angiogenic tissues: towards predictable pharmacokinetics.

    PubMed

    Yaehne, Kristin; Tekrony, Amy; Clancy, Aisling; Gregoriou, Yiota; Walker, John; Dean, Kwin; Nguyen, Trinh; Doiron, Amber; Rinker, Kristina; Jiang, Xiao Yu; Childs, Sarah; Cramb, David

    2013-09-23

    Nanoparticles are increasingly used in medical applications such as drug delivery, imaging, and biodiagnostics, particularly for cancer. The design of nanoparticles for tumor delivery has been largely empirical, owing to a lack of quantitative data on angiogenic tissue sequestration. Using fluorescence correlation spectroscopy, the deposition rate constants of nanoparticles into angiogenic blood vessel tissue are determined. It is shown that deposition is dependent on surface charge. Moreover, the size dependency strongly suggests that nanoparticles are taken up by a passive mechanism that depends largely on geometry. These findings imply that it is possible to tune nanoparticle pharmacokinetics simply by adjusting nanoparticle size.

  18. Pharmacokinetic and tissue distribution studies of 1,9-pyrazoloanthrone, a c-Jun-N-terminal kinase inhibitor in Wistar rats by a simple and sensitive HPLC method.

    PubMed

    Ambhore, Nilesh Sudhakar; Yamjala, Karthik; Mohire, Shubhashri; Raju, Kalidhindi Rama Satyanarayana; Mulukutla, Shashank; Murthy, Vishakantha; Tondhawada, Mahesh; Elango, Kannan

    2016-02-20

    JNK pathway activates c-Jun(s) which are responsible for cell apoptosis; as a result, inhibitors of JNK pathway have the potential to prevent dopaminergic neurons from death and decrease the loss of dopamine in substantia nigra pars compacta (SNpc). Recent in-vitro studies show that 1,9-pyrazoloanthrone (1,9-P) a potent JNK-3 inhibitor prevents the apoptosis of dopaminergic cells of brain. In the present study we formulated liposomes to increase the bioavailability of 1,9-P in the brain and developed a simple, sensitive and selective high performance liquid chromatographic method and validated for the estimation of 1,9-P in Wistar rat plasma and tissue samples. Plasma and tissue samples were extracted by protein precipitation technique using acetonitrile (ACN) and rasagiline as the internal standards. Chromatography was performed on Hibar C18 column with mobile phase of ammonium acetate (10mM, pH 8.0 adjusted with ammonia) and ACN at a flow rate of 1mL/min. The lower limit of quantification of the developed method was found to be 2.0ng/mL and 4.0ng/g in plasma and tissue samples respectively. The liposomes of 1,9-P administered to animals at the dose equivalent to 15mg/kg orally demonstrated remarkable absorption into the systemic circulation with maximum concentration (∼7500ng/mL) within 2.0h. The order of the area under curve was found to be kidney>liver>brain>lungs>spleen>heart. The liposomes of 1,9-P were rapidly taken up into brain and showed a good brain concentration after 2.0h; sustenance up to 4.0h was achieved which is better than 1,9-P solution.

  19. Ultra performance liquid chromatography coupled with electrospray and atmospheric pressure chemical ionization (ESCi)-quadrupole time-of-flight mass spectrometry with novel mass spectrometry(Elevated Energy) (MS(E)) data collection technique: determination and pharmacokinetics, tissue distribution and biliary excretion study of ergone in rat.

    PubMed

    Zhao, Ying-Yong; Cheng, Xian-Long; Wei, Feng; Bai, Xu; Lin, Rui-Chao

    2012-07-01

    Ergosta-4,6,8(14),22-tetraen-3-one (ergone) has been proved to have novel antitumor effects on HepG2 cells. The aim of this study was to investigate the pharmacokinetics, tissue distribution, and biliary excretion of ergone in rats following a single oral administration (5, 10, and 20 mg/kg). The levels of ergone in plasma, tissues, and bile were measured by ultra performance liquid chromatography coupled with electrospray and atmospheric pressure chemical ionization (ESCi)-quadrupole time-of-flight mass spectrometry with novel mass spectrometry(Elevated Energy) (MS(E)) data collection technique method. The results show ergone was distributed and eliminated from rat plasma and in non-linear pharmacokinetics from a dose range of 5-20 mg/kg. The ergone was found to distribute widely in the internal organs, with tissue concentrations in order of lungs, spleen, liver, intestine, kidneys, heart, stomach, parorchis, teasticles, and brain. At 12 h after dosing, the tissue concentrations in the organs were markedly decreased. The lungs, spleen, and liver were the dominant organs with high tissue concentrations that might be the primary sites for metabolism and elimination of ergone. Total recoveries of ergone within 24 h in bile were 34.14%.

  20. 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.

  1. Pharmacokinetics, pharmacodynamics, metabolism, distribution, and excretion of carfilzomib in rats.

    PubMed

    Yang, Jinfu; Wang, Zhengping; Fang, Ying; Jiang, Jing; Zhao, Frances; Wong, Hansen; Bennett, Mark K; Molineaux, Christopher J; Kirk, Christopher J

    2011-10-01

    Carfilzomib [(2S)-N-[(S)-1-[(S)-4-methyl-1-[(R)-2-methyloxiran-2-yl]-1-oxopentan-2-ylcarbamoyl]-2-phenylethyl]-2-[(S)-2-(2-morpholinoacetamido)-4-phenylbutanamido]-4-methylpentanamide, also known as PR-171] is a selective, irreversible proteasome inhibitor that has shown encouraging results in clinical trials in multiple myeloma. In this study, the pharmacokinetics, pharmacodynamics, metabolism, distribution, and excretion of carfilzomib in Sprague-Dawley rats were characterized. After intravenous administration, the plasma concentration of carfilzomib declined rapidly in a biphasic manner. Carfilzomib displayed high plasma clearance [195-319 ml/(min · kg)], a short-terminal half-life (5-20 min), and rapid and wide tissue distribution in rats. The exposure to carfilzomib (C(max) and area under the curve) increased dose proportionally from 2 to 4 mg/kg but less than dose proportionally from 4 to 8 mg/kg. The high clearance was mediated predominantly by extrahepatic metabolism through peptidase cleavage and epoxide hydrolysis. Carfilzomib was excreted mainly as metabolites resulting from peptidase cleavage. Carfilzomib and its major metabolites in urine and bile accounted for approximately 26 and 31% of the total dose, respectively, for a total of 57% within 24 h postdose. Despite the high systemic clearance, potent proteasome inhibition was observed in blood and a variety of tissues. Together with rapid and irreversible target binding, the high clearance may provide an advantage in that "unnecessary" exposure to the drug is minimized and potential drug-related side effects may be reduced.

  2. A Pharmacokinetic Model of a Tissue Implantable Cortisol Sensor.

    PubMed

    Lee, Michael A; Bakh, Naveed; Bisker, Gili; Brown, Emery N; Strano, Michael S

    2016-12-01

    Cortisol is an important glucocorticoid hormone whose biochemistry influences numerous physiological and pathological processes. Moreover, it is a biomarker of interest for a number of conditions, including posttraumatic stress disorder, Cushing's syndrome, Addison's disease, and others. An implantable biosensor capable of real time monitoring of cortisol concentrations in adipose tissue may revolutionize the diagnosis and treatment of these disorders, as well as provide an invaluable research tool. Toward this end, a mathematical model, informed by the physiological literature, is developed to predict dynamic cortisol concentrations in adipose, muscle, and brain tissues, where a significant number of important processes with cortisol occur. The pharmacokinetic model is applied to both a prototypical, healthy male patient and a previously studied Cushing's disease patient. The model can also be used to inform the design of an implantable sensor by optimizing the sensor dissociation constant, apparent delay time, and magnitude of the sensor output versus system dynamics. Measurements from such a sensor would help to determine systemic cortisol levels, providing much needed insight for proper medical treatment for various cortisol-related conditions.

  3. Impact of acute fat mobilization on the pharmacokinetics of the highly fat distributed compound TAK-357, investigated by physiologically-based pharmacokinetic (PBPK) modeling and simulation.

    PubMed

    Goto, Akihiko; Tagawa, Yoshihiko; Moriya, Yuu; Sato, Sho; Furukawa, Yoshiyuki; Wakabayashi, Takeshi; Tsukamoto, Tetsuya; DeJongh, Joost; van Steeg, Tamara J; Moriwaki, Toshiya; Asahi, Satoru

    2017-03-03

    In a dog toxicokinetic study, an unusual plasma concentration increase of the highly lipophilic compound TAK-357 was observed 2-weeks after termination of a 2-week repeated dosing in one dog with acute body weight loss. The present study investigates the cause of this increase. A physiologically based pharmacokinetic (PBPK) model was constructed using the rat and dog pharmacokinetic data. Using the constructed model, the TAK-357 concentration profile in case of body weight change was simulated. PBPK model-derived simulation suggested that redistribution from adipose tissues to plasma due to loss of body fat caused the observed concentration increase of TAK-357 in dog plasma. The analysis demonstrates that the disposition of a highly lipophilic and fat-distributed compound can be affected by acute changes in adipose tissue mass. PBPK modeling and simulation proved to be efficient tools for quantitative hypothesis testing of apparently atypical PK phenomena resulting from acute physiological changes.

  4. Pharmacokinetics and tissue residues of Telazol in free-ranging polar bears.

    PubMed

    Semple, H A; Gorecki, D K; Farley, S D; Ramsay, M A

    2000-10-01

    A pharmacokinetic and tissue residue study was conducted to assess the risks associated with human consumption of polar bears in arctic Canada that have been exposed to the immobilizing drug Telazol, a mixture of tiletamine hydrochloride and zolazepam hydrochloride. Twenty-two bears were remotely injected with about 10 mg/kg of Telazol. Following immobilization, serum samples were collected serially at regular intervals until the bears awakened. Sixteen of the bears were relocated and killed under permit by local hunters at various times from 0.5 to 11 days after dosing. Serum, kidney, muscle and adipose tissue samples were collected immediately after death. All samples were stored at -70 C until analysis by HPLC. The concentration-time data of tiletamine and zolazepam in serum during the immobilization period were fitted to curves by computer and the pharmacokinetic parameters assessed. In addition, the serum and tissue samples collected at the time of death were analyzed for both parent drugs, for one metabolite of tiletamine (CI-398), and for three metabolites of zolazepam (metabolites 1, 2 and 4). A one-compartment model with first-order absorption and elimination best fit the time-series data for the drugs in serum during the immobilization period. This model gave half-lives (mean +/- SE) for tiletamine and zolazepam of 1.8+/-0.2 h and 1.2+/-0.08 h, respectively, clearance values of 2.1+/-0.3 l x h(-1) x kg(-1) and 1.1+/-0.1 l x h(-1) x kg(-1), and volumes of distribution of 5.2+/-0.6 l/kg and 1.8+/-0.2 l/kg. The concentrations of both drugs and their metabolites declined rapidly to trace levels by 24 h post-dosing, although extremely low concentrations of some metabolites were encountered sporadically over the entire sampling period. In particular, zolazepam metabolite 2, remained detectable in fat and muscle tissue at the end of the study, 11 days after dosing. It was concluded that during immobilization, both tiletamine and zolazepam levels decline rapidly

  5. The pharmacokinetics and tissue levels of polymyxin B, colistin and gentamicin in calves.

    PubMed

    Ziv, G; Nouws, J F; van Ginneken, C A

    1982-03-01

    Following a single intravenous injection of polymyxin B, colistin (5 mg/kg, each) and gentamicin (3 mg/kg) to calves, the decline in serum antibiotic concentration generally suggested a three-compartment (open system) pharmacokinetic model. Tissue binding is a dominant factor in the distribution and elimination kinetics of the drugs. Less than 65% of the dose of polymyxin B and colistin was recovered in the urine during 48 h after treatment. Concentrations of nonbound polymyxin B and colistin in the kidney, liver, lung, heart, and skeletal muscles were similar to total (free and bound) serum drug levels, but considerably higher concentrations were found, in bound form, in chloroform-ethanol extracts of these organs. At 24 h after treatment, more than 50% of the doses of polymyxin B and colistin were present bound to the tissues; the largest amount was in the skeletal muscles. Gentamicin was concentrated in the kidney, predominantly in the free form. At 48 h after treatment the amount of gentamicin in the kidney was 6.3% of the administered dose, being more than five times greater than the corresponding amounts of polymyxin B and colistin. The extent of tissue uptake of polymyxin B and colistin limits the usefulness of kinetic values, which are derived from the analysis of serum drug levels, for the purpose of designing dosage schedules. The strong affinity of the polymyxins to the muscle tissue, and gentamicin to the kidney, can result in drug residues persisting in the body for several weeks.

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

    PubMed

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

    2014-10-01

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

  7. 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.

  8. 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

  9. Influence of molecular size on tissue distribution of antibody fragments

    PubMed Central

    Li, Zhe; Krippendorff, Ben-Fillippo; Sharma, Sharad; Walz, Antje C.; Lavé, Thierry; Shah, Dhaval K.

    2016-01-01

    Biodistribution coefficients (BC) allow estimation of the tissue concentrations of proteins based on the plasma pharmacokinetics. We have previously established the BC values for monoclonal antibodies. Here, this concept is extended by development of a relationship between protein size and BC values. The relationship was built by deriving the BC values for various antibody fragments of known molecular weight from published biodistribution studies. We found that there exists a simple exponential relationship between molecular weight and BC values that allows the prediction of tissue distribution of proteins based on molecular weight alone. The relationship was validated by a priori predicting BC values of 4 antibody fragments that were not used in building the relationship. The relationship was also used to derive BC50 values for all the tissues, which is the molecular weight increase that would result in 50% reduction in tissue uptake of a protein. The BC50 values for most tissues were found to be ~35 kDa. An ability to estimate tissue distribution of antibody fragments based on the BC vs. molecular size relationship established here may allow better understanding of the biologics concentrations in tissues responsible for efficacy or toxicity. This relationship can also be applied for rational development of new biotherapeutic modalities with optimal biodistribution properties to target (or avoid) specific tissues. PMID:26496429

  10. Influence of molecular size on tissue distribution of antibody fragments.

    PubMed

    Li, Zhe; Krippendorff, Ben-Fillippo; Sharma, Sharad; Walz, Antje C; Lavé, Thierry; Shah, Dhaval K

    2016-01-01

    Biodistribution coefficients (BC) allow estimation of the tissue concentrations of proteins based on the plasma pharmacokinetics. We have previously established the BC values for monoclonal antibodies. Here, this concept is extended by development of a relationship between protein size and BC values. The relationship was built by deriving the BC values for various antibody fragments of known molecular weight from published biodistribution studies. We found that there exists a simple exponential relationship between molecular weight and BC values that allows the prediction of tissue distribution of proteins based on molecular weight alone. The relationship was validated by a priori predicting BC values of 4 antibody fragments that were not used in building the relationship. The relationship was also used to derive BC50 values for all the tissues, which is the molecular weight increase that would result in 50% reduction in tissue uptake of a protein. The BC50 values for most tissues were found to be ~35 kDa. An ability to estimate tissue distribution of antibody fragments based on the BC vs. molecular size relationship established here may allow better understanding of the biologics concentrations in tissues responsible for efficacy or toxicity. This relationship can also be applied for rational development of new biotherapeutic modalities with optimal biodistribution properties to target (or avoid) specific tissues.

  11. Pharmacokinetics of bisphenol A in serum and adipose tissue following intravenous administration to adult female CD-1 mice.

    PubMed

    Doerge, Daniel R; Twaddle, Nathan C; Vanlandingham, Michelle; Fisher, Jeffrey W

    2012-06-01

    Bisphenol A (BPA) is an important industrial chemical used as the monomer for polycarbonate plastic and in epoxy resins for use in food can liners. Worldwide biomonitoring studies consistently find high prevalence of BPA conjugates in urine consistent with pervasive exposure at levels typically below 1 μg/kg bw/day. The current study used LC/MS/MS to measure serum pharmacokinetics of unconjugated (active) and conjugated (inactive) BPA in adult female CD-1 mice following intravenous (IV) injection, which produces higher serum levels by circumventing the processes of absorption from the GI tract and presystemic metabolism that occur after oral administration. Deuterated BPA (100 μg/kg bw) was used to avoid interference by background contamination from trace amounts of native BPA. Additionally, the pharmacokinetics of unconjugated BPA were determined in adipose tissue, a proposed site of action and "depot" for BPA. After IV injection, unconjugated BPA rapidly distributed out of the circulation (t(1/2)=0.2 h) and terminal elimination also proceeded rapidly (t(1/2)=0.8 h). Consistent with the degree of aqueous solubility, lipid/water solubility ratio, and partitioning from blood into adipose tissue in vivo, the levels of unconjugated BPA in mouse adipose tissue rapidly reached a maximal level (0.25 h) that did not exceed the serum maximum at the initial sampling time (0.08 h). Terminal elimination of unconjugated BPA from adipose tissue (t(1/2)=7.0 h) was similar to that for conjugated BPA in serum (t(1/2)=6.6 h) and <0.01% of the administered dose remained in adipose tissue after 24 h. These plasma and tissue kinetics are consistent with rapid equilibria and underscore the non-persistent nature of BPA, particularly when compared with slowly metabolized lipophilic organic pollutants like halogenated dibenzodioxins.

  12. 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.

  13. 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

  14. 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.

  15. [Pharmacokinetics and distribution of 5-Fu magnetic albumin deuto-microsphere in normal and tumor-bearing mice].

    PubMed

    Xu, Rong; Shi, Shao-Jun; Zhou, Shun-Chang; Zheng, Jian-Wei; Chen, Hui; Zou, Sheng-Quan; Zeng, Fan-Dian

    2007-01-01

    To observe the pharmacokinetic and tissue-distribution characters of 5-flourouracil magnetic albumin deuto-microsphere (5-Fu-MAD) in normal and tumor-bearing mice, HPLC method for the determination of 5-Fu in plasma and tissues was established and applied to determine 5-Fu in mouse plasma and tissue samples. A Flame atomic absorption spectrometer was used to detect the iron concentration in mouse tissue. Plasma concentration-time curves of free 5-Fu, 5-Fu-MAD and 5-Fu-MAD plus the magnetic frame (MF) conformed to two compartment model of first order absorption and they had C(max) of 34.9, 7.95 and 5.97 mg x L(-1); T1/2 (Ke) of 22.26, 76.0 and 124.6 min, V(d) of 3.28, 30.7 and 66.1 L x kg; AUC(0-t), of 233.9, 78.3 and 50.2 mg x min x L(-1); AUC(0-infinity) of 237.2, 89.3 and 68.1 mg x min x L(-1), respectively. The distribution of 5-Fu and iron was the highest in the plenty blood perfusion organs like the liver, tumor, spleen and lung, while lower in the kidney and heart and lowest in brain and muscle. The tissue distribution of muscle and tumor increased significantly when a magnetic frame was inserted there. The pharmacokinetics and tissue distribution of 5-Fu-MAD exhibited sustained-release and target characteristics.

  16. Two-level time-domain decomposition based distributed method for numerical solutions of pharmacokinetic models.

    PubMed

    Liu, Li; Lai, Choi-Hong; Zhou, Shao-Dan; Xie, Fen; Rui, Lu

    2011-04-01

    In order to predict variations of drug concentration during a given period of time, numerical solutions of pharmacokinetic models need to be obtained efficiently. Analytical solutions of linear pharmacokinetic models are usually obtained using the Laplace transform and inverse Laplace tables. The derivations of solutions to complex nonlinear models are tedious, and such solution process may be difficult to implement as a robust software code. For nonlinear models, the fourth-order Runge-Kutta (RK4) is the most classical numerical method in obtaining approximate numerical solutions, which is impossible to be implemented in distributed computing environments without much modification. The reason is that numerical solutions obtained by using RK4 can only be computed in sequential time steps. In this paper, time-domain decomposition methods are adapted for nonlinear pharmacokinetic models. The numerical Inverse Laplace method for PharmacoKinetic models (ILPK) is implemented to solve pharmacokinetic models with iterative inverse Laplace transform in each time interval. The distributed ILPK algorithm, which is based on a two-level time-domain decomposition concept, is proposed to improve its efficiency. Solutions on the coarser temporal mesh at the top level are obtained one by one, and then those on the finer temporal mesh at the bottom level are calculated concurrently by using those initial solutions that have been obtained at the top level decomposition. Accuracy and efficiency of the proposed algorithm and its distributed equivalent are investigated by using several test models. Results indicate that the ILPK algorithm and its distributed equivalent are good candidates for both linear and nonlinear pharmacokinetic models.

  17. Nonlinear mixed-effects models for pharmacokinetic data analysis: assessment of the random-effects distribution.

    PubMed

    Drikvandi, Reza

    2017-02-13

    Nonlinear mixed-effects models are frequently used for pharmacokinetic data analysis, and they account for inter-subject variability in pharmacokinetic parameters by incorporating subject-specific random effects into the model. The random effects are often assumed to follow a (multivariate) normal distribution. However, many articles have shown that misspecifying the random-effects distribution can introduce bias in the estimates of parameters and affect inferences about the random effects themselves, such as estimation of the inter-subject variability. Because random effects are unobservable latent variables, it is difficult to assess their distribution. In a recent paper we developed a diagnostic tool based on the so-called gradient function to assess the random-effects distribution in mixed models. There we evaluated the gradient function for generalized liner mixed models and in the presence of a single random effect. However, assessing the random-effects distribution in nonlinear mixed-effects models is more challenging, especially when multiple random effects are present, and therefore the results from linear and generalized linear mixed models may not be valid for such nonlinear models. In this paper, we further investigate the gradient function and evaluate its performance for such nonlinear mixed-effects models which are common in pharmacokinetics and pharmacodynamics. We use simulations as well as real data from an intensive pharmacokinetic study to illustrate the proposed diagnostic tool.

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

    PubMed

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

    2012-12-01

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

  19. Pharmacokinetics and Efficacy of Topically Applied Nonsteroidal Anti-Inflammatory Drugs in Retinochoroidal Tissues in Rabbits

    PubMed Central

    Kida, Tetsuo; Kozai, Seiko; Takahashi, Hiroaki; Isaka, Mitsuyoshi; Tokushige, Hideki; Sakamoto, Taiji

    2014-01-01

    Purpose To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) in the retinochoroidal tissues of rabbits. Methods The cyclooxygenase (COX) inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits. Results The half-maximal inhibitory concentration (IC50) of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC50 of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (P = 0.026) but not the other two NSAIDs. Conclusions Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit than diclofenac and

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

    PubMed Central

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

    2010-01-01

    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

  1. 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

  2. Usefulness of minipigs for predicting human pharmacokinetics: Prediction of distribution volume and plasma clearance.

    PubMed

    Yoshimatsu, Hiromichi; Konno, Yoshihiro; Ishii, Kunikazu; Satsukawa, Masahiro; Yamashita, Shinji

    2016-02-01

    In this study, advantages of minipigs to use in preclinical study for new drug development were evaluated in terms of prediction of human pharmacokinetic (PK) parameters of various drugs. Fourteen model drugs having diverse physicochemical properties were selected and intravenously administered to mice, rats and minipigs to obtain their PK parameters. The human volume of distribution (Vd) and clearance (CL) of model drugs were predicted from PK parameters in each animal species. When Vd of 14 drugs in each species were directly compared with those in humans, minipigs showed the highest correlation. Correction of Vd with an unbound fraction of drugs in tissues further improved the correlation. Allometric scaling that included minipig data resulted in high accuracy in the prediction of human Vd, clearly indicating an importance of minipig data. Minipigs also showed the high predictability of human CL. The prediction of human CL by allometric scaling showed a high accuracy when the data of minipigs were included. In conclusion, potential advantages of minipigs for predicting human Vd and CL were clearly demonstrated. Reliable prediction of human PK from data of minipigs appears to be possible in preclinical PK study, without relying on PK analysis in other species.

  3. Pharmacokinetics and tissue tolerance of azithromycin after intramuscular administration to rabbits.

    PubMed

    Escudero, E; Fernández-Varón, E; Marín, P; Espuny, A; Nájera, M D; Cárceles, C M

    2006-12-01

    The pharmacokinetics of azithromycin after intravenous and intramuscular injection at a single dose rate of 10mg/kg bodyweight were investigated in rabbits by using a modified agar diffusion bioassay for determining plasma concentrations. The plasma creatine kinase activity was determined after i.m. administration for the evaluation of the tissue tolerance. The elimination half-lives of azithromycin after intravenous and intramuscular administration were 24.1 and 25.1h, respectively. After intramuscular administration mean peak plasma concentration was 0.26+/-0.01 mg/L and bioavailability was 97.7%. Plasma CK activity rose sharply within 8h after i.m. injection of azithromycin; activity returned to pre-treatment level by 48-72 h post-treatment. The transient rise in serum CK activity indicates some degree of muscle tissue damage at the injection site.

  4. 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.

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

    PubMed

    Poulin, Patrick

    2015-07-01

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

  6. 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.

  7. 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

  8. Bioavailability, tissue distribution, and excretion characteristics of the novel carbonic anhydrase inhibitor tolsultazolamide in rats

    PubMed Central

    Wang, Jin-da; Shi, Yong-ping; Yin, Jing; Pan, Zhi-yuan; Cui, Wen-yu; Zhang, Yan-fang; Wang, Hai

    2014-01-01

    Aim: Tolsultazolamide, a novel carbonic anhydrase inhibitor, is designed for the prophylaxis and treatment of acute mountain sickness. The aim of this study was to investigate the pharmacokinetics, tissue distribution, and excretion characteristics of tolsultazolamide and the sex difference in pharmacokinetics in rats. Methods: For pharmacokinetic study, rats were intravenously injected tolsultazolamide at 1 and 2 mg/kg or orally administered tolsultazolamide at 20, 40, or 80 mg/kg) in a pharmacokinetic study. The concentrations of tolsultazolamide in plasma were determined with high-performance liquid chromatography, with a liquid–liquid extraction. For tissue distribution study, tolsultazolamide (80 mg/kg) was orally administered to overnight fasted rats (six per group and three per sex). Samples were collected from the brain, heart, lung, liver, spleen, muscle, kidney, stomach, fat, intestines, pancreas and sexual gland. For excretion study, tolsultazolamide (40 mg/kg) was orally administered to 6 rats (three per sex). The urine, feces, and bile samples were collected at 24, 48, and 72 h. Results: After its intravenous administration, tolsultazolamide was rapidly eliminated from the plasma, with T1/2 of about 60–90 min. The AUC0–t and the initial concentration (C0) values were proportional to the intravenous doses. After its oral administration, tolsultazolamide showed dose-independent pharmacokinetic characteristics, with Tmax and T1/2 of approximately 2 h and 5–7 h, respectively, and good oral absolute bioavailability of about 60%. Tolsultazolamide was distributed widely in various tissues. The highest tolsultazolamide levels were detected in the stomach, intestine, spleen, lung, and kidney. Total excretion of unchanged tolsultazolamide in the urine, feces, and bile was less than 2%. The Cmax and AUC of tolsultazolamide were significantly higher in female rats than those in male rats. Clearance and volume of distribution were greater in male rats than

  9. Single Dose Pharmacokinetics of Oral Tenofovir in Plasma, Peripheral Blood Mononuclear Cells, Colonic Tissue, and Vaginal Tissue

    PubMed Central

    Louissaint, Nicolette A.; Cao, Ying-Jun; Skipper, Paul L.; Liberman, Rosa G.; Tannenbaum, Steven R.; Nimmagadda, Sridhar; Anderson, Jean R.; Everts, Stephanie; Bakshi, Rahul; Fuchs, Edward J.

    2013-01-01

    Abstract HIV seroconversion outcomes in preexposure prophylaxis (PrEP) trials of oral tenofovir (TFV)-containing regimens are highly sensitive to drug concentration, yet less-than-daily dosing regimens are under study. Description of TFV and its active moiety, TFV diphosphate (TFV-DP), in blood, vaginal tissue, and colon tissue may guide the design and interpretation of PrEP clinical trials. Six healthy women were administered a single oral dose of 300 mg tenofovir disoproxil fumarate (TDF) and 4.3 mg (12.31 MBq, 333 μCi) 14C-TDF slurry. Blood was collected every 4 h for the first 24 h, then at 4, 8, 11, and 15 days postdosing. Colonic and vaginal samples (tissue, total and CD4+ cells, luminal fluid and cells) were collected 1, 8 and 15 days postdose. Samples were analyzed for TFV and TFV-DP. Plasma TFV demonstrated triphasic decay with terminal elimination half-life median [interquartile range (IQR)] 69 h (58–77). Peripheral blood mononuclear cell (PBMC) TFV-DP demonstrated biphasic peaks (median 12 h and 96 h) followed by a terminal 48 h (38–76) half-life; Cmax was 20 fmol/million cells (2–63). One day postdose, the TFV-DP paired colon:vaginal tissue concentration ratio was 1 or greater in all subjects' tissue homogenates, median 124 (range 1–281), but was not sustained. The ratio was lower and more variable in cells extracted from tissue. Among all sample types, TFV and TFV-DP half-life ranged from 23 to 139 h. PBMC TFV-DP rose slowly in the hours after dosing indicating that success with exposure-driven dosing regimens may be sensitive to timing of the dose prior to exposure. Colonic tissue homogenate TFV-DP concentrations were greater than in vaginal homogenate at 24 h, but not in cells extracted from tissue. These and the other pharmacokinetic findings will guide the interpretation and design of future PrEP trials. PMID:23600365

  10. 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

  11. 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

  12. Coefficient of distribution of some organophosphorous pesticides in rat tissue.

    PubMed

    Garcia-Repetto, R; Martinez, D; Repetto, M

    1995-06-01

    Coefficient of distribution in tissue is proposed as an indicator of the affinity of xenobiotics for different tissues and their tendency to accumulate. The present study shows the distribution of some organophosphorous pesticides in rat tissues. Using the coefficient of distribution we established the preference of these insecticides for the various tissues. Each pesticide had a specific pattern of affinity for different tissues.

  13. Pharmacokinetics of a single 1g dose of azithromycin in rectal tissue in men

    PubMed Central

    Rupasinghe, Thusitha W.; Simpson, Julie A.; Vodstrcil, Lenka A.; Fairley, Christopher K.; McConville, Malcolm J.; Hocking, Jane S.

    2017-01-01

    Chlamydia is the most common bacterial sexually transmitted infection among men who have sex with men. Repeat infection following treatment with 1g azithromycin is common and treatment failure of up to 22% has been reported. This study measured the pharmacokinetics of azithromycin in rectal tissue in men following a single 1g dose to assess whether azithromycin reaches the rectal site in adequate concentrations to kill chlamydia. Ten healthy men took a single oral dose of 1g azithromycin and provided nine self-collected swabs and one blood sample over 14 days. Participant demographics, medications, sexual behaviour, treatment side effects, lubricant use and douching practices were recorded with each swab. Drug concentration over time was determined using liquid chromatography–mass spectrometry and total exposure (AUC0-∞) was estimated from the concentration-time profiles. Following 1g of azithromycin, rectal concentrations peaked after a median of 24 hours (median 133mcg/g) and remained above the minimum inhibitory concentration for chlamydia (0.125mcg/mL) for at least 14 days in all men. AUC0-∞ was the highest ever reported in human tissue (13103((mcg/g).hr)). Tissue concentrations were not associated with weight (mg/kg), but data suggest that increased gastric pH could increase azithromycin levels and diarrhoea or use of water-based lubricants could decrease concentrations. High and sustained concentrations of azithromycin were found in rectal tissue following a single 1g dose suggesting that inadequate concentrations are unlikely to cause treatment failure. Factors effecting absorption (pH and diarrhoea) or drug depletion (douching and water-based lubricants) may be more important determinants of concentrations in situ. PMID:28350806

  14. 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.

  15. Pharmacokinetics of doxycycline and tissue concentrations of an experimental long-acting parenteral formulation of doxycycline in Wistar rats.

    PubMed

    Vargas-Estrada, Dinorah; Gutiérrez, Lilia; Juarez-Rodríguez, Ivan; Sumano, Héctor

    2008-01-01

    Doxycycline hyclate (CAS 24390-14-5, doxycycline-h), an antibacterial with time-dependent action, was formulated as a non-irritating long-acting parenteral formulation based on a beta-cyclodextrin: poloxamer-based matrix (doxycycline-h-LA). Tissue and serum concentrations vs time profile were investigated after its subcutaneous injection to Wistar rats. Serum concentration profiles and key pharmacokinetic (PK) variables of doxycycline-h-LA were compared to the corresponding profiles and PK values obtained with an aqueous formulation of doxycycline-h administered either intramuscularly, orally or intravenously to Wistar rats. In all groups, the dose was 10 mg/kg. Doxycycline-h-LA showed outstanding bioavailability (951% or 477% if a correction formula is considered), as compared to the one obtained with an aqueous formulation (106-82%, respectively). Corresponding values for maximum serum concentration were 3.19 microg/ml and 3.00 microg/ml, respectively, and elimination half-lives were completely different: 42.49 h and 2.77 h for doxycycline-h-LA and the aqueous formulation, respectively. Considering minimal inhibitory concentrations of doxycycline for sensitive and resistant bacteria (from < or = 0.5 to > or =1.5 microg/ml), doxycycline-h-LA could be injected every 2 or 3 days, while aqueous doxycycline-h would require a dosing interval from 7.5 to 11 h. But if tissue concentrations are taken as braking points, the dosing interval will vary from 48 to 94 h. For doxycycline-h-LA, mean tissue:serum ratios were 2:1 for lungs, 9.8:1 for kidneys and 2.2:1 for intestine homogenates. These values are in close agreement with those found for the distribution of doxycycline in other species.

  16. Physiologically-based pharmacokinetic analysis of grepafloxacin.

    PubMed

    Nakajima, Y; Hattori, K; Shinsei, M; Matsunaga, N; Iizasa, H; Sasabe, H; Akiyama, H; Miyanmoto, G; Nakashima, E

    2000-09-01

    Grepafloxacin (GPFX) is a synthetic new quinolone antimicrobial agent that possesses an extensive tissue distribution and exhibits a strong antibacterial activity in vivo. In this study, the tissue distribution characteristics of GPFX were examined using tissue concentration-time profiles following intravenous administration to rats. Subsequently, the pharmacokinetics of GPFX were analyzed based on the physiological pharmacokinetic model. The tissue-to-plasma partition coefficients (Kp) of GPFX in rats were high in all tissues except brain. A pharmacokinetic model for rabbits, monkeys and dogs was constructed using the tissue-to-plasma free concentration ratio (Kp,f) of GPFX in rats to simulate the GPFX concentration-time profile in plasma following intravenous administration of GPFX to each animal. The calculation-derived concentrations correlated well with the experimentally-derived data, suggesting that there are no interspecies differences in the high tissue distribution characteristics of GPFX. The clearance rates of GPFX in humans were predicted from the pharmacokinetic parameters of rats, rabbits, monkeys and dogs by an animal scale-up method and a pharmacokinetic model for humans was constructed. The GPFX concentration-time profiles in plasma, following oral administration of GPFX to humans, were predicted within 0.5-1.0 h of mean absorption time and the calculation-derived results were in good agreement with the experimental data. Thus, it is suggested that the concentration-time profile in plasma and all human organs can be predicted from the pharmacokinetic data of animals.

  17. Pharmacokinetics of unbound linezolid in plasma and tissue interstitium of critically ill patients after multiple dosing using microdialysis.

    PubMed

    Buerger, Cornelia; Plock, Nele; Dehghanyar, Pejman; Joukhadar, Christian; Kloft, Charlotte

    2006-07-01

    The antimicrobial agent linezolid is approved for the treatment of severe infections caused by, e.g., methicillin-resistant Staphylococcus strains. In order to evaluate the penetration of linezolid into the interstitial space fluid (ISF) of subcutaneous adipose tissue and skeletal muscle of the target population, a microdialysis study was performed with 12 patients with sepsis or septic shock after multiple intravenous infusions. Unbound linezolid concentrations were determined for plasma and microdialysates by use of a validated high-performance liquid chromatography method. Individual compartmental pharmacokinetic (PK) analysis was performed using WinNonlin. In vivo microdialysis was found to be feasible for the determination of unbound linezolid concentrations at steady state in the ISF of critically ill patients. On average, linezolid showed good distribution into ISF but with high interindividual variability. A two-compartment model was fitted to unbound concentrations in plasma with a geometric mean distribution volume of 62.9 liters and a mean clearance of 9.18 liters/h at steady state. However, disposition characteristics changed intraindividually within the time course. In addition, an integrated model for simultaneous prediction of concentrations in all matrices was developed and revealed similar results. Based on the model-predicted unbound concentrations in ISF, a scheme of more-frequent daily dosing of linezolid for some critically ill patients might be taken into consideration to avoid subinhibitory unbound concentrations in the infected tissue. The developed integrated model will be a valuable basis for further PK data analysis to explore refined dosing guidelines that achieve effective antimicrobial therapy in all patients by use of the population PK approach.

  18. The subcellular distribution of small molecules: from pharmacokinetics to synthetic biology.

    PubMed

    Zheng, Nan; Tsai, Hobart Ng; Zhang, Xinyuan; Rosania, Gus R

    2011-10-03

    The systemic pharmacokinetics and pharmacodynamics of small molecules are determined by subcellular transport phenomena. Although approaches used to study the subcellular distribution of small molecules have gradually evolved over the past several decades, experimental analysis and prediction of cellular pharmacokinetics remains a challenge. In this review, we survey the progress of subcellular distribution research since the 1960s, with a focus on the advantages, disadvantages and limitations of the various experimental techniques. Critical review of the existing body of knowledge points to many opportunities to advance the rational design of organelle-targeted chemical agents. These opportunities include (1) development of quantitative, non-fluorescence-based, whole cell methods and techniques to measure the subcellular distribution of chemical agents in multiple compartments; (2) exploratory experimentation with nonspecific transport probes that have not been enriched with putative, organelle-targeting features; (3) elaboration of hypothesis-driven, mechanistic and modeling-based approaches to guide experiments aimed at elucidating subcellular distribution and transport; and (4) introduction of revolutionary conceptual approaches borrowed from the field of synthetic biology combined with cutting edge experimental strategies. In our laboratory, state-of-the-art subcellular transport studies are now being aimed at understanding the formation of new intracellular membrane structures in response to drug therapy, exploring the function of drug-membrane complexes as intracellular drug depots, and synthesizing new organelles with extraordinary physical and chemical properties.

  19. Factors influencing elimination and distribution of fleroxacin: metaanalysis of individual data from 10 pharmacokinetic studies.

    PubMed Central

    Reigner, B G; Welker, H A

    1996-01-01

    A metaanalysis was conducted on data from 172 subjects (healthy volunteers and uninfected patients) included in 10 pharmacokinetic studies of fleroxacin after oral administration. The objectives of this analysis were (i) to estimate the typical values of two key pharmacokinetic parameters, clearance over systemic availability (CL/F) and volume of distribution over systemic availability (V/F), after the administration of therapeutic doses and (ii) to study qualitatively and quantitatively the factors which influence the elimination and distribution of fleroxacin. The main pharmacokinetic parameters, CL/F and V/F, were analyzed separately by a standard two-stage approach. The covariates investigated were predicted creatinine clearance (CLCR), age, gender, body surface area, body weight, and lean body weight (LBW). The predicted CL/F and V/F were 83.5 ml/min and 101 liters, respectively, for a typical male subject (CLCR, 70 ml/min; LBW, 54 kg; age, 54 years). Modeling of CL/F indicated that this parameter increases linearly with CLCR, decreases linearly with age, and is 10.8 ml/min lower in females than in males. The best model for V/F showed a linear increase with LBW and a linear decrease with age. V/F was found to be 20.4 liters greater in males than in females. In conclusion, this metaanalysis has shown that CLCR, age, and gender influence the elimination of fleroxacin from the body, whereas V/F is influenced by LBW, age, and gender. PMID:8851573

  20. ANF disappearance and tissue distribution in rats

    SciTech Connect

    Widimsky, J. Jr.; Debinski, W.; Kuchel, O.; Buu, N.T. )

    1990-01-01

    The disappearance of ({sup 125}I)atrial natriuretic factor (ANF; Ser99-Tyr126) from the circulation and its tissue distribution with or without nonlabeled ANF pretreatment were investigated in normotensive Sprague-Dawley rats. Preadministration of the cold peptide increased plasma radioactivity levels for over 8 min following labeled ANF injection but did not change the half-life of circulating labeled ANF. The metabolic clearance rate (MCR) and volume of distribution in the first, second, and steady state phase were significantly decreased after cold ANF pretreatment. Circulating iodo-labeled ANF was taken up by several organs, even by tissues such as fat or bone, but its urinary excretion was very low. The highest uptake was found in the liver (16 +/- 1% of the injected dose), lung (14 +/- 1%), and kidney (12 +/- 1%), diminishing by 21, 89, and 59%, respectively, after cold ANF preinjection. The brain radioactivity was negligible implying an inability of ({sup 125}I)ANF to cross the blood-brain barrier. Our data underscore the importance of the uptake-mediated, cold ANF preadministration suppressible clearance of ANF from the circulation, probably one of its basic elimination mechanisms. The liver, lung, and kidney are probably the most important participants in the MCR of ANF.

  1. 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%)

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

    PubMed

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

    2015-01-01

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

  3. 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 ...

  4. 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...

  5. 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

  6. 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.

  7. Blood and tissue distribution of posaconazole in a rat model of invasive pulmonary aspergillosis.

    PubMed

    Cendejas-Bueno, E; Forastiero, A; Ruiz, I; Mellado, E; Gavaldà, J; Gomez-Lopez, A

    2017-02-01

    Posaconazole is the recommended prophylactic agent in patients at high risk of invasive fungal infection, since adequate drug levels seem to be reached in target sites despite the relatively low levels detected in blood. The objective of this study is to obtain pharmacokinetic (PK) information associated to blood and tissue distribution of posaconazole in an animal model of invasive pulmonary aspergillosis. The PK parameters in lung samples were systematically higher than in serum. After multiple-dose administration of posaconazole, a significant accumulation of the drug was evident in lung tissue. The PK behavior of posaconazole in this particular experimental model is similar to that observed in humans. Thus, we believe this model could be a valid tool to evaluate posaconazole exposure-response relationship.

  8. 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.

  9. 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.

  10. Validated LC-MS/MS method for simultaneous quantification of resveratrol levels in mouse plasma and brain and its application to pharmacokinetic and brain distribution studies.

    PubMed

    Ramalingam, Prakash; Ko, Young Tag

    2016-02-05

    A rapid, selective, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determine resveratrol levels in plasma and brain tissue in mice for supporting pharmacokinetic and brain distribution studies. Analytes were separated using a Sepax BR-C18 analytical column (5μm, 120Å, 1.0×100mm) and eluted using an isocratic elution mobile phase acetonitrile and 0.01% formic acid [60:40, v/v] at a flow rate of 0.1mL/min. Precursor and product ion transitions for analyte resveratrol m/z 226.9>184.8 and curcumin m/z 367.1>148.9 were monitored using triple quadrupole mass spectrometer with multiple reaction monitoring (MRM) in negative ionization mode. The method was validated with respect to accuracy, within- and between-day precision, linearity, limit of quantification, recovery, and matrix effects of analyte. The inter- and intra-day accuracy and precision were within the range of the US Food and Drug Administration (FDA) acceptance criteria, for both matrices. The method was also successfully applied to pharmacokinetic and brain distribution studies of resveratrol after intravenous administration of free resveratrol and resveratrol-loaded solid lipid nanoparticles to mice. The combined use of serial blood sampling, small sample volume, simple extraction, and capillary depletion method drastically improved resveratrol analysis from biological matrices.

  11. Distribution of Oxycodone in Postmortem Fluids and Tissues

    DTIC Science & Technology

    2010-06-01

    Distribution of Oxycodone in Postmortem Fluids and Tissues Sabra R. Botch Robert D. Johnson Arvind K. Chaturvedi Russell J. Lewis Civil Aerospace...Title and Subtitle 5. Report Date June 2010 6. Performing Organization Code Distribution of Oxycodone in Postmortem Fluids and Tissues 7...16. Abstract Introduction: Oxycodone is a heavily used and abused analgesic agent. Its pharmacological effects, including euphoria, respiratory

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. Disposition and tissue distribution of imatinib in a liposome formulation after intravenous bolus dose to mice.

    PubMed

    Moo, Kai Shing; Radhakrishnan, Shantini; Teoh, Magdalene; Narayanan, Prasad; Bukhari, Nadeem Irfan; Segarra, Ignacio

    2010-07-01

    Imatinib is an efficacious anticancer drug with a spectrum of potential antitumour applications limited by poor biodistribution at therapeutic concentrations to the tissues of interest. We assess the pharmacokinetic and tissue distribution profile of imatinib in a liposome formulation. Its single dose (6.25 mg x kg(-1)) in a liposome formulation was administered iv to male mice. Imatinib concentration was measured in plasma, spleen, liver, kidney and brain using a HPLC assay. Non-compartmental pharmacokinetic approach was used to assess the disposition parameters. The plasma disposition profile was biphasic with a plateau-like second phase. The AUC(0-->infinity) was 11.24 microg x h x mL(-1), the elimination rate constant (k(el)) was 0.348 h(-1) and the elimination half life (t(1/2)) was 2.0 h. The mean residence time (MRT) was 2.59 h, V(SS) was 1.44 L x kg(-1) and clearance was 0.56 L x h x kg(-1). Liver achieved the highest tissue exposure: CMAX = 18.72 microg x mL(-1); AUC(0-->infinity)= 58.18 microg x h x mL(-1) and longest t(1/2) (4.29 h) and MRT (5.31 h). Kidney and spleen AUC(0-->infinity) were 47.98 microg x h x mL(-1) and 23.46 microg x h x mL(-1), respectively. Half-life was 1.83 h for the kidney and 3.37 h for the spleen. Imatinib penetrated into the brain reaching approximately 1 microg x g(-1). Upon correction by organ blood flow the spleen showed the largest uptake efficiency. Liposomal imatinib presented extensive biodistribution. The drug uptake kinetics showed mechanism differences amongst the tissues. These findings encourage the development of novel imatinib formulations to treat other cancers.

  17. [Delta-9-tetrahydrocannabinol pharmacokinetics].

    PubMed

    Goullé, J-P; Saussereau, E; Lacroix, C

    2008-08-01

    Delta-9-tetrahydrocannabinol (Delta-9-THC) is the main psychoactive ingredient of cannabis. Smoking is currently most common use of cannabis. The present review focuses on the pharmacokinetics of THC. The variability of THC in plant material which has significantly increased in recent years leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. This variability of THC content has an important impact on drug pharmacokinetics and pharmacology. After smoking THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level near 160 ng/mL occurs approximately 10 min after inhalation. THC is eliminated quickly from plasma in a multiphasic manner and is widely distributed to tissues, which is responsible for its pharmacologic effects. Body fat then serves as a long-term storage site. This particular pharmacokinetics explains the noncorrelation between THC blood level and clinical effects as is observed for ethanol. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20 and 100% of parent, respectively). The elimination of THC and its many metabolites, mainly THC-COOH, occurs via the feces and urine for several weeks. Thus, to confirm abstinence, urine THC-COOH analysis would be a useful tool. A positive result could be checked by gas chromatography-mass spectrometry THC blood analysis, indicative of a recent cannabis exposure.

  18. 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.

  19. Trace element concentration distributions in breast, lung and colon tissues

    NASA Astrophysics Data System (ADS)

    Majewska, Urszula; Banas, Dariusz; Braziewicz, Janusz; Gózdz, Stanislaw; Kubala-Kukus, Aldona; Kucharzewski, Marek

    2007-07-01

    The concentrations of Fe, Cu, Zn and Se in cancerous and benign tissues of breast, lung and intestine (colon) have been determined. In the cases when the element concentration has not been determined in all samples the Kaplan-Meier method has been used for the reconstruction of the original concentration distributions and estimation of the true mean concentrations and medians. Finally, the log-rank test has been applied to compare the elemental concentration distributions between cancerous and benign tissues of the same organ, between cancerous tissues and between benign tissues taken from different organs. Comparing benign and malignant neoplastic tissues, statistically significant differences have been found between Fe and Se concentration distributions of breast as well as for Cu and Zn in the case of lung tissues and in the case of colon tissues for Zn. The concentrations of all elements have been found to be statistically different in cancer tissues as well as in benign ones when comparing the different organs, i.e. groups 'breast-colon' and 'breast-lung'. Concentrations of Fe and Cu have been found to be statistically different in lung and colon cancerous tissues. For benign tissues of lung and colon a statistically significant difference has been found only for Zn.

  20. 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

  1. Scale up and pharmacokinetic study of a novel mutated chimeric tissue plasminogen activator (mt-PA) in rats

    PubMed Central

    Raigani, Mozhgan; Rouini, Mohammad-Reza; Golabchifar, Ali-Akbar; Mirabzadeh, Esmat; Vaziri, Behrouz; Barkhordari, Farzaneh; Davami, Fatemeh; Mahboudi, Fereidoun

    2017-01-01

    Because of high mortality caused by cardiovascular diseases, various fibrinolytic agents with diverse pharmacokinetic and pharmacodynamic properties have been developed. A novel mutated chimeric tissue plasminogen activator (mt-PA) was developed by the removal of first three domains of t-PA, insertion of GHRP sequence and mutation towards resistance to plasminogen activator inhibitor-1 (PAI-1). Mt-PA protein was expressed in Expi293F cells. The expression level of mt-PA was found to be 5000 IU/mL. Following purification, the pharmacokinetic properties of mt-PA were evaluated in three doses in rats. Data related to mt-PA were best fitted to two compartment model. With the increase in dose, the Area Under the plasma concentration-time Curve (AUC0→∞) increased. The elimination half-life (t1/2) of mt-PA was in the range of 19.1–26.1 min in three doses while that of Alteplase was 8.3 min. The plasma clearance (CLp) of mt-PA ranged from 3.8 to 5.9 mL/min in three doses, which was several times lower than that of Alteplase (142.6 mL/min). The mean residence time (MRT) of mt-PA ranged from 23.3–31.8 min in three doses, which was 4–5 times greater than that of Alteplase (6 min). Mt-PA showed extended half-life and mean residence time and is a good candidate for further clinical studies. PMID:28223717

  2. 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

    2016-03-07

    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

  3. 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)...

  4. 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

    2016-05-05

    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).

  5. Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling.

    PubMed

    Moss, Darren Michael; Siccardi, Marco

    2014-09-01

    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.

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

    PubMed

    Puliafito, Alberto; Primo, Luca; Celani, Antonio

    2017-03-01

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

  7. Biocompatible microemulsion modifies the tissue distribution of doxorubicin.

    PubMed

    Candido, Caroline Damico; Campos, Michel Leandro; Correa Vidigal Assumpção, Juliana Uruguay; Pestana, Kelly Chrystina; Padilha, Elias Carvalho; Carlos, Iracilda Zeppone; Peccinini, Rosângela Gonçalves

    2014-10-01

    The incorporation of doxorubicin (DOX) in a microemulsion (DOX-ME) has shown beneficial consequences by reducing the cardiotoxic effects of DOX. The aim of this study was to determine the distribution of DOX-ME in Ehrlich solid tumor (EST) and the heart, and compare it with that of free DOX. The distribution study was conducted with female Swiss mice with EST (n = 7 per group; 20-25 g). Animals received a single dose (10 mg/kg, i.p.) of DOX or DOX-ME 7 days after tumor inoculation. Fifteen minutes after administration, the animals were sacrificed, and the tumor and heart tissues were taken for immediate analysis by ultra-performance liquid chromatography. No difference was observed in DOX concentration in tumor tissue between DOX and DOX-ME administration. However, the most remarkable result in this study was the statistically significant reduction in DOX concentration in heart tissue of animals given DOX-ME. Mean DOX concentration in heart tissue was 0.92 ± 0.54 ng mg(-1) for DOX-ME and 1.85 ± 0.34 ng mg(-1) for free DOX. In conclusion, DOX-ME provides a better tissue distribution profile, with a lower drug concentration in heart tissue but still comparable tumor drug concentration, which indicates that antitumor activity would not be compromised.

  8. Distribution of tissue enzymes in three species of pinnipeds.

    PubMed

    Fauquier, Deborah A; Mazet, Jonna A K; Gulland, Frances M D; Spraker, Terry R; Christopher, Mary M

    2008-03-01

    In domestic animal medicine, changes in serum enzyme levels are routinely used as diagnostic tools to detect liver disease. Hepatic disease occurs in pinnipeds, but limited data are available on the tissue distribution of serum enzymes in marine mammals. The objectives of this study were to determine the tissue distribution of seven serum enzymes in three pinniped species. Enzymes evaluated were alanine aminotransferase (ALT), aspartate aminotransferase (AST), sorbitol dehydrogenase (SDH), lactate dehydrogenase (LDH), creatine kinase (CK), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) in tissues from California sea lions (Zalophus californianus) (n = 5), harbor seals (Phoca vitulina) (n = 5), and northern elephant seals (Mirounga angustirostris) (n = 5) that stranded and then died at a rehabilitation center. Samples were evaluated in duplicate from liver, skeletal muscle, cardiac muscle, kidney, adrenal, spleen, pancreas, lung, lymph node, and intestine. Patterns of tissue enzyme distribution were similar in all species, with SDH activity highest in liver and kidney, CK activity highest in skeletal and cardiac muscle, ALP activity highest in adrenal, and GGT activity highest in the kidney. Aspartate aminotransferase and LDH activities were less specific, with high activity in multiple tissues. Tissue ALT activity was high in the liver of all species, but was also high in cardiac muscle (California sea lions), skeletal muscle (harbor seals), and kidney (elephant seals). These results suggest that concurrent analysis of SDH, ALT, and CK would provide high specificity and sensitivity for the detection of hepatic lesions, and allow differentiation of liver from skeletal muscle lesions in pinniped species.

  9. Isatin, regional distribution in rat brain and tissues.

    PubMed

    Watkins, P; Clow, A; Glover, V; Halket, J; Przyborowska, A; Sandler, M

    1990-01-01

    Isatin has recently been identified in rat tissues and normal human urine, where it forms the major proportion of the endogenous monoamine oxidase inhibitor, tribulin. In this paper, we show that isatin, measured by gas chromatography/mass spectrometry, has a distinct regional distribution in rat tissues, with highest concentrations in seminal vesicles (1.6 ?g/g) and vas deferens (3.4 ?g/g). There was also a discontinuous distribution within rat brain, concentrations being highest in the hippocampus (0.13 ?g/g).

  10. 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.

  11. Plasma pharmacokinetics, tissue disposition, excretion and metabolism of vinleucinol in mice as determined by high-performance liquid chromatography.

    PubMed

    van Tellingen, O; Sonneveldt, A L; Beijnen, J H; Nooijen, W J; Kettenes-van den Bosch, J J; Versluis, C; Bult, A

    1994-01-01

    We investigated the pharmacokinetics of the experimental semisynthetic vinca alkaloid vinleucinol (VileE; O4-deacetyl-3-de(methoxycarbonyl)-3-[[[1-ethoxycarbonyl-2- methylbutyl]amino]carbonyl]-vincaleukoblastine). The study was performed in male FVB mice receiving 10.5 mg/kg VileE i.v. or p.o. Plasma, urine, faeces and tissue samples were analysed by a selective method based on ion-exchange normal-phase high-performance liquid chromatography (HPLC) with fluorescence detection and liquid-liquid extraction for sample clean-up. Apart from the parent drug, two other metabolic compounds were detected. One of these metabolites is vinleucinol acid (VileA; O4-deacetyl-3-de(methoxycarbonyl)-3-[[[1-carboxyl-2- methylbutyl]amino]carbonyl]-vincaleukoblastine), which possesses no cytotoxic activity. The structure proposed for the second metabolite (VileX) was based on tandem mass spectrometry (MS-MS) and infrared (IR) spectroscopy data. Metabolization of VileE to VileX must occur in the amino acid moiety of the molecule, with a (beta- or gamma-) lactone ring being formed after oxidation of the (beta- or gamma) carbon of the amino acid. VileX is a major metabolite, which is excreted in faeces and urine after i.v. administration and accounting for up to 23% of the administered dose. The activity of VileX against cultured L1210 cells is four times that of the parent drug VileE and comparable with that of vinblastine (VBL). At 48 h after administration of VileE, the concentration of VileX exceeds that of the parent drug in many tissues. These findings indicate that the metabolite VileX may be at least largely responsible for the activity observed against xenografts in mice after administration of the parent drug, VileE.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. Effect of ketoprofen and indomethacin on methotrexate pharmacokinetics in mice plasma and tumor tissues.

    PubMed

    Elmorsi, Yasmine M; El-Haggar, Sahar M; Ibrahim, Osama M; Mabrouk, Mokhtar M

    2013-03-01

    Methotrexate (MTX) has been used in combination with nonsteroidal anti-inflammatory drugs in the treatment of inflammatory diseases as well as malignancies. Severe adverse effects with this combination may occur, usually resulting from inhibition of renal transporters. Solid Ehrlich carcinoma was experimentally induced by implantation of Ehrlich ascites Carcinoma cells subcutaneously into the thigh of mice, and after 30 days, mice were divided into three groups: Group I that served as control group received MTX (50 mg/kg, i.p.); Group II received ketoprofen (100 mg/kg, i.p.) and then after half an hour received MTX (50 mg/kg, i.p.); Group III received indomethacin (10 mg/kg, i.p.) and then after half an hour received MTX (50 mg/kg, i.p.). Plasma and tissue samples were collected at different time points and then MTX concentrations were determined by HPLC. The injection of ketoprofen or indomethacin before MTX injection resulted in significant increase in the AUC and CPmax of MTX (p < 0.05) and significant decrease in CL/F and Vd/F of MTX (p < 0.05) in mice plasma. The effects were more significant after injection of indomethacin than in case of ketoprofen. The study showed that administration of ketoprofen or indomethacin prior to MTX caused significant decrease in MTX elimination and significant increase in MTX extent of absorption which may lead to severe adverse effects if coadministered in human.

  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. 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.

  19. 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.

  20. PK and tissue distribution of docetaxel in rabbits after i.v. administration of liposomal and injectable formulations.

    PubMed

    Zhao, Ling; Wei, Yu-Meng; Zhong, Xiao-Dong; Liang, Yan; Zhang, Xue-Mei; Li, Wei; Li, Bi-Bo; Wang, Ya; Yu, Yu

    2009-05-01

    A simple and sensitive HPLC method was established and validated for the determination of docetaxel (DTX) in rabbit plasma and tissue samples. Biosamples were spiked with paclitaxel as an internal standard and pre-treated by solid phase extraction (SPE). Sample separation was performed on a reverse-phase HPLC column at 30 degrees C by using a mobile phase of acetonitrile-methanol-0.02 M ammonium acetate buffer (pH 5.0) (20:47.5:32.5, v/v/v) at flow rate of 1.0 mL/min The UV absorbance of the samples was measured at the wavelength of 230 nm. The standard curves were linear over the ranges of 0.02525-2.525 microg/mL for plasma, 1.010-202.00 microg/g for lung, 0.202-20.20 microg/g for spleen, liver and kidney, 0.202-10.10 microg/g for heart and stomach, 0.0505-2.02 microg/g for brain, respectively. The limits of quantification (LOQ) were 10.0 ng/mL in the plasma samples and 20.0 ng/g in the tissue samples, respectively. The analysis method was successfully applied to pharmacokinetics and tissue distribution studies of DTX liposomes and DTX injection after i.v. administration to the rabbits. The results showed that the liposome carrier led to a significant difference in pharmacokinetics and tissue distribution profile compared to the conventional DTX injection.

  1. Paediatric pharmacokinetics: key considerations

    PubMed Central

    Batchelor, Hannah Katharine; Marriott, John Francis

    2015-01-01

    A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in paediatric populations compared with adults can influence the concentration of drug within the plasma or tissue. Healthcare professionals need to be aware of anatomical and physiological changes that affect pharmacokinetic profiles of drugs to understand consequences of dose adjustments in infants and children. Pharmacokinetic clinical trials in children are complicated owing to the limitations on blood sample volumes and perception of pain in children resulting from blood sampling. There are alternative sampling techniques that can minimize the invasive nature of such trials. Population based models can also limit the sampling required from each individual by increasing the overall sample size to generate robust pharmacokinetic data. This review details key considerations in the design and development of paediatric pharmacokinetic clinical trials. PMID:25855821

  2. Paediatric pharmacokinetics: key considerations.

    PubMed

    Batchelor, Hannah Katharine; Marriott, John Francis

    2015-03-01

    A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in paediatric populations compared with adults can influence the concentration of drug within the plasma or tissue. Healthcare professionals need to be aware of anatomical and physiological changes that affect pharmacokinetic profiles of drugs to understand consequences of dose adjustments in infants and children. Pharmacokinetic clinical trials in children are complicated owing to the limitations on blood sample volumes and perception of pain in children resulting from blood sampling. There are alternative sampling techniques that can minimize the invasive nature of such trials. Population based models can also limit the sampling required from each individual by increasing the overall sample size to generate robust pharmacokinetic data. This review details key considerations in the design and development of paediatric pharmacokinetic clinical trials.

  3. [Tissue distribution of arsenic of liushen pills and realgar].

    PubMed

    Zhang, Qing-Li; Wu, Qian; Xie, Yuan-Yuan; Shen, Lian-Zhong; Fan, Min-Wei; Liang, Qiong-Lin; Wang, Yi-Ming; Luo, Guo-An

    2011-06-01

    This study is to report the tissue distribution of arsenic after giving different doses of realgar and Liushen pills to Beagle dogs, in order to provide basis for the safety evaluation of Liushen pills. ICP-MS was used to measure arsenic concentration, and HPLC-ICP-MS was used to analyze arsenic speciation. The concentration of total arsenic and As(III) + DMA (arsenite + dimethylarsenic acid) increased with dosing of realgar. Total arsenic concentration in most tissues and As(III) + DMA concentration in all tissues of Liushen pills group are lower than that of realgar group, but AsB concentration in liver, spleen and kidney of Liushen pills group increased. The concentration of total arsenic showed a dose-dependent manner with dosage administered. It was indicated that components in Liushen pills can reduce solubility of arsenic in realgar, which may decrease toxicity of realgar.

  4. Distribution of B lymphocyte subsets in normal lymphoid tissue.

    PubMed Central

    Murray, L J; Swerdlow, S H; Habeshaw, J A

    1984-01-01

    Using the ABC avidin-biotin peroxidase techniques and a series of monoclonal antibodies against B cell associated antigens, the anatomical distribution of B lymphocyte subsets was studied in reactive lymph node, tonsil and spleen. Evidence is presented for at least five major phenotypically distinct B cell subsets, each localized to specific compartments of peripheral lymphoid tissue. The possible relationship of these subsets of B lymphocytes to activation, maturation and function in the B cell lineage is discussed. Images Fig. 2 PMID:6375918

  5. 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.

  6. Safety, Pharmacokinetics, Pharmacodynamics, and Plasma Lipoprotein Distribution of Eritoran (E5564) during Continuous Intravenous Infusion into Healthy Volunteers

    PubMed Central

    Rossignol, Daniel P.; Wasan, Kishor M.; Choo, Eugene; Yau, Edwin; Wong, Nancy; Rose, Jeffrey; Moran, Jeffrey; Lynn, Melvyn

    2004-01-01

    Eritoran, a structural analogue of the lipid A portion of lipopolysaccharide (LPS), is an antagonist of LPS in animal and human endotoxemia models. Previous studies have shown that low doses (350 to 3,500 μg) of eritoran have demonstrated a long pharmacokinetic half-life but a short pharmacodynamic half-life. The present study describes the safety, pharmacokinetics and pharmacodynamics, and lipid distribution profile of eritoran during and after a 72-h intravenous infusion of 500, 2,000, or 3,500 μg/h into healthy volunteers. Except for the occurrence of phlebitis, eritoran administration over 72 h was safe and well tolerated. Eritoran demonstrated a slow plasma clearance (0.679 to 0.930 ml/h/kg of body weight), a small volume of distribution (45.6 to 49.8 ml/kg), and a relatively long half-life (50.4 to 62.7 h). In plasma, the majority (∼55%) of eritoran was bound to high-density lipoproteins. During infusion and for up to 72 h thereafter, ex vivo response of blood to 1- or 10-ng/ml LPS was inhibited by ≥85%, even when the lowest dose of eritoran (500 μg/h) was infused. Inhibition of response was dependent on eritoran dose and the concentration of LPS used as an agonist. Finally, in vitro analysis with purified lipoprotein and protein fractions from plasma obtained from healthy volunteers indicated that eritoran is inactivated by high-density but not low-density lipoproteins, very-low-density lipoproteins, or albumin. From these results, we conclude that up to 252 mg of eritoran can be safely infused into normal volunteers over 72 h and even though it associates extensively with high-density lipoproteins, antagonistic activity is maintained, even after infusion ceases. PMID:15328078

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

    PubMed

    Berezhkovskiy, Leonid M

    2011-06-01

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

  8. 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.

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

    PubMed

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

    2015-01-01

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

  10. Pharmacokinetics and Brain Distribution and Metabolite Identification of Coptisine, a Protoberberine Alkaloid with Therapeutic Potential for CNS Disorders, in Rats.

    PubMed

    Su, Jin; Miao, Qing; Miao, Peipei; Zhao, Yuanyuan; Zhang, Yuanyuan; Chen, Ning; Zhang, Yujie; Ma, Shuangcheng

    2015-01-01

    Coptisine (COP), a protoberberine alkaloid (PBA) from Chinese medicinal plants (such as family Berberidaceae), may be useful for improving central nervous system disorders. However, its pharmacokinetics, disposition and metabolism are not well defined. In the present study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the analysis of COP in biological samples. To better understand its in vivo pharmacological activities, COP concentrations in rat plasma were determined after oral (50 mg/kg) and intravenous administration (10 mg/kg). For the brain distribution study, the concentration of COP in five different regions was examined after intravenous administration at 10 mg/kg. Pharmacokinetic parameters from the COP concentration-time profiles in plasma and brain, and the brain-to-plasma coefficient (Kp, brain) were calculated by non-compartmental analysis. The metabolites of COP in rats in vivo and in vitro (urine, bile, liver microsomes and intestinal bacteria incubation) were also identified. Seventeen metabolites, including 11 unconjugated metabolites formed by hydroxylation, hydrogenation, demethylation, dehydrogenation, demethylation, and 6 glucuronide and sulfate conjugates were identified for the first time. The results suggested that COP had low oral bioavailability of 8.9% and a short (plasma) half-life (T1/2=0.71 h) in rats. After intravenous administration, it quickly crossed the blood-brain barrier, accumulating at higher concentrations and then was slowly eliminated from different brain regions. Moreover, COP was transformed into metabolites through multiple metabolic pathways in vivo and in vitro. These results should help to promote further research on COP and contribute to clarifying the metabolic pathways of PBAs.

  11. Imepitoin as novel treatment option for canine idiopathic epilepsy: pharmacokinetics, distribution, and metabolism in dogs

    PubMed Central

    Rundfeldt, C; Gasparic, A; Wlaź, P

    2014-01-01

    Imepitoin is a novel anti-epileptic licensed in the European Union for the treatment of canine idiopathic epilepsy. The aim of this study was to characterize the pharmacokinetics of imepitoin in dogs and to evaluate the interaction with drug metabolizing enzymes. Upon administration of imepitoin tablets at a dose of 30 mg/kg to beagle dogs, high plasma levels were observed within 30 min following oral dosing, with maximal plasma concentrations of 14.9–17.2 μg/mL reached after 2–3 h. In a crossover study, co-administration of imepitoin tablets with food reduced the total AUC by 30%, but it did not result in significant changes in Tmax and Cmax, indicating lack of clinical relevance. No clinically relevant effects of sex and no accumulation or metabolic tolerance were observed upon twice daily dosing. Following single dose administration of 10–100 mg/kg, dose linearity was found. Administering [14C] imepitoin, high enteral absorption of 92% and primary fecal excretion were identified. Plasma protein binding was only 55%. At therapeutic plasma concentrations, imepitoin did not inhibit microsomal cytochrome P450 family liver enzymes in vitro. In rats, no relevant induction of liver enzymes was found. Therefore, protein binding or metabolism-derived drug–drug interactions are unlikely. Based on these data, imepitoin can be dosed twice daily, but the timing of tablet administration in relation to feeding should be kept consistent. PMID:24611573

  12. [Dalbavancin: pharmacokinetic and pharmacodynamic parameters].

    PubMed

    Azanza, José Ramón; Sádaba, Belén; Reis, Joana

    2017-01-01

    Dalbavancin is a new lipoglycopeptide antibiotic whose structure influences its pharmacokinetic profile. It is not absorbed after oral administration and is therefore administered intravenously. It is distributed through intracellular fluid, reaching adequate concentrations in the skin, bone, blister fluid and synovial fluid. Plasma protein binding is very high. Concentrations in brain tissue and cerebrospinal fluid (CSF) are inadequate. Excretion is through non-microsomal metabolism with inactive metabolites and through the kidneys by glomerular filtration. Dalbavancin is eliminated slowly, as shown by its clearance value and its terminal elimination half-life, which exceeds 300 hours. This means that adequate concentrations of the drug remain in plasma and tissues for a prolonged period and explains the dosing regimen: a first dose of 1g followed 7 days later by a 500mg dose. The pharmacokinetics are linear and show little intra- and interindividual variability. There are no pharmacokinetic interactions. Dose adjustment is not required for patients with mild or moderate renal insufficiency (creatinine clearance ≥ 30 to 79ml/min). Dosage adjustment is not required in patients regularly receiving elective haemodialysis (3 times/week) and the drug can be administered without consideration of haemodialysis times. In patients with chronic renal insufficiency, whose creatinine clearance is < 30ml/min and who are not regularly receiving elective haemodialysis, the recommended dose should be reduced to 750mg per week, followed 1 week later by 375mg. Dosage adjustment does not seem necessary in patients with liver failure or in older patients. There is no information on the most appropriate dosage in children. The pharmacokinetic/pharmacodynamics parameter that best describes the effectiveness of dalbavancin is the ratio between the area under the curve and the minimum inhibitory concentration.

  13. 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.

  14. Pharmacokinetics of TJ-8117 (Onpi-to), a drug for renal failure (I): Plasma concentration, distribution and excretion of [3H]-(-)epicatechin 3-O-gallate in rats and dogs.

    PubMed

    Takizawa, Yukiho; Nishimura, Hiroaki; Morota, Takashi; Tomisawa, Hiroki; Takeda, Shuichi; Aburada, Masaki

    2004-01-01

    TJ-8117 (Onpi-to) is an herbal medicine extracted from a mixture of five crude medicinals (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber), which has been developed as a drug for chronic renal failure. (-)Epicatechin 3-O-gallate (ECG), one of the active components of TJ-8117, was labeled with tritium and added to TJ-8117. Pharmacokinetics in plasma, tissue distribution and excretion of radioactivity were investigated following a single oral administration of TJ-8117 containing [3H]ECG ([3H]TJ-8117) in rats and dogs. 1. Following oral administration of [3H]TJ-8117, radioactivity exhibited linear pharmacokinetics in Cmax. Linearity of AUC(0-72 h) was lost at the highest dose of [3H]TJ-8117. Cmax and AUC(0-72 h) were higher in female rats than in male rats, a finding which suggested a sex difference in rats. Plasma levels of radioactivity displayed curves with one peak in dogs, which suggested a species difference between rats and dogs. 2. No accumulation was observed in any tissues in male rats. 3. Within 168 h after administration of [3H]TJ-8117 to male rats, 18.7%, 84.1% and 0.9% of the dose was excreted in urine, feces and expired air, respectively. Data from bile-duct cannulated rats indicated that at least 18.4% of the dose was absorbed.

  15. 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

  16. Natural killer cell distribution and trafficking in human tissues

    PubMed Central

    Carrega, Paolo; Ferlazzo, Guido

    2012-01-01

    Few data are available regarding the recirculation of natural killer (NK) cells among human organs. Earlier studies have been often impaired by the use of markers then proved to be either not sufficiently specific for NK cells (e.g., CD57, CD56) or expressed only by subsets of NK cells (e.g., CD16). At the present, available data confirmed that human NK cells populate blood, lymphoid organs, lung, liver, uterus (during pregnancy), and gut. Several studies showed that NK cell homing appears to be subset-specific, as secondary lymphoid organs and probably several solid tissues are preferentially inhabited by CD56brightCD16neg/dull non-cytotoxic NK cells. Similar studies performed in the mouse model showed that lymph node and bone marrow are preferentially populated by CD11bdull NK cells while blood, spleen, and lung by CD27dull NK cells. Therefore, an important topic to be addressed in the human system is the contribution of factors that regulate NK cell tissue homing and egress, such as chemotactic receptors or homeostatic mechanisms. Here, we review the current knowledge on NK cell distribution in peripheral tissues and, based on recent acquisitions, we propose our view regarding the recirculation of NK cells in the human body. PMID:23230434

  17. Tissue distribution of 3H-terbutaline in rabbits.

    PubMed

    Hsu, C H; Robinson, C P; Basmadjian, G P

    1994-01-01

    Terbutaline is a widely used, selective beta 2-adrenergic agonist whose penetration into brain has not been demonstrated in laboratory animals. Although its tissue uptake has been reported in some animals, no uptake into brain has been demonstrated. A single dose of 20 microCi of 3H-terbutaline along with 10 mg/kg of unlabeled terbutaline was injected into a rabbit marginal ear vein. The distribution of 3H-terbutaline in several tissues was determined 0.5, 1, 3, or 6 hr later. Radioactivity in the brain was well-maintained over the 6 hr observation period. In most tissues, radioactivity peaked in less than 1 hr, then declined. Radioactivity in the urine was high at all time periods and was highest at 3 hr. Thus, terbutaline or a metabolite(s) does cross the blood-brain barrier in rabbits, and the radioactivity in the rabbit brain does not decrease during the 6 hours following terbutaline injection.

  18. Selenium proteins in ovine tissues: III. Distribution of selenium and glutathione peroxidases in tissue cytosols.

    PubMed

    Black, R S; Tripp, M J; Whanger, P D; Weswig, P H

    1978-01-01

    Three 6 week-old lambs were injected with carrier-free selenium-75 as sodium selenite initially and again after 6 days. One lamb received no further injections whereas the other two received injections of either vitamin E or unlabeled Na2SeO3 when the first selenium-75 injection was given. Selected tissues were removed at autopsy 10 days after the first injection. The cytosol from homogenates of these tissues was subjected to gel chromatography, and the elution profiles determined for radioactivity, protein content, and glutathione peroxidase activity using either hydrogen peroxide or cumene hydroperoxide as substrates. The selenium-75 was found to be distributed mainly between 2 different MW peaks. The larger MW seleno-peak (90,000) possessed both glutathione:hydrogen peroxide oxidoreductase, and glutathione:cumene hydroperoxide oxidoreductase activities, but the smaller MW seleno-peak (about 10,000) possessed no glutathione peroxidase activity. A peak of about 60,000 daltons containing only glutathione:cumene hydroperoxide oxidoreductase activity and no selenium-75 was found primarily in the liver and kidney. Vitamin E had no effect on the elution profiles. Selenium status of the animal had only a minor effect on the selenium-75 distribution in the cytosol, but had a marked effect on the absolute amount of the label taken up by tissues.

  19. 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).

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

    PubMed

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

    2015-05-01

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

  1. 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.

  2. Pharmacokinetics of Tyrosol Metabolites in Rats.

    PubMed

    Lee, Da-Hye; Kim, Yang-Ji; Kim, Min Jung; Ahn, Jiyun; Ha, Tae-Youl; Lee, Sang Hee; Jang, Young Jin; Jung, Chang Hwa

    2016-01-21

    Tyrosol is considered a potential antioxidant; however, little is known regarding the pharmacokinetics of its metabolites. To study the pharmacokinetics of tyrosol-derived metabolites after oral administration of a single dose of tyrosol, we attempted to identify tyrosol metabolites in rat plasma by using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Two tyrosol metabolites (M1 and M2) were detected in the plasma. M1 was identified as tyrosol-4-sulfate (T4S) with an [M - H](-) ion at m/z 217. While M2 showed an [M - H](-) ion at m/z 151.0, its metabolite was not identified. Pharmacokinetic analysis of T4S and M2 showed rapid uptake after oral administration of tyrosol within 1 h. The metabolites were rapidly distributed in most organs and tissues and eliminated within 4 h. The greatest T4S deposition by tissue weight was observed in the liver, followed by the kidney and spleen, while M2 was most concentrated in the kidney followed by the liver and spleen. These findings indicate that T4S and M2 were distributed mainly in tissues with an abundant blood supply and were rapidly excreted in urine.

  3. Obstetric analgesia. Clinical pharmacokinetic considerations.

    PubMed

    Kanto, J

    1986-01-01

    All drugs used in obstetric analgesia are more or less lipophilic, their site of action is in the central nervous system, and they have good membrane penetrability in the fetomaternal unit. Thus the dose and method of administration as well as the duration of treatment are important clinical determinants of drug effects in the fetus and newborn. In the past, too much emphasis has been placed on fetomaternal blood concentration ratios of different agents; it is now appreciated that the extent of fetal tissue distribution and the neonatal elimination rate are pharmacokinetically much more important. Extensive fetal tissue distribution is reflected in a low fetomaternal drug concentration ratio, which may be followed by prolonged neonatal elimination of the drug. Currently, the most effective and safest method for obstetric analgesia is regional epidural administration of bupivacaine or lignocaine (lidocaine); only low doses are needed and the newborn is able to handle these agents efficiently. On the basis of pharmacokinetic and neurobehavioural assessments, inhalational anaesthetic agents appear to be more attractive than pethidine (meperidine) or benzodiazepines. Intermittent administration and fast pulmonary elimination of inhalational agents ensure that long-lasting residual effects are unlikely to occur. The kinetics of epidural and intrathecal opiates explain the problems associated with their use in obstetrics. Among the newer drugs used in obstetric analgesia, the properties of meptazinol and isoflurane appear interesting and these agents warrant further study. All drugs used in obstetric analgesia have a potentially detrimental effect on the neonate and, therefore, knowledge of fetal and neonatal pharmacokinetics is of importance to the clinician.

  4. Tissue distribution and subcellular localization of hyaluronan synthase isoenzymes.

    PubMed

    Törrönen, Kari; Nikunen, Kaisa; Kärnä, Riikka; Tammi, Markku; Tammi, Raija; Rilla, Kirsi

    2014-01-01

    Hyaluronan synthases (HAS) are unique plasma membrane glycosyltransferases secreting this glycosaminoglycan directly to the extracellular space. The three HAS isoenzymes (HAS1, HAS2, and HAS3) expressed in mammalian cells differ in their enzymatic properties and regulation by external stimuli, but clearly distinct functions have not been established. To overview the expression of different HAS isoenzymes during embryonic development and their subcellular localization, we immunostained mouse embryonic samples and cultured cells with HAS antibodies, correlating their distribution to hyaluronan staining. Their subcellular localization was further studied by GFP-HAS fusion proteins. Intense hyaluronan staining was observed throughout the development in the tissues of mesodermal origin, like heart and cartilages, but also for example during the maturation of kidneys and stratified epithelia. In general, staining for one or several HASs correlated with hyaluronan staining. The staining of HAS2 was most widespread, both spatially and temporally, correlating with hyaluronan staining especially in early mesenchymal tissues and heart. While epithelial cells were mostly negative for HASs, stratified epithelia became HAS positive during differentiation. All HAS isoenzymes showed cytoplasmic immunoreactivity, both in tissue sections and cultured cells, while plasma membrane staining was also detected, often in cellular extensions. HAS1 had brightest signal in Golgi, HAS3 in Golgi and microvillous protrusions, whereas most of the endogenous HAS2 immunoreactivity was localized in the ER. This differential pattern was also observed with transfected GFP-HASs. The large proportion of intracellular HASs suggests that HAS forms a reserve that is transported to the plasma membrane for rapid activation of hyaluronan synthesis.

  5. Polyester scaffolds with bimodal pore size distribution for tissue engineering.

    PubMed

    Sosnowski, Stanislaw; Woźniak, Piotr; Lewandowska-Szumieł, Małgorzata

    2006-06-16

    This paper presents a method for the preparation of porous poly(L-lactide)/poly[(L-lactide)-co-glycolide] scaffolds for tissue engineering. Scaffolds were prepared by a mold pressing-salt leaching technique from structured microparticles. The total porosity was in the range 70-85%. The pore size distribution was bimodal. Large pores, susceptible for osteoblasts growth and proliferation had the dimensions 50-400 microm. Small pores, dedicated to the diffusion of nutrients or/and metabolites of bone forming cells, as well as the products of hydrolysis of polyesters from the walls of the scaffold, had sizes in the range 2 nm-5 microm. The scaffolds had good mechanical strength (compressive modulus equal to 41 MPa and a strength of 1.64 MPa for 74% porosity). Scaffolds were tested in vitro with human osteoblast-like cells (MG-63). It was found that the viability of cells seeded within the scaffolds obtained using the mold pressing-salt leaching technique from structured microparticles was better when compared to cells cultured in scaffolds obtained by traditional methods. After 34 d of culture, cells within the tested scaffolds were organized in a tissue-like structure. Photos of section of macro- and mesoporous PLLA/PLGA scaffold containing 50 wt.-% of PLGA microspheres after 34 d of culture. Dark spots mark MG-63 cells, white areas belong to the scaffold. The specimen was stained with haematoxylin/eosin. Bar = 100 microm.

  6. Distribution of opiate alkaloids in brain tissue of experimental animals.

    PubMed

    Djurendic-Brenesel, Maja; Pilija, Vladimir; Mimica-Dukic, Neda; Budakov, Branislav; Cvjeticanin, Stanko

    2012-12-01

    The present study examined regional distribution of opiate alkaloids from seized heroin in brain regions of experimental animals in order to select parts with the highest content of opiates. Their analysis should contribute to resolve causes of death due to heroin intake. The tests were performed at different time periods (5, 15, 45 and 120 min) after male and female Wistar rats were treated with seized heroin. Opiate alkaloids (codeine, morphine, acetylcodeine, 6-acetylmorphine and 3,6-diacetylmorphine) were quantitatively determined in brain regions known for their high concentration of µ-opiate receptors: cortex, brainstem, amygdala and basal ganglia, by using gas chromatography-mass spectrometry (GC-MS). The highest content of opiate alkaloids in the brain tissue of female animals was found 15 min and in male animals 45 min after treatment. The highest content of opiates was determined in the basal ganglia of the animals of both genders, indicating that this part of brain tissue presents a reliable sample for identifying and assessing contents of opiates after heroin intake.

  7. Distribution of adenosine deaminase complexing protein (ADCP) in human tissues.

    PubMed

    Dinjens, W N; ten Kate, J; van der Linden, E P; Wijnen, J T; Khan, P M; Bosman, F T

    1989-12-01

    The normal distribution of adenosine deaminase complexing protein (ADCP) in the human body was investigated quantitatively by ADCP-specific radioimmunoassay (RIA) and qualitatively by immunohistochemistry. In these studies we used a specific rabbit anti-human ADCP antiserum. In all 19 investigated tissues, except erythrocytes, ADCP was found by RIA in the soluble and membrane fractions. From all tissues the membrane fractions contained more ADCP (expressed per mg protein) than the soluble fractions. High membrane ADCP concentrations were found in skin, renal cortex, gastrointestinal tract, and prostate. Immunoperoxidase staining confirmed the predominant membrane-associated localization of the protein. In serous sweat glands, convoluted tubules of renal cortex, bile canaliculi, gastrointestinal tract, lung, pancreas, prostate gland, salivary gland, gallbladder, mammary gland, and uterus, ADCP immunoreactivity was found confined to the luminal membranes of the epithelial cells. These data demonstrate that ADCP is present predominantly in exocrine glands and absorptive epithelia. The localization of ADCP at the secretory or absorptive apex of the cells suggests that the function of ADCP is related to the secretory and/or absorptive process.

  8. 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.

  9. Population Pharmacokinetic Modeling of the Unbound Levofloxacin Concentrations in Rat Plasma and Prostate Tissue Measured by Microdialysis

    PubMed Central

    Hurtado, Felipe K.; Weber, Benjamin; Derendorf, Hartmut; Hochhaus, Guenther

    2014-01-01

    Levofloxacin is a broad-spectrum fluoroquinolone used in the treatment of both acute and chronic bacterial prostatitis. Currently, the treatment of bacterial prostatitis is still difficult, especially due to the poor distribution of many antimicrobials into the prostate, thus preventing the drug to reach effective interstitial concentrations at the infection site. Newer fluoroquinolones show a greater penetration into the prostate. In the present study, we compared the unbound levofloxacin prostate concentrations measured by microdialysis to those in plasma after a 7-mg/kg intravenous bolus dose to Wistar rats. Plasma and dialysate samples were analyzed using a validated high-pressure liquid chromatography-fluorescence method. Both noncompartmental analysis (NCA) and population-based compartmental modeling (NONMEM 6) were performed. Unbound prostate tissue concentrations represented 78% of unbound plasma levels over a period of 12 h by comparing the extent of exposure (unbound AUC0–∞) of 6.4 and 4.8 h·μg/ml in plasma and tissue, respectively. A three-compartment model with simultaneous passive diffusion and saturable distribution kinetics from the prostate to the central compartment gave the best results in terms of curve fitting, precision of parameter estimates, and model stability. The following parameter values were estimated by the population model: V1 (0.38 liter; where V1 represents the volume of the central compartment), CL (0.22 liter/h), k12 (2.27 h−1), k21 (1.44 h−1), k13 (0.69 h−1), Vmax (7.19 μg/h), kM (0.35 μg/ml), V3/fuprostate (0.05 liter; where fuprostate represents the fraction unbound in the prostate), and k31 (3.67 h−1). The interindividual variability values for V1, CL, Vmax, and kM were 21, 37, 42, and 76%, respectively. Our results suggest that levofloxacin is likely to be substrate for efflux transporters in the prostate. PMID:24217697

  10. Population pharmacokinetic modeling of the unbound levofloxacin concentrations in rat plasma and prostate tissue measured by microdialysis.

    PubMed

    Hurtado, Felipe K; Weber, Benjamin; Derendorf, Hartmut; Hochhaus, Guenther; Dalla Costa, Teresa

    2014-01-01

    Levofloxacin is a broad-spectrum fluoroquinolone used in the treatment of both acute and chronic bacterial prostatitis. Currently, the treatment of bacterial prostatitis is still difficult, especially due to the poor distribution of many antimicrobials into the prostate, thus preventing the drug to reach effective interstitial concentrations at the infection site. Newer fluoroquinolones show a greater penetration into the prostate. In the present study, we compared the unbound levofloxacin prostate concentrations measured by microdialysis to those in plasma after a 7-mg/kg intravenous bolus dose to Wistar rats. Plasma and dialysate samples were analyzed using a validated high-pressure liquid chromatography-fluorescence method. Both noncompartmental analysis (NCA) and population-based compartmental modeling (NONMEM 6) were performed. Unbound prostate tissue concentrations represented 78% of unbound plasma levels over a period of 12 h by comparing the extent of exposure (unbound AUC0-∞) of 6.4 and 4.8 h·μg/ml in plasma and tissue, respectively. A three-compartment model with simultaneous passive diffusion and saturable distribution kinetics from the prostate to the central compartment gave the best results in terms of curve fitting, precision of parameter estimates, and model stability. The following parameter values were estimated by the population model: V1 (0.38 liter; where V1 represents the volume of the central compartment), CL (0.22 liter/h), k12 (2.27 h(-1)), k21 (1.44 h(-1)), k13 (0.69 h(-1)), Vmax (7.19 μg/h), kM (0.35 μg/ml), V3/fuprostate (0.05 liter; where fuprostate represents the fraction unbound in the prostate), and k31 (3.67 h(-1)). The interindividual variability values for V1, CL, Vmax, and kM were 21, 37, 42, and 76%, respectively. Our results suggest that levofloxacin is likely to be substrate for efflux transporters in the prostate.

  11. A tissue dose-based comparative exposure assessment of manganese using physiologically based pharmacokinetic modeling-The importance of homeostatic control for an essential metal.

    PubMed

    Gentry, P Robinan; Van Landingham, Cynthia; Fuller, William G; Sulsky, Sandra I; Greene, Tracy B; Clewell, Harvey J; Andersen, Melvin E; Roels, Harry A; Taylor, Michael D; Keene, Athena M

    2017-02-22

    A physiologically-based pharmacokinetic (PBPK) model (Schroeter et al., 2011) was applied to simulate target tissue manganese (Mn) concentrations following occupational and environmental exposures. These estimates of target tissue Mn concentrations were compared to determine margins of safety (MOS) and to evaluate the biological relevance of applying safety factors to derive acceptable Mn air concentrations. Mn blood concentrations measured in occupational studies permitted verification of the human PBPK models, increasing confidence in the resulting estimates. Mn exposure was determined based on measured ambient air Mn concentrations and dietary data in Canada and the United States (US). Incorporating dietary and inhalation exposures into the models indicated that increases in target tissue concentrations above endogenous levels only begin to occur when humans are exposed to levels of Mn in ambient air (i.e. >10μg/m(3)) that are far higher than those currently measured in Canada or the US. A MOS greater than three orders of magnitude was observed, indicating that current Mn air concentrations are far below concentrations that would be required to produce the target tissue Mn concentrations associated with subclinical neurological effects. This application of PBPK modeling for an essential element clearly demonstrates that the conventional application of default factors to "convert" an occupational exposure to an equivalent continuous environmental exposure, followed by the application of safety factors, is not appropriate in the case of Mn. PBPK modeling demonstrates that the relationship between ambient Mn exposures and dose-to-target tissue is not linear due to normal tissue background levels and homeostatic controls.

  12. The Tissue Distribution of Nesfatin-1/NUCB2 in Mouse

    PubMed Central

    Kim, Jinhee; Chung, Yiwa; Kim, Heejeong; Im, Eunji; Lee, Hyojin; Yang, Hyunwon

    2014-01-01

    Nesfatin-1, an anorexic nucleobindin-2 (NUCB2)-derived hypothalamic peptide, controls appetite and energy metabolism. Recent studies show that nesfatin-1/NUCB2 is expressed not only in the brain but also in gastric and adipose tissues. Thus, we investigated the distributions of nesfatin-1/NUCB2 in various tissues of male and female mice by real-time PCR, western blotting, and immunohistochemical staining. Real-time PCR analyses showed that NUCB2 mRNA was predominantly expressed in the pituitary and at lower levels in the hypothalamus, spleen, thymus, heart, liver, and muscle of both male and female mice. Expression was much higher in reproductive organs, such as the testis, epididymis, ovary, and uterus, than in the hypothalamus. Western blot analysis of the nesfatin-1 protein level showed similar results to the real-time PCR analyses in both male and female mice. These results suggest that nesfatin-1/NUCB2 have widespread physiological effects in endocrine and non-endocrine organs. In addition, immunohistochemical staining revealed that nesfatin-1 was localized in interstitial cells, including Leydig cells and in the columnar epithelium of the epididymis. Nesfatin-1 was also expressed in theca cells and interstitial cells in the ovary and in epithelial cells of the endometrium and uterine glands in the uterus. These results suggest that nesfatin-1 is a novel potent regulator of steroidogenesis and gonadal function in male and female reproductive organs. Further studies are required to elucidate the functions of nesfatin-1 in various organs of male and female mice. PMID:25949201

  13. [The pharmacokinetics of monoclonal antibodies].

    PubMed

    Keizer, R J; Huitema, A D R; Damen, C W N; Schellens, J H M; Beijnen, J H

    2007-03-24

    Monoclonal antibodies (MOABs) are, due to their specificity, increasingly being deployed for therapeutic purposes. MOABs are derived from immunoglobulins and are fully or partially of murine or human origin. They are administered parenterally: mostly intravenously, but subcutaneous or intramuscular administration is also possible, in which case absorption probably occurs through the lymphatic system. The distribution of MOABs from the bloodstream into the tissues is slow and is hampered by the high molecular size of the MOABs, which is a lesser problem for fragments of antibodies (Fab fragments). MOABs are metabolised to peptides and amino acids. This process takes place in many tissues of the body, but probably predominantly in epithelial cells. As a consequence of the saturable binding of the MOAB to its target, a dose-dependent (non-linear) elimination is often observed. Immune reactions can accelerate the elimination of antibodies, partially depending on the degree ofhumanisation of the antibody. Antibodies and endogenous immunoglobulins are protected from elimination by binding to protective receptors (neonatal Fc-receptor; FcRn), which explains their long half-lives (up to 4 weeks). Metabolic pharmacokinetic interactions with other drugs have not been reported and are not expected. It is expected that in the years to come, new MOABs directed towards new targets will appear on the market, as well as existing antibodies with improved pharmacokinetic properties.

  14. 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.

  15. Cellular localization and tissue distribution of endogenous DFCP1 protein.

    PubMed

    Nanao, Tomohisa; Koike, Masato; Yamaguchi, Junji; Sasaki, Mitsuho; Uchiyama, Yasuo

    2015-01-01

    Autophagy is essential for the maintenance of cellular metabolism. Once autophagy is induced in cells, the isolation membrane forms a so-called phagophore. The endoplasmic reticulum (ER) is one of several candidates for the membrane source for phagophores. Recently, LC3-positive isolation membranes were found to emerge from a DFCP1 (double FYVE domain-containing protein)-positive, ER-associated compartment called the omegasome. Although the GFP-tagged DFCP1 protein has been examined in cultured cells, little is known about the precise cellular and tissue distribution of this endogenous protein. To determine the expression of the endogenous DFCP1 protein, we produced antibodies specific to mouse DFCP1 protein. The antibody recognized both human and mouse DFCP1 proteins, both of which have molecular masses of approximately 87 kDa. In HeLa cells under normal conditions, immunoreactivity for DFCP1 was found dotted or tubular along Tom20-positive filamentous mitochondria and was only partially co-localized in the ER or Golgi apparatus. Moreover, under starved conditions, distinct DFCP1-positive structures became more dotted and scattered in the cytoplasm, while one part of the LC3-positive autophagosomes were immunopositive for DFCP1. These results indicate that an antibody raised against DFCP1 could be a useful tool in explaining the mechanism of phagophore formation from omegasome compartments.

  16. Spatial tissue distribution of polyacetylenes in carrot root.

    PubMed

    Baranska, Malgorzata; Schulz, Hartwig

    2005-06-01

    The presented results show the usefulness of Raman spectroscopy in the investigation of polyacetylenes in carrot root. The components are measured directly in the plant tissue without any preliminary sample preparation. Compared with the strong polyacetylene signals the spectral impact of the surrounding biological matrix is weak, except for carotenoids, and therefore it does not contribute significantly to the obtained results. Three different Raman mapping techniques applied here have revealed essential information about the investigated compounds. Using point acquisition several spectra have been measured to demonstrate the complex composition of the polyacetylene fraction in carrot root. The molecular structures of falcarinol, falcarindiol and falcarindiol 3-acetate are similar but their Raman spectra exhibit differences demonstrated by the shift of their -C triple bond C- mode. Line mapping performed along the diameter of transversely cut carrot roots has been used to investigate the relative concentration of polyacetylenes and carotenoids. An area map provides detailed information regarding the distribution of both components. It has been found that high accumulation of polyacetylenes is located in the outer section of the root, namely the pericyclic parenchyma, and in the phloem part close to the secondary cambium. The highest concentration of carotenes is seen in the immediate vicinity to polyacetylene conglomerates.

  17. 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

  18. Tissue Penetration and Pharmacokinetics of Tigecycline in Diabetic Patients with Chronic Wound Infections Described by Using In Vivo Microdialysis▿

    PubMed Central

    Bulik, Catharine C.; Wiskirchen, Dora E.; Shepard, Ashley; Sutherland, Christina A.; Kuti, Joseph L.; Nicolau, David P.

    2010-01-01

    Tissue penetration of systemic antibiotics is an important consideration for positive outcomes in diabetic patients. Herein we describe the exposure profile and penetration of tigecycline in the interstitial fluid of wound margins versus that of uninfected thigh tissue in 8 adult diabetic patients intravenously (IV) administered 100 mg and then 50 mg of tigecycline twice daily for 3 to 5 doses. Prior to administration of the first dose, 2 microdialysis catheters were inserted into the subcutaneous tissue, the first within 10 cm of the wound margin and the second in the thigh of the same extremity. Samples for determination of plasma and tissue concentrations were simultaneously collected over 12 h under steady-state conditions. Tissue concentrations were corrected for percent in vivo recovery by the retrodialysis technique. Plasma samples were also collected for determination of protein binding at 1, 6, and 12 h postdose for each patient. Protein binding data were corrected using a fitted polynomial equation. The mean patient weight was 95.1 kg (range, 63.6 to 149.2 kg), the mean patient age was 63.5 ± 9.4 years, and 75% of the patients were males. The mean values for the plasma, thigh, and wound free area under the concentration-time curve from 0 to 24 h (fAUC0-24) were 2.65 ± 0.33, 2.52 ± 1.15, and 2.60 ± 1.02 μg·h/ml, respectively. Protein binding was nonlinear, with the percentage of free drug increasing with decreasing serum concentrations. Exposure values for thigh tissue and wound tissue were similar (P = 0.986). Mean steady-state tissue concentrations for the thigh and wound were similar at 0.12 ± 0.02 μg/ml, and clearance from the tissues appeared similar to that from plasma. Tissue penetration ratios (tissue fAUC/plasma fAUC) were 99% in the thigh and 100% in the wound (P = 0.964). Tigecycline penetrated equally well into wound and uninfected tissue of the same extremity. PMID:20921312

  19. 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.

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

    PubMed

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

    2017-03-07

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

  1. Pharmacokinetic analysis of the microscopic distribution of enzyme-conjugated antibodies and prodrugs: comparison with experimental data.

    PubMed Central

    Baxter, L. T.; Jain, R. K.

    1996-01-01

    A mathematical model was developed to improve understanding of the biodistribution and microscopic profiles of drugs and prodrugs in a system using enzyme-conjugated antibodies as part of a two-step method for cancer treatment. The use of monoclonal antibodies alone may lead to heterogeneous uptake within the tumour tissue; the use of a second, low molecular weight agent may provide greater penetration into tumour tissue. This mathematical model was used to describe concentration profiles surrounding individual blood vessels within a tumour. From these profiles the area under the curve and specificity ratios were determined. By integrating these results spatially, average tissue concentrations were determined and compared with experimental results from three different systems in the literature; two using murine antibodies and one using humanised fusion proteins. The maximum enzyme conversion rate (Vmax) and the residual antibody concentration in the plasma and normal tissue were seen to be key determinants of drug concentration and drug-prodrug ratios in the tumour and other organs. Thus, longer time delays between the two injections, clearing the antibody from the blood stream and the use of 'weaker' enzymes (lower Vmax) will be important factors in improving this prodrug approach. Of these, the model found the effective clearance of the antibody outside of the tumour to be the most effective. The use of enzyme-conjugated antibodies may offer the following advantages over the bifunctional antibody-hapten system: (i) more uniform distribution of the active agent; (ii) higher concentrations possible for the active agent; and (iii) greater specificity (therapeutic index). PMID:8595158

  2. Impact of APCI ionization source in liquid chromatography tandem mass spectrometry based tissue distribution studies.

    PubMed

    Khatal, Laxman; Gaur, Ashwani; Naphade, Ashish; Kandikere, Vishwottam; Mookhtiar, Kasim

    2016-10-01

    Measurement of test article concentration in tissue samples has been an important part of pharmacokinetic study and has helped to co-relate pharmacokinetic/pharmacodynamic relationships since the 1950s. Bioanalysis of tissue samples using LC-MS/MS comes with unique challenges in terms of sample handling and inconsistent analyte response owing to nonvolatile matrix components. Matrix effect is a phenomenon where the target analyte response is either suppressed or enhanced in the presence of matrix components. Based on previous reports electrospray ionization (ESI) mode of ionization is believed to be more affected by matrix components than atmospheric pressure chemical ionization (APCI) or atmospheric pressure photoionization. To explore the impact of ionization source with respect to bioanalysis of tissue samples, five structurally diverse compounds - atenolol, verapamil, diclofenac, propranolol and flufenamic acid - were selected. Quality control standards were spiked into 10 different biological matrices like whole blood, liver, heart, brain, spleen, kidney, skeletal muscle, eye and skin tissue and were quantified against calibration standards prepared in rat plasma. Quantitative bioanalysis was performed utilizing both APCI and ESI mode and results were compared. Quality control standards when analyzed with APCI mode were found to be more consistent in terms of accuracy and precision as compared with ESI mode. Additionally, for some instances, up to 20-fold broader dynamic linearity range was observed with APCI mode as compared with ESI mode. As phospholid interferences have poor response in APCI mode, protein precipitation extraction technique can be used for multimatrix quantitation, which is more amenable to automation. The approach of multiple biological matrix quantitation against a single calibration curve helps bioanalysts to reduce turnaround time. Copyright © 2016 John Wiley & Sons, Ltd.

  3. Pharmacokinetic drivers of toxicity for basic molecules: Strategy to lower pKa results in decreased tissue exposure and toxicity for a small molecule Met inhibitor

    SciTech Connect

    Diaz, Dolores; Ford, Kevin A.; Hartley, Dylan P.; Harstad, Eric B.; Cain, Gary R.; Achilles-Poon, Kirsten; Nguyen, Trung; Peng, Jing; Zheng, Zhong; Merchant, Mark; Sutherlin, Daniel P.; Gaudino, John J.; Kaus, Robert; Lewin-Koh, Sock C.; Choo, Edna F.; Liederer, Bianca M.; Dambach, Donna M.

    2013-01-01

    Several toxicities are clearly driven by free drug concentrations in plasma, such as toxicities related to on-target exaggerated pharmacology or off-target pharmacological activity associated with receptors, enzymes or ion channels. However, there are examples in which organ toxicities appear to correlate better with total drug concentrations in the target tissues, rather than with free drug concentrations in plasma. Here we present a case study in which a small molecule Met inhibitor, GEN-203, with significant liver and bone marrow toxicity in preclinical species was modified with the intention of increasing the safety margin. GEN-203 is a lipophilic weak base as demonstrated by its physicochemical and structural properties: high LogD (distribution coefficient) (4.3) and high measured pKa (7.45) due to the basic amine (N-ethyl-3-fluoro-4-aminopiperidine). The physicochemical properties of GEN-203 were hypothesized to drive the high distribution of this compound to tissues as evidenced by a moderately-high volume of distribution (Vd > 3 l/kg) in mouse and subsequent toxicities of the compound. Specifically, the basicity of GEN-203 was decreased through addition of a second fluorine in the 3-position of the aminopiperidine to yield GEN-890 (N-ethyl-3,3-difluoro-4-aminopiperidine), which decreased the volume of distribution of the compound in mouse (Vd = 1.0 l/kg), decreased its tissue drug concentrations and led to decreased toxicity in mice. This strategy suggests that when toxicity is driven by tissue drug concentrations, optimization of the physicochemical parameters that drive tissue distribution can result in decreased drug concentrations in tissues, resulting in lower toxicity and improved safety margins. -- Highlights: ► Lower pKa for a small molecule: reduced tissue drug levels and toxicity. ► New analysis tools to assess electrostatic effects and ionization are presented. ► Chemical and PK drivers of toxicity can be leveraged to improve safety.

  4. Clinical pharmacokinetics of therapeutic monoclonal antibodies.

    PubMed

    Keizer, Ron J; Huitema, Alwin D R; Schellens, Jan H M; Beijnen, Jos H

    2010-08-01

    Monoclonal antibodies (mAbs) have been used in the treatment of various diseases for over 20 years and combine high specificity with generally low toxicity. Their pharmacokinetic properties differ markedly from those of non-antibody-type drugs, and these properties can have important clinical implications. mAbs are administered intravenously, intramuscularly or subcutaneously. Oral administration is precluded by the molecular size, hydrophilicity and gastric degradation of mAbs. Distribution into tissue is slow because of the molecular size of mAbs, and volumes of distribution are generally low. mAbs are metabolized to peptides and amino acids in several tissues, by circulating phagocytic cells or by their target antigen-containing cells. Antibodies and endogenous immunoglobulins are protected from degradation by binding to protective receptors (the neonatal Fc-receptor [FcRn]), which explains their long elimination half-lives (up to 4 weeks). Population pharmacokinetic analyses have been applied in assessing covariates in the disposition of mAbs. Both linear and nonlinear elimination have been reported for mAbs, which is probably caused by target-mediated disposition. Possible factors influencing elimination of mAbs include the amount of the target antigen, immune reactions to the antibody and patient demographics. Bodyweight and/or body surface area are generally related to clearance of mAbs, but clinical relevance is often low. Metabolic drug-drug interactions are rare for mAbs. Exposure-response relationships have been described for some mAbs. In conclusion, the parenteral administration, slow tissue distribution and long elimination half-life are the most pronounced clinical pharmacokinetic characteristics of mAbs.

  5. 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.

  6. 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)

  7. 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.

  8. 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.

  9. Correlation between pharmacokinetic/pharmacodynamic indices and clinical outcomes in Japanese patients with skin and soft tissue infections treated with daptomycin: analysis of a phase III study.

    PubMed

    Takesue, Yoshio; Mikamo, Hiroshige; Kusachi, Shinya; Watanabe, Shinichi; Takahashi, Kenichi; Yoshinari, Tomoko; Ishii, Mikio; Aikawa, Naoki

    2015-09-01

    The relationships between pharmacokinetic (PK)/pharmacodynamic (PD) indices and outcomes were investigated in patients with skin and soft tissue infection (SSTI) who received daptomycin at 4 mg/kg/day. Efficacy was evaluated in 55 patients from whom Staphylococcus aureus was isolated, with success rates of 94.5% and 69.1% for clinical and microbiological responses, respectively. The odds ratio for the relationship between the area under the day 1 concentration-time curve (AUC0-24h) to the MIC and the probability of clinical success was 1.03 (95% confidence interval [CI] 0.73-1.45), and that for the relationship for probability of microbiological success was 0.94 (95% CI 0.81-1.09). In 82 patients in the safety analysis, only 1 met the creatine phosphokinase (CPK) elevation criteria, and this patient's minimum concentration (C(min)) of plasma daptomycin was 5.37 μg/mL. No significant relationship was found between peak CPK and C(min) (Pearson's correlation coefficient -0.0452). In conclusion, no clear correlation between PK/PD indices and the probability of efficacy or safety events was demonstrated when daptomycin was administered in SSTI patients using the clinically recommended dosage of 4 mg/kg/day.

  10. Comparison of 225actinium chelates: tissue distribution and radiotoxicity.

    PubMed

    Davis, I A; Glowienka, K A; Boll, R A; Deal, K A; Brechbiel, M W; Stabin, M; Bochsler, P N; Mirzadeh, S; Kennel, S J

    1999-07-01

    The biodistribution and tissue toxicity of intravenously administered 225-actinium (225Ac) complexed with acetate, ethylene diamine tetraacetic acid (EDTA), 1, 4, 7, 10, 13-pentaazacyclopentadecane-N, N', N", N"', N"-pentaacetic acid (PEPA), or the "a" isomer of cyclohexyl diethylenetriamine pentaacetic acid (CHX-DTPA), were examined. The percent of injected dose per organ and per gram of tissue for each chelate complex was determined. 225Ac-CHX-DTPA was evaluated further for radiotoxic effects. Mice receiving > or =185 kBq 225Ac-CHX-DTPA suffered 100% morbidity by 5 days and 100% mortality by 8 days postinjection, and all animals evaluated had significant organ damage. The in vivo instability of the 225Ac-CHX-DTPA complex likely allowed accumulation of free 225Ac in organs, which resulted in tissue pathology.

  11. 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.

  12. [Distribution and accumulation of antibiotics in cells and tissues and toxicity studies by immunocytochemistry].

    PubMed

    Fujiwara, Kunio

    2011-01-01

    No true immunocytochemistry (ICC) for drugs nor its application to pharmacokinetic studies is available. Recently, our studies have shown that ICC for drugs is extremely useful for such studies by utilizing easy and safe techniques, and gives direct evidence of drug localization. We have therefore developed antibodies and a series of pretreatment conditions for the immunodetection of drugs and have localized sites of drug uptake or accumulation in several tissues of rats following the administration of drugs. This review describes preparation of anti-drug antibody, specificity of antibody, fixation of drug in situ in rat tissues and cells, treatment of paraffin section specimens prior to immunoreaction, precision, and their application to a variety of types of antibiotics anti-cancer anthracyclines daunorubicin, doxorubicin, and epirubicin, bleomycin analog peplomycin, antimicrobial agents gentamicin, and amoxicillin. ICC for the anti-cancer anthracyclines demonstrated that the drug accumulates in a characteristic pattern in the heart, liver, kidney, gastrointestinal tract, and hair follicles, which represent the sites targeted by the drug toxicity. Some, but not all, of these drug accumulations are associated with the induction of apoptosis. It was also noted that there are striking differences in accumulation among the anthracyclines in rat tissues, maybe contributing the mechanisms of the differences in anti-tumor activities of the anthracyclines. Both ICCs for gentamicin and peplomycin identified characteristic necrotic-like cells in the specific sites of the kidney, suggesting the sites are readily affected by some chemotherapeutic agents. ICC for amoxicillin demonstrated that the sites of the drug accumulation in small intestine, liver and kidney are closely correlated with the specific sites in which certain transporter systems for penicillin occur. Thus, an ICC method is a potential new tool for pharmacokinetic studies of wide variety types of drugs

  13. 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...

  14. Effects of iron status on transpulmonary transport and tissue distribution of Mn and Fe.

    PubMed

    Brain, Joseph D; Heilig, Elizabeth; Donaghey, Thomas C; Knutson, Mitchell D; Wessling-Resnick, Marianne; Molina, Ramon M

    2006-03-01

    Manganese transport into the blood can result from inhaling metal-containing particles. Intestinal manganese and iron absorption is mediated by divalent metal transporter 1 (DMT1) and is upregulated in iron deficiency. Since iron status alters absorption of Fe and Mn in the gut, we tested the hypothesis that iron status may alter pulmonary transport of these metals. DMT1 expression in the lungs was evaluated to explore its role in metal transport. The pharmacokinetics of intratracheally instilled 54Mn or 59Fe in repeatedly bled or iron oxide-exposed rats were compared with controls. Iron oxide exposure caused a reduction in pulmonary transport of 54Mn and 59Fe, and decreased uptake in other major organs. Low iron status from repeated bleeding also reduced pulmonary transport of iron but not of manganese. However, uptake of manganese in the brain and of iron in the spleen increased in bled rats. DMT1 transcripts were detected in airway epithelium, alveolar macrophages, and bronchial-associated lymphoid tissue in all rats. Focal increases were seen in particle-containing macrophages and adjacent epithelial cells, but no change was observed in bled rats. Although lung DMT1 expression did not correlate with iron status, differences in pharmacokinetics of instilled metals suggest that their potential toxicity can be modified by iron status.

  15. 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

  16. Ultrasonic backscattering in tissue: characterization through Nakagami-generalized inverse Gaussian distribution.

    PubMed

    Agrawal, Rajeev; Karmeshu

    2007-02-01

    Ultrasonic tissue characterization through composite probability distributions such as Nakagami-lognormal, Nakagami-gamma, Nakagami-inverse Gaussian has been found to be useful. Such a probabilistic description also depicts heavy tails which arise from multiple scattering in tissue besides local and global variations in scattering cross-sections. A new composite probability distribution, viz. Nakagami-generalized inverse Gaussian distribution (NGIGD) with four parameters is proposed which under different limiting conditions results in approximating the known distributions. A salient aspect of the new distribution is that the probability density function (pdf) of NGIGD variate is available in closed form and is analytically tractable.

  17. Distribution of plasminogen activator inhibitor (PAI-1) in tissues.

    PubMed Central

    Simpson, A J; Booth, N A; Moore, N R; Bennett, B

    1991-01-01

    Extracts of human tissue were analysed for plasminogen activator inhibitor (PAI-1) antigen and activity. PAI-1 was localised in tissues by an immunochemical method, using monoclonal antibodies. PAI-1 occurred throughout the body; its concentration and activity differed considerably from organ to organ. Extracts of liver and spleen had the greatest abundance of PAI-1, but the activity of the inhibitor was much higher in liver than in spleen: the liver may be a source of plasma PAI-1. Immunochemical staining for PAI-1 was observed in endothelium, platelets and their precursor cells, the megakaryocytes, and locations central to the process of haemostasis. PAI-1 also occurred in neutrophil polymorphs and macrophages, cells important in inflammatory and immune processes, but not in lymphocytes. Other cell types, in particular, vascular smooth muscle cells and mesangial cells, also stained positively for PAI-1 and such cells seem to represent an important reservoir of PAI-1. Images PMID:1864986

  18. Nanodrugs: pharmacokinetics and safety

    PubMed Central

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

    2014-01-01

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

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. 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

  4. Species and tissue distribution of the regulatory protein of glucokinase.

    PubMed

    Vandercammen, A; Van Schaftingen, E

    1993-09-01

    Rat liver is known to contain a regulatory protein that inhibits glucokinase (hexokinase IV or D) competitively versus glucose. This inhibition is greatly reinforced by the presence of fructose 6-phosphate and antagonized by fructose 1-phosphate and by KCl. This protein was now measured in various rat tissues and in the livers of various species by the inhibition it exerts on rat liver glucokinase. Rat, mouse, rabbit, guinea-pig and pig liver, all of which contain glucokinase, also contained between 60 and 200 units/g of tissue of a regulatory protein displaying the properties mentioned above. By contrast, this protein could not be detected in cat, goat, chicken or trout liver, or in rat brain, heart, skeletal muscle, kidney and spleen, all tissues from which glucokinase is missing. Fructose 1-phosphate stimulated glucokinase in extracts of human liver, indicating the presence of regulatory protein. In addition, antibodies raised against rat regulatory protein allowed the detection of an approximately 60 kDa polypeptide in rat, guinea pig, rabbit and human liver. The livers of the toad Bufo marinus, of Xenopus laevis and of the turtle Pseudemys scripta elegans contained a regulatory protein similar to that of the rat, with, however, the major difference that it was not sensitive to fructose 6-phosphate or fructose 1-phosphate. In rat liver, the regulatory protein was detectable 4 days before birth. Its concentration increased afterwards to reach the adult level at day 30 of extrauterine life, whereas glucokinase only appeared after day 15. In the liver of the adult rat, starvation and streptozotocin-diabetes caused a 50-60% decrease in the concentration of regulatory protein after 7 days, whereas glucokinase activity fell to about 20% of its initial level. When 4-day-starved rats were refed, or when diabetic rats were treated with insulin, the concentration of regulatory protein slowly increased to reach about 85% of the control level after 3 days, whereas the

  5. Development and validation of a high performance liquid chromatography quantification method of levo-tetrahydropalmatine and its metabolites in plasma and brain tissues: application to a pharmacokinetic study.

    PubMed

    Abdallah, Inas A; Huang, Peng; Liu, Jing; Lee, David Y; Liu-Chen, Lee-Yuan; Hassan, Hazem E

    2017-04-01

    Levo-tetrahydropalmatine (l-THP) is an alkaloid isolated from Chinese medicinal herbs of the Corydalis and Stephania genera. It has been used in China for more than 40 years mainly as an analgesic with sedative/hypnotic effects. Despite its extensive use, its metabolism has not been quantitatively studied, nor there a sensitive reliable bioanalytical method for its quantification simultaneously with its metabolites. As such, the objective of this study was to develop and validate a sensitive and selective HPLC method for simultaneous quantification of l-THP and its desmethyl metabolites l-corydalmine (l-CD) and l-corypalmine (l-CP) in rat plasma and brain tissues. Rat plasma and brain samples were processed by liquid-liquid extraction using ethyl acetate. Chromatographic separation was achieved on a reversed-phase Symmetry® C18 column (4.6 × 150 mm, 5 μm) at 25°C. The mobile phase consisted of acetonitrile-methanol-10 mm ammonium phosphate (pH 3) (10:30:60, v/v) and was used at a flow rate of 0.8 mL/min. The column eluent was monitored at excitation and emission wavelengths of 230 and 315 nm, respectively. The calibration curves were linear over the concentration range of 1-10,000 ng/mL. The intra- and interday reproducibility studies demonstrated accuracy and precision within the acceptance criteria of bioanalytical guidelines. The validated HPLC method was successfully applied to analyze samples from a pharmacokinetic study of l-THP in rats. Taken together, the developed method can be applied for bioanalysis of l-THP and its metabolites in rodents and potentially can be transferred for bioanalysis of human samples.

  6. Simultaneous determination of nicotine and its metabolite, cotinine, in rat blood and brain tissue using microdialysis coupled with liquid chromatography: pharmacokinetic application.

    PubMed

    Chang, Yuh-Lih; Tsai, Pi-Lo; Chou, Yueh-Ching; Tien, Jung-Hsiung; Tsai, Tung-Hu

    2005-09-23

    To elucidate the disposition of nicotine in the brain is important because the neuropharmacological effects from nicotine exposure are centrally predominated. The aim of the present study was to develop a rapid and simple method for the simultaneous determination of unbound nicotine and its main metabolite, cotinine, in rat blood and brain tissue. We coupled a multiple sites microdialysis sampling technique with HPLC-UV system to characterize the pharmacokinetics of both nicotine and cotinine. Microdialysis probes were inserted into the jugular vein/right atrium and brain striatum of Sprague-Dawley rats, and nicotine (2 mg/kg, i.v.) was administered via the femoral vein. Dialysates were collected every 10 min and injected directly into a HPLC system. Both nicotine and cotinine were separated by a phenyl-hexyl column (150 mm x 4.6 mm) from dialysates within 12 min. The mobile phase consisted of an acetonitrile-methanol-20 mM monosodium phosphate buffer (55:45:900, v/v/v, pH adjusted to 5.1) with a flow-rate of 1 ml/min. The wavelength of the UV detector was set at 260 nm. The limit of quantification for nicotine and cotinine were 0.25 microg/ml and 0.05 microg/ml, respectively. Intra- and inter-day precision and accuracy of both measurements fell well within the predefined limits of acceptability. The blood and brain concentration-time profile of nicotine and cotinine suggests that nicotine is easily to get into the central nervous system and cotinine exhibits a long retention time and accumulates in blood.

  7. MEETING AT BALTIMORE, MD: DISTRIBUTION OF CHIRAL PCBS IN SELECTED TISSUES IN THE LABORATORY RAT

    EPA Science Inventory

    In order to investigate the tissue distribution and enantiomeric fractions (EFs) of Polychlorinated Biphenyl (PCB) atropisomers, immature male Sprague-Dawley rats were administered environmentally relevant doses of (a) Aroclor 1254 or (b) an environmental mixture extracted from s...

  8. Distribution of biglycan and decorin in rat dental tissue.

    PubMed

    Tenório, D M H; Santos, M F; Zorn, T M T

    2003-08-01

    Biglycan and decorin are small leucine-rich proteoglycans that play several biological and structural roles in different tissues and organs. Several reports have indicated that biglycan participates in odontoblast and ameloblast differentiation and in the calcification process. In the present study we show that the expression of biglycan changes from within the ameloblasts and odontoblasts to the extracellular space according to the stage of animal development. In predentin and in the pulp space, however, biglycan was continually expressed throughout the period of investigation. In contrast, decorin was absent in odontoblasts and in ameloblasts and was exclusively expressed in predentin throughout the period of observation. In young rats, however, decorin was expressed in the extracellular spaces of the pulp, where it was concentrated mainly in the peripheral pulp.

  9. Human pyridoxal phosphatase. Molecular cloning, functional expression, and tissue distribution.

    PubMed

    Jang, Young Min; Kim, Dae Won; Kang, Tae-Cheon; Won, Moo Ho; Baek, Nam-In; Moon, Byung Jo; Choi, Soo Young; Kwon, Oh-Shin

    2003-12-12

    Pyridoxal phosphatase catalyzes the dephosphorylation of pyridoxal 5'-phosphate (PLP) and pyridoxine 5'-phosphate. A human brain cDNA clone was identified to the PLP phosphatase on the basis of peptide sequences obtained previously. The cDNA predicts a 296-amino acid protein with a calculated Mr of 31698. The open reading frame is encoded by two exons located on human chromosome 22q12.3, and the exon-intron junction contains the GT/AG consensus splice site. In addition, a full-length mouse PLP phosphatase cDNA of 1978 bp was also isolated. Mouse enzyme encodes a protein of 292 amino acids with Mr of 31512, and it is localized on chromosome 15.E1. Human and mouse PLP phosphatase share 93% identity in protein sequence. A BLAST search revealed the existence of putative proteins in organism ranging from bacteria to mammals. Catalytically active human PLP phosphatase was expressed in Escherichia coli, and characteristics of the recombinant enzyme were similar to those of erythrocyte enzyme. The recombinant enzyme displayed Km and kcat values for pyridoxal of 2.5 microM and 1.52 s(-1), respectively. Human PLP phosphatase mRNA is differentially expressed in a tissue-specific manner. A single mRNA transcript of 2.1 kb was detected in all human tissues examined and was highly abundant in the brain. Obtaining the molecular properties for the human PLP phosphatase may provide new direction for investigating metabolic pathway involving vitamin B6.

  10. Pharmacokinetics of grepafloxacin.

    PubMed

    Efthymiopoulos, C

    1997-12-01

    Grepafloxacin is a fluoroquinolone antibiotic which is rapidly absorbed in healthy volunteers following oral dosing. It reaches peak plasma levels around 2 h after administration, then declines bi-exponentially, with an extended half-life of around 12 h. Grepafloxacin is eliminated primarily through metabolism and is excreted mainly in the faeces. Renal clearance accounts for only 10-15% of the administered dose. Grepafloxacin plasma concentrations increase disproportionately with increasing doses, but this is unlikely to be of clinical significance over the range of therapeutic doses. The rate and extent of absorption are not affected by food or elevated intragastric pH. The pharmacokinetics of grepafloxacin are affected by gender, with these differences relating to variations in body weight. No effect of age on the pharmacokinetics of grepafloxacin was found. Renal impairment does not affect grepafloxacin pharmacokinetics, whereas peak plasma concentrations, areas under plasma concentration-time curves and renal excretion are increased in patients with hepatic impairment. Grepafloxacin can be co-administered with warfarin and theophylline, though reduction of the theophylline dose is necessary. Following oral administration, higher grepafloxacin concentrations are achieved in lung and genital tissues than in serum, indicating its potential in the treatment of respiratory and sexually transmitted diseases. In addition, it exceeds therapeutically effective levels in bile and gall-bladder tissues, and accumulates in polymorphonuclear leucocytes such that it may be useful against intracellular pathogens.

  11. 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…

  12. Acute toxicity and tissue distributions of malathion in Ambystoma tigrinum.

    PubMed

    Henson-Ramsey, H; Kennedy-Stoskopf, S; Levine, J F; Taylor, S K; Shea, D; Stoskopf, M K

    2008-10-01

    The kinetics of the bioaccumulation of malathion (O,O-dimethyl phosphorodithioate of diethyl mercaptosuccinate) and the biological impact of exposure for tiger salamanders, Ambystoma tigrinum, were assessed through exposure to soil surface contaminated with 50 microg/cm(2) or 100 microg/cm(2 )malathion and ingestion of an earthworm exposed to soil contaminated with 200 microg/cm(2) malathion. Malathion and malaoxon burdens in salamanders sampled at different times after exposure(s) were measured by gas chromatography in four tissue/organ subgroups: liver, epaxial muscle, pooled viscera (except the liver and brain), and pooled avisceral carcass (muscle, skin, and bone). The total tiger salamander xenobiotic burdens were calculated from these data. The malathion/malaoxon burden 1 day after exposure was greatest in the avisceral carcass and 2 days after exposure was greatest in the viscera. Bioconcentration and bioaccumulation factors remained less than unity throughout the experiment and did not support the hypothesis of bioaccumulation of malathion in the tiger salamander. Biological impact was assessed with a colorimetric brain cholinesterase microassay. Brain cholinesterase activities in salamanders exposed to malathion-contaminated soil (50 microg/cm(2) or 100 microg/cm(2 )malathion) were suppressed approximately 50-65% and 90%, respectively, compared to unexposed controls. The exposed animals did not exhibit overt clinical signs of malathion toxicosis.

  13. Tissue composition effect on dose distribution in neutron brachytherapy/neutron capture therapy

    PubMed Central

    Khosroabadi, Mohsen; Farhood, Bagher; Ghorbani, Mahdi; Hamzian, Nima; Moghaddam, Homa Rezaei; Davenport, David

    2016-01-01

    Aim The aim of this study is to assess the effect of the compositions of various soft tissues and tissue-equivalent materials on dose distribution in neutron brachytherapy/neutron capture therapy. Background Neutron brachytherapy and neutron capture therapy are two common radiotherapy modalities. Materials and methods Dose distributions were calculated around a low dose rate 252Cf source located in a spherical phantom with radius of 20.0 cm using the MCNPX code for seven soft tissues and three tissue-equivalent materials. Relative total dose rate, relative neutron dose rate, total dose rate, and neutron dose rate were calculated for each material. These values were determined at various radial distances ranging from 0.3 to 15.0 cm from the source. Results Among the soft tissues and tissue-equivalent materials studied, adipose tissue and plexiglass demonstrated the greatest differences for total dose rate compared to 9-component soft tissue. The difference in dose rate with respect to 9-component soft tissue varied with compositions of the materials and the radial distance from the source. Furthermore, the total dose rate in water was different from that in 9-component soft tissue. Conclusion Taking the same composition for various soft tissues and tissue-equivalent media can lead to error in treatment planning in neutron brachytherapy/neutron capture therapy. Since the International Commission on Radiation Units and Measurements (ICRU) recommends that the total dosimetric uncertainty in dose delivery in radiotherapy should be within ±5%, the compositions of various soft tissues and tissue-equivalent materials should be considered in dose calculation and treatment planning in neutron brachytherapy/neutron capture therapy. PMID:26900352

  14. Influence of heterogeneous and anisotropic tissue conductivity on electric field distribution in deep brain stimulation.

    PubMed

    Aström, Mattias; Lemaire, Jean-Jacques; Wårdell, Karin

    2012-01-01

    The aim was to quantify the influence of heterogeneous isotropic and heterogeneous anisotropic tissue on the spatial distribution of the electric field during deep brain stimulation (DBS). Three finite element tissue models were created of one patient treated with DBS. Tissue conductivity was modelled as (I) homogeneous isotropic, (II) heterogeneous isotropic based on MRI, and (III) heterogeneous anisotropic based on diffusion tensor MRI. Modelled DBS electrodes were positioned in the subthalamic area, the pallidum, and the internal capsule in each tissue model. Electric fields generated during DBS were simulated for each model and target-combination and visualized with isolevels at 0.20 (inner), and 0.05 V mm(-1) (outer). Statistical and vector analysis was used for evaluation of the distribution of the electric field. Heterogeneous isotropic tissue altered the spatial distribution of the electric field by up to 4% at inner, and up to 10% at outer isolevel. Heterogeneous anisotropic tissue influenced the distribution of the electric field by up to 18 and 15% at each isolevel, respectively. The influence of heterogeneous and anisotropic tissue on the electric field may be clinically relevant in anatomic regions that are functionally subdivided and surrounded by multiple fibres of passage.

  15. 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.

  16. 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

  17. Leptin pharmacokinetics in male mice

    PubMed Central

    Dobos, Robin C; Agnew, Linda L; Smart, Neil A; McFarlane, James R

    2017-01-01

    Pharmacokinetics of leptin in mammals has not been studied in detail and only one study has examined more than one time point in non-mutant mice and this was in a female mice. This is the first study to describe leptin distribution over a detailed time course in normal male mice. A physiologic dose (12 ng) of radiolabelled leptin was injected into adult male mice via the lateral tail vein and tissues were dissected out and measured for radioactivity over a time course of up to two hours. Major targets were the digestive tract, kidneys, skin and lungs. The brain was not a major target, and 0.15% of the total dose was recovered from the brain 5 min after administration. Major differences appear to exist in the distribution of leptin between the male and female mice, indicating a high degree of sexual dimorphism. Although the half-lives were similar between male and female mice, almost twice the proportion of leptin was recovered from the digestive tract of male mice in comparison to that reported previously for females. This would seem to indicate a major difference in leptin distribution and possibly function between males and females. PMID:27998953

  18. 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

  19. A Phase 1 Randomized, Blinded Comparison of the Pharmacokinetics and Colonic Distribution of Three Candidate Rectal Microbicide Formulations of Tenofovir 1% Gel with Simulated Unprotected Sex (CHARM-02)

    PubMed Central

    Hiruy, Hiwot; Fuchs, Edward J.; Marzinke, Mark A.; Bakshi, Rahul P.; Breakey, Jennifer C.; Aung, Wutyi S.; Manohar, Madhuri; Yue, Chen; Caffo, Brian S.; Du, Yong; Abebe, Kaleab Z.; Spiegel, Hans M.L.; Rohan, Lisa C.; McGowan, Ian

    2015-01-01

    Abstract CHARM-02 is a crossover, double-blind, randomized trial to compare the safety and pharmacokinetics of three rectally applied tenofovir 1% gel candidate rectal microbicides of varying osmolalities: vaginal formulation (VF) (3111 mOsmol/kg), the reduced glycerin vaginal formulation (RGVF) (836 mOsmol/kg), and an isoosmolal rectal-specific formulation (RF) (479 mOsmol/kg). Participants (n = 9) received a single, 4 ml, radiolabeled dose of each gel twice, once with and once without simulated unprotected receptive anal intercourse (RAI). The safety, plasma tenofovir pharmacokinetics, colonic small molecule permeability, and SPECT/CT imaging of lower gastrointestinal distribution of drug and virus surrogate were assessed. There were no Grade 3 or 4 adverse events reported for any of the products. Overall, there were more Grade 2 adverse events in the VF group compared to RF (p = 0.006) and RGVF (p = 0.048). In the absence of simulated unprotected RAI, VF had up to 3.8-fold greater systemic tenofovir exposure, 26- to 234-fold higher colonic permeability of the drug surrogate, and 1.5- to 2-fold greater proximal migration in the colonic lumen, when compared to RF and RGVF. Similar trends were observed with simulated unprotected RAI, but most did not reach statistical significance. SPECT analysis showed 86% (standard deviation 19%) of the drug surrogate colocalized with the virus surrogate in the colonic lumen. There were no significant differences between the RGVF and RF formulation, with the exception of a higher plasma tenofovir concentration of RGVF in the absence of simulated unprotected RAI. VF had the most adverse events, highest plasma tenofovir concentrations, greater mucosal permeability of the drug surrogate, and most proximal colonic luminal migration compared to RF and RGVF formulations. There were no major differences between RF and RGVF formulations. Simultaneous assessment of toxicity, systemic and luminal pharmacokinetics, and

  20. 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...

  1. Quantitative bioluminescence imaging--a method for the detection of metabolite distributions in frozen tissues

    NASA Astrophysics Data System (ADS)

    Mueller-Klieser, Wolfgang; Walenta, Stefan; Schwickert, Georg

    1994-02-01

    A novel technique allows for measurement of metabolite distributions in tissue cryosections at a microscopic level using bioluminescence, single photon imaging, and computerized image analysis. Metabolites, such as ATP, glucose and lactate are registered in absolute concentration units, and the respective images can be correlated with each other and with histological structures by specific algorithms. One striking difference between malignant tumors and normal tissue is the pronounced heterogeneity of metabolite distributions in malignancies contrasted by rather homogeneous patterns obtained in many normal organs. The heterogeneous distribution of metabolites in solid tumors reflects the chaotic organization of the histological architecture and of the microvascular supply in cancerous tissue. Pixel-to-pixel comparison of metabolite distributions measured in cervix cancers of patients revealed a negative linear correlation between glucose and ATP concentrations at identical locations. In contrast, local lactate concentration was positively correlated with ATP.

  2. Liposomal anticancer therapy: pharmacokinetic and clinical aspects.

    PubMed

    Di Paolo, A

    2004-11-01

    Liposomes, which are vesicles composed of a phospholipid bilayer surrounding an aqueous milieu, represent a new strategy for anticancer drug delivery. Extravasation and accumulation of liposomal drugs within neoplastic tissues are possible because of the leaky vasculature and scarce lymphatic vessels of tumours (the enhanced permeability and retention effect). Furthermore, liposomal chemotherapeutic agents display distinctive pharmacokinetic characteristics, because they possess longer elimination half-lives, reduced clearance and smaller volume of distribution with respect to corresponding free drugs. Taken together, these features lead to highest levels of cytotoxic agents in tumours, as demonstrated in preclinical models and clinical trials, whereas healthy tissues are spared from toxicity. In fact, liposomal drugs (i.e., doxorubicin), alone or in combination with other cytotoxic agents, lead to improved clinical effectiveness and ameliorated toxicity profile with respect to corresponding free drugs when they are used for the treatment of metastatic breast and ovarian cancers, and Kaposi's sarcoma.

  3. Ordinary differential equation models for ethanol pharmacokinetic based on anatomy and physiology.

    PubMed

    Han, Jae-Joon; Plawecki, Martin H; Doerschuk, Peter C; Ramchandani, Vijay A; O'Connor, Sean

    2006-01-01

    Physiologically-based pharmacokinetic (PBPK) models have been used to describe the distribution and elimination characteristics of intravenous ethanol administration. Further, these models have been used to estimate the ethanol infusion profile required to prescribe a specific breath ethanol concentration time course in a specific human being, providing a platform upon which other pharmacokinetic and pharmacodynamic investigations are based. In these PBPK models, the equivalence of two different peripheral tissue models are shown and issues concerning the mass flow into the liver in comparison with ethanol metabolism in the liver are explained.

  4. Pharmacokinetics and ocular penetration of grepafloxacin in albino and pigmented rabbits.

    PubMed

    Perez, S; Solans, C; Bregante, M A; Pinilla, I; García, M A; Honrubia, F

    2002-10-01

    The pharmacokinetics of grepafloxacin were determined in albino and pigmented rabbits following a single 10 mg/kg intravenous administration. The penetration of grepafloxacin into various ocular tissues was also determined after continuous intravenous infusion in both types of animal. Grepafloxacin showed a bicompartmental model of distribution in both pigmented and albino rabbits with significant differences in the pharmacokinetics between the two types of animal. After continuous intravenous infusion, significantly greater penetration of grepafloxacin was found in the iris, cornea and chorioretina of pigmented rabbits compared with albino rabbits.

  5. 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.

  6. 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.

  7. 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.

  8. 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

    1992-04-02

    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)

  9. 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.

  10. Issues in the Pharmacokinetics of Trichloroethylene and Its Metabolites

    PubMed Central

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

    2006-01-01

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

  11. Distribution of inclusion bodies in tissues from 100 dogs infected with canine distemper virus.

    PubMed

    Kubo, Takuya; Kagawa, Yumiko; Taniyama, Hiroyuki; Hasegawa, Atsuhiko

    2007-05-01

    One hundred dogs that were positive for canine distemper virus antigen and inclusion bodies in the tonsils were examined for the distribution of inclusion bodies in various tissues. Inclusion bodies were found in the lungs (70 dogs), brains (20 dogs), urinary bladders (73 dogs), stomachs (78 dogs), spleens (77 dogs), and lymph nodes (81 dogs) of the dogs. Based on these results, the tonsils may be the most suitable tissue for detection of inclusion bodies in canine distemper.

  12. Application of Spatially Distributed Field of Electric Impulses for Correction of Angiogenesis in Ischemic Muscular Tissue

    PubMed Central

    Kublanov, V.S.; Danilova, I.G.; Goette, I.F.; Brykina, I.A.; Shalyagin, M.A.

    2010-01-01

    Influence of spatially distributed field of electric impulses in a projection to cervical ganglions of the sympathetic nervous system on angiogenesis in ischemic muscular tissue of a rat’s shin has been studied. It is revealed that blood supply of animals, influenced by the field, is restored through increase in quantity of capillaries in ischemic tissues, and number of products of endogenous intoxication is reduced. PMID:23675207

  13. Population pharmacokinetics, brain distribution, and pharmacodynamics of 2nd generation dopamine transporter selective benztropine analogs developed as potential substitute therapeutics for treatment of cocaine abuse.

    PubMed

    Syed, Shariq A; Newman, Amy H; Othman, Ahmed A; Eddington, Natalie D

    2008-05-01

    A second generation of N-substituted 3alpha-[bis(4'-fluorophenyl)methoxy]-tropanes (GA 1-69, JHW 005 and JHW 013) binds with high affinity to the dopamine transporter (DAT) and are highly selective toward DAT compared to muscarinic receptor binding (M1). The objective of this study was to characterize brain distribution, pharmacokinetics, and pharmacodynamics [extracellular brain dopamine (DA) levels] of three novel N-substituted benztropine (BZT) analogs in male Sprague-Dawley rats. The BZT analogs displayed a higher distribution (Vd = 8.69-34.3 vs. 0.9 L/kg) along with longer elimination (t l/2: 4.1-5.4 vs. 0.5 h) than previously reported for cocaine. Brain-to-plasma partition coefficients were 1.3-2.5 vs. 2.1 for cocaine. The effect of the BZT analogs on extracellular brain (DA) levels ranged from minimal effects (GA 1-69) to several fold elevation (approximately 850% of basal DA for JHW 013) at the highest dose evaluated. PK/PD analysis of exposure-response data resulted in lower IC50 values for the BZT analogs compared to cocaine indicating their higher potency to inhibit DA reuptake (0.1-0.3 vs. 0.7 mg/L). These BZT analogs possess significantly different PK and PD profiles as compared to cocaine suggesting that further evaluation as cocaine abuse therapeutics is warranted.

  14. Effect of urinary excretion on the bladder tissue distribution of fluoroquinolones in rats.

    PubMed

    Izawa, Shigeru; Yamaoka, Makiko; Deguchi, Takashi

    2015-04-01

    The purpose of this study was to evaluate which of blood or urine has the greater effect on bladder tissue concentrations of fluoroquinolones important for the treatment of urinary tract infections by measuring concentrations of fluoroquinolones in the vesical tissue (chemically and immunohistochemically) and intravesical space (chemically). Thirty-minute incubation of isolated rat bladders with fluoroquinolones showed only a 1.9-fold difference in transferability among norfloxacin, levofloxacin, ciprofloxacin and sparfloxacin. Intravesical instillation of norfloxacin and sparfloxacin in rats yielded similar vesical tissue distributions. Thus, there were no large differences in vesical tissue transfer among the four fluoroquinolones. The bladder tissue/plasma concentration ratios of norfloxacin (high urinary excretion-type) and sparfloxacin (low urinary excretion-type) at 1 h after a single oral dose (10 mg/kg) to rats were 15.4 and 1.3, respectively. The bladder tissue/plasma concentration ratios of norfloxacin after an intravenous injection (10 mg/kg) to ureter-catheterized and sham-operated rats were 1.36 and 57.8. Thus the bladder tissue distribution was significantly higher in the urine-exposed bladder. Immunohistochemical examination of the vesical tissue localization of norfloxacin in rats given a single intravenous dose revealed the presence of the drug-positive image in the cytoplasm of surface layer cells (both in umbrella and cover cells) of the bladder transitional epithelium. In conclusion, the results suggest that norfloxacin and other fluoroquinolones are excreted into urine and then transferred to the surface layer of the bladder transitional epithelium. Therefore, the urine levels have a greater effect on the vesicle tissue distribution of fluoroquinolones than the plasma levels in rats.

  15. Tissue distribution of lycopene in ferrets and rats after lycopene supplementation.

    PubMed

    Ferreira, A L; Yeum, K J; Liu, C; Smith, D; Krinsky, N I; Wang, X D; Russell, R M

    2000-05-01

    To determine lycopene uptake and tissue distribution in ferrets (Mustela putorius furo) and F344 rats, we supplemented orally 4.6 mg/(kg body wt.d) lycopene in a tomato oleoresin-corn oil mixture (experimental groups). After 9 wk of supplementation, the animals were killed and blood and organs were collected. Plasma and tissue carotenoids were extracted and measured using HPLC. Mean concentrations of lycopene (nmol/kg wet tissue) in saponified tissues of ferrets were as follows: liver 933, intestine 73, prostate 12.7 and stomach 9.3. Levels of lycopene (nmol/kg wet tissue) in saponified tissue of rats were as follows: liver 14213, intestine 3125, stomach 78.6, prostate 24 and testis 3.9. When these organs were extracted without saponification, the lycopene levels were lower, except for rat testis. All-trans-lycopene was the predominant isomer found in tomato oleoresin and in the majority of rat tissues, whereas cis-lycopenes were predominant in rat prostate and plasma. This pattern was reversed in ferrets. The results show the following: 1) lycopene from tomato oleoresin is absorbed and stored primarily in the liver of both animals; 2) saponification generally improves the extraction of lycopene from most tissues of both animals; 3) cis-lycopene and all-trans-lycopene are the predominant isomers in ferret and rat tissues, respectively; and 4) rats absorb lycopene more effectively than ferrets.

  16. 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.

  17. 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

  18. A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers.

    PubMed

    Tett, S E; Cutler, D J; Day, R O; Brown, K F

    1988-09-01

    1. The pharmacokinetics of hydroxychloroquine were studied in five healthy volunteers following an intravenous infusion of 155 mg (2.47 +/- 0.25 mg kg-1) racemic hydroxychloroquine. Four of these volunteers also received a further 310 mg (4.92 +/- 0.45 mg kg-1) infusion of hydroxychloroquine and evidence of nonlinearities in the pharmacokinetics of hydroxychloroquine were sought. 2. No nonlinear elimination or distribution processes appeared to be operating at the doses of hydroxychloroquine used in this study, supporting the hypothesis that in the therapeutic dosing range the pharmacokinetics of hydroxychloroquine are linear. 3. Half-life and mean residence time were long (around 40 days) and large volumes of distribution were calculated (5,522 l from blood, 44,257 l from plasma). Sequestration into the tissues is an important feature of the disposition of hydroxychloroquine. The persistence of hydroxychloroquine in the body is due primarily to this extensive tissue distribution, rather than to low clearance (667 ml min-1 based on plasma data, 96 ml min-1 based on blood data). 4. Plasma data were more variable than blood data. Blood to plasma concentration ratios were not constant (mean +/- s.d.: 7.2 +/- 4.2). The data indicate that it is preferable to measure whole blood concentrations of hydroxychloroquine, rather than plasma concentrations, in pharmacokinetic studies. 5. The pharmacokinetics of hydroxychloroquine are similar to those of chloroquine.

  19. Occurrence and distribution of n-alkanes in sucking-calf tissues.

    PubMed

    Di Muccio, A; Lintas, C; Filos, M; Bernardini, M P

    1984-06-01

    Samples of subcutaneous and perirenal fat, muscle, heart, liver, kidney, and spleen from eleven 4-month-old sucking calves were analyzed for their hydrocarbon composition. Qualitative and quantitative determinations were carried out by gas chromatography. Ranges of total hydrocarbons and odd-even hydrocarbon distribution for each tissues are reported. In general, a predominance of odd-numbered hydrocarbons in the high carbon number range was observed. As compared to adult bovines, calf tissues, with the exception of adipose tissues, show higher amounts of total hydrocarbons.

  20. 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.

  1. Lacteal secretion, fetal and maternal tissue distribution of dasatinib in rats.

    PubMed

    He, Kan; Lago, Michael W; Iyer, Ramaswamy A; Shyu, Wen-Chyi; Humphreys, William G; Christopher, Lisa J

    2008-12-01

    Dasatinib [N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide; BMS-354825] is a potent and broad-spectrum kinase inhibitor used for the treatment of chronic myeloid leukemia and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Dasatinib exhibited extensive lacteal secretion in Sprague-Dawley rats following a single p.o. dose of [14C]dasatinib (10 mg/kg, 300 microCi/kg). Radioactivity was detected through 72 h postdose, with a milk/plasma area under concentration-time curve from 0 to infinity (AUC(0-inf)) ratio of approximately 25. The majority of the total radioactivity in milk was attributed to unchanged dasatinib. After a single dose of [14C]dasatinib to pregnant Sprague-Dawley rats at gestation day 18, radioactivity was extensively distributed in maternal tissues. The radioactivity detected by tissue excision or quantitative whole-body autoradiography was highest in adrenal gland, mammary tissue, lungs, kidneys, liver, and placenta. Compared with maternal tissues, a relatively low level of radioactivity was detected in fetal tissues. The concentrations of dasatinib-equivalents in fetal liver and kidneys were <13% of the respective maternal organs. The C(max) of dasatinib-equivalents in fetal blood was approximately 39% of that in maternal blood; however, the AUC values were comparable. Fetal brain/blood ratios of C(max) and AUC(0-inf) were approximately 1.58 and 1.48, respectively, which were much greater than the maternal ratios of 0.12 and 0.13. In summary, dasatinib was extensively distributed in maternal tissues and secreted into milk, but its penetration into the adult brain was limited. Transporters may be involved in mediating dasatinib distribution in the adult rat, whereas in the fetus, tissue and blood exposures were similar, suggesting that distribution in the fetus is predominantly mediated by diffusion.

  2. Tissue distribution and urinary excretion of inorganic arsenic and its methylated metabolites in C57BL6 mice following subchronic exposure to arsenate in drinking water

    SciTech Connect

    Kenyon, E.M. Hughes, M.F.; Adair, B.M.; Highfill, J.H.; Crecelius, E.A.; Clewell, H.J.; Yager, J.W.

    2008-11-01

    The relationship of exposure and tissue concentration of parent chemical and metabolites over prolonged exposure is a critical issue for chronic toxicities mediated by metabolite(s) rather than parent chemical alone. This is an issue for As{sup V} because its trivalent metabolites have unique toxicities and relatively greater potency compared to their pentavalent counterparts for many endpoints. In this study, dose-dependency in tissue distribution and urinary excretion for inorganic arsenic and its methylated metabolites was assessed in female C57Bl/6 mice exposed to 0, 0.5, 2, 10 or 50 ppm arsenic (as arsenate, As{sup V}) in their drinking water for 12 weeks. No adverse effects were observed and body weight gain did not differ significantly among groups. Urinary excretion of arsenite monomethylarsonous acid (MMA{sup III}), dimethylarsinous acid (DMA{sup III}), dimethylarsinic acid (DMA{sup V}), and trimethylarsine oxide (TMAO) increased linearly with dose, whereas As{sup V} and monomethylarsonic acid (MMA{sup V}) excretion was non-linear with respect to dose. Total tissue arsenic accumulation was greatest in kidney > lung > urinary bladder >>> skin > blood > liver. Monomethyl arsenic (MMA, i.e. MMA{sup III} + MMA{sup V}) was the predominant metabolite in kidney, whereas dimethylarsenic (DMA, i.e., DMA{sup III} + DMA{sup V}) was the predominant metabolite in lung. Urinary bladder tissue had roughly equivalent levels of inorganic arsenic and dimethylarsenic, as did skin. These data indicate that pharmacokinetic models for arsenic metabolism and disposition need to include mechanisms for organ-specific accumulation of some arsenicals and that urinary metabolite profiles are not necessarily reflective of target tissue dosimetry.

  3. 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).

  4. Population pharmacokinetics of exenatide

    PubMed Central

    Mager, Donald E.

    2016-01-01

    Aim The aim of the present analysis was to develop a core population pharmacokinetic model for the pharmacokinetic properties of immediate‐release (IR) exenatide, which can be used in subsequent analyses of novel sustained‐release formulations. Methods Data from eight clinical trials, evaluating a wide range of doses and different administration routes, were available for analysis. All modelling and simulations were conducted using the nonlinear mixed‐effect modelling program NONMEM. External model validation was performed using data from the phase III clinical trials programme through standard visual predictive checks. Results The pharmacokinetics of IR exenatide was described by a two‐compartment model, and the absorption of subcutaneous exenatide was described with a sequential zero‐order rate constant followed by a saturable nonlinear absorption process. Drug elimination was characterized by two parallel routes (linear and nonlinear), with significant relationships between renal function and the linear elimination route, and between body weight and volume of distribution. For a subject with normal renal function, the linear clearance was estimated to be 5.06 l hr−1. The nonlinear elimination was quantified with a Michaelis–Menten constant (K m) of 567 pg ml−1 and a maximum rate of metabolism (V max) of 1.6 μg h−1. For subcutaneous administration, 37% of the subcutaneous dose is absorbed via the zero‐order process, and the remaining 63% via the nonlinear pathway. Conclusions The present analysis provides a comprehensive population pharmacokinetic model for exenatide, expanding the elimination process to include both linear and nonlinear components, providing a suitable platform for a broad range of concentrations and patient conditions that can be leveraged in future modelling efforts of sustained‐release exenatide formulations. PMID:27650681

  5. [Distribution of compact bone mesenchymal stem cells in lung tissue and bone marrow of mouse].

    PubMed

    Wang, Rui-Ping; Wu, Ren-Na; Guo, Yu-Qing; Zhang, Bin; Chen, Hu

    2014-02-01

    This study was aimed to investigate the distribution of compact bone mesenchymal stem cells(MSC) marked with lentiviral plasmid pGC FU-RFP-LV in lung tissue and bone marrow of mouse. The MSC were infected by lentivirus with infection efficiency 78%, the infected MSC were injected into BALB/c mice via tail veins in concentration of 1×10(6) /mouse. The mice were randomly divided into 4 group according to 4 time points as 1, 2, 5 and 7 days. The lung tissue and bone marrow were taken and made of frozen sections and smears respectively in order to observed the distributions of MSC. The results indicated that the lentiviral infected MSC displayed phenotypes and biological characteristics which conformed to MSC by immunophenotyping analysis and induction differentiation detection. After the MSC were infected with optimal viral titer MOI = 50, the cell growth no significantly changed; the fluorescent microscopy revealed that the distributions of MSC in bone marrow on day 1, 2, 5 and 7 were 0.50 ± 0.20, 0.67 ± 0.23, 0.53 ± 0.14, 0.33 ± 0.16; those in lung tissue were 0.55 ± 0.15, 0.47 ± 0.13, 0.29 ± 0.13, 0.26 ± 0.08. It is concluded that the distribution of MSC in lung tissue reaches a peak on day 1, while distribution of MSC in bone marrow reaches a peak on day 2. The distribution of mouse MSC relates with RFP gene expression and implantation of MSC in lung tissue and bone marrow.

  6. Pharmacokinetics of ampicillin and sulbactam in patients undergoing heart surgery.

    PubMed Central

    Wildfeuer, A; Müller, V; Springsklee, M; Sonntag, H G

    1991-01-01

    The pharmacokinetics of ampicillin and sulbactam, a new beta-lactamase inhibitor, were investigated in 16 patients undergoing prosthetic cardiac valve insertion. The combination of 2 g of ampicillin and 1 g of sulbactam was administered as perioperative prophylaxis intravenously over 3 to 6 days. Several serum pharmacokinetic parameters were similar for the two drugs after three intravenous doses were given to patients following surgery. The half-lives of elimination of ampicillin and sulbactam were 79 +/- 4.9 and 88 +/- 5.9 min, the volumes of distribution were 15.6 +/- 1.4 and 17.7 +/- 1.2 liters/70 kg, and the total plasma clearances were 144.4 +/- 14.5 and 147.2 +/- 14.5 ml/min, respectively. The peak concentrations of ampicillin and sulbactam in serum were calculated to be 134.3 +/- 1.3 and 58.3 +/- 1.2 micrograms/ml, respectively. Ampicillin and sulbactam rapidly penetrated from the blood into various tissues collected during heart surgery, such as sternum, pericardium, myocardium, and endocardium. The concentrations of ampicillin in tissue ranged from 17.8 +/- 9.9 to 50 +/- 29.5 micrograms/g, and those of sulbactam in tissue ranged from 8.8 +/- 6.2 to 19.6 +/- 10.1 micrograms/g. The concentrations of ampicillin and sulbactam in serum and tissue also apparently exceeded the MICs against most beta-lactamase-producing bacteria usually involved in postoperative wound infections and prosthetic valve endocarditis. The ratio of the two compounds was approximately 2:1 in serum and in the various tissues affected by the operation. The pharmacokinetics of ampicillin and sulbactam in serum and investigated tissues suggest that the combination of the two beta-lactams will be effective in the perioperative prophylaxis of patients undergoing heart surgery. PMID:1952846

  7. Distribution of EV71 receptors SCARB2 and PSGL-1 in human tissues.

    PubMed

    Jiao, Xiao-Yang; Guo, Li; Huang, Dong-Yang; Chang, Xiao-Lan; Qiu, Qian-Cheng

    2014-09-22

    The aim of this study was to investigate the distribution of Enterovirus 71 (EV71) receptors SCARB2 and PSGL-1 in human tissues. The samples were chosen from archived specimens, and the profiles of two receptors were detected in the gastrointestinal tract, lung, and brain in situ by immunohistochemistry. SCARB2 was detected in all the tissues studied, and strong staining was observed in the gastric fundus gland, mucosal and glandular epithelia of the intestine. Similar expression was found in bronchial epithelia and pneumocytes. In addition, SCARB2 was observed in the esophagus/gastric mucosal epithelia, neuron, glial cells, and blood vessels and the perivascular tissues of the brain. By comparison, PSGL-1 was expressed weakly in the mucosal and glandular epithelia of the small intestine and colon. PSGL-1 was expressed in a few bronchial epithelia, and weak staining was observed in the pneumocytes. However, PSGL-1 was found easily in the lamina propria of all the tissues studied, and strong staining of PSGL-1 was also observed in the neurons and glial cells. The distribution of the SCARB2 and PSGL-1 in human gastrointestinal tract, lung, and brain tissues correlated with the distribution of pathological changes seen in EV71 infection. The widespread prevalence of these receptors may help explain the multiple organ involvement in infection with EV71.

  8. 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.

  9. Tissue distribution of Thorotrast and role of internal irradiation in carcinogenesis.

    PubMed

    Yamasaki, Kyoko; Yamasaki, Aiichi; Tosaki, Mitsuo; Isozumi, Yasuto; Hiai, Hiroshi

    2004-10-01

    Carcinogenesis in Thorotrastosis has been assumed due to direct bombardment by alpha-particle with high linear energy transfer during decay of 232Th. To revisit the mechanism of carcinogenesis by Thorotrast (THR), we examined the tissue distribution of THR granules and two-dimensional distribution of radioactivity in the organs of Thorotrastosis patients and studied their spatial relationship to histopathological changes. The high radioactivity in the patients' organ was predominantly derived from decay of Thorium series and showed unique distribution, while the far lower natural radioactivity was mainly from Uranium series decay and fairly evenly distributed. It was found that a large majority of THR granules were phagocytized by macrophages and were embedded in extensive fibrosis. Cancer was rarely in the center of THR deposition but rather at a distance from the deposits. These observations may indicate that the predominant feature of THR deposition is the tissue damage by direct hit of alpha-particles and subsequent fibrosis. The effect of THR resembles action of toxic chemical agents, as several authors have pointed out. We therefore assume that carcinogenesis in Thorotrastosis is a combination of events, such as regeneration of liver tissue after radiation damage, emission of secondary electrons, ionization of the surrounding tissue, and beta- or gamma-ray from daughter nuclei of Thorium (Th). In this context, the role of alpha-particle is important but more intriguing.

  10. c-myc protein in normal tissue. Effects of fixation on its apparent subcellular distribution.

    PubMed Central

    Loke, S. L.; Neckers, L. M.; Schwab, G.; Jaffe, E. S.

    1988-01-01

    The c-myc protein is thought to be a DNA-associated nuclear protein. However, immunohistochemical studies on normal or tumor tissues have shown conflicting findings on its subcellular distribution. By using various fixation procedures on cytospin preparations of HL60 cells, the authors found the subcellular distribution of the c-myc protein to be dependent on the method of fixation. When studying mouse tissues in frozen sections using a biotinylated monoclonal antibody against the c-myc protein, they found the protein to be widely distributed in various normal adult mouse tissues, in most cases localized to the nucleus. However, when these tissues were studied after formalin fixation and paraffin embedding, a loss of nuclear staining was observed concurrent with the appearance of c-myc protein immunoreactivity in the cytoplasm. It is concluded that immunohistochemical studies on the expression of this oncogene should take into consideration the effects of fixation when its subcellular distribution is being examined. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:3281469

  11. Early tissue distribution of therapeutic 131I in a patient with thyrotoxicosis.

    PubMed

    Vachal, E; Wegst, A; Preston, D; Tomita, T

    1979-01-01

    A therapeutic dose of 131I was given to a 53-year-old man with thyrotoxicosis three and one-half hours prior to death. The distribution of 131I in the thyroid gland was studied by autoradiography, and the radioactivity in various fresh tissues was measured. Radioactivity was distributed evenly throughout the colloid; small amounts were present in follicular cells. Radioactivity was not localized to the periphery of colloid follicles as observed in an earlier report. Papillary projections were associated with increased radioactivity. Decreased radioactivity was associated with oxyphilic cells. Measurement of 131I in individual tissues showed that per gram of tissue the thyroid gland contained approximately 50 times that of intestine and spleen and approximately 100 times that of liver and bone.

  12. 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

  13. 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...

  14. 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

    2015-10-06

    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.

  15. 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.

  16. Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets

    PubMed Central

    Sathaliyawala, Taheri; Kubota, Masaru; Yudanin, Naomi; Turner, Damian; Camp, Philip; Thome, Joseph J. C.; Bickham, Kara L.; Lerner, Harvey; Goldstein, Michael; Sykes, Megan; Kato, Tomoaki; Farber, Donna L.

    2012-01-01

    SUMMARY Knowledge of human T cells derives chiefly from studies of peripheral blood, whereas their distribution and function in tissues remains largely unknown. Here, we present a unique analysis of human T cells in lymphoid and mucosal tissues obtained from individual organ donors, revealing tissue-intrinsic compartmentalization of naive, effector and memory subsets conserved between diverse individuals. Effector-memory CD4+ T cells producing IL-2 predominated in mucosal tissues and accumulated as central-memory subsets in lymphoid tissue, whereas CD8+ T cells were maintained as naïve subsets in lymphoid tissues and IFN-γ-producing effector-memory CD8+ T cells in mucosal sites. The T cell activation marker, CD69, was constitutively expressed by memory T cells in all tissues, distinguishing them from circulating subsets, with mucosal memory T cells exhibiting additional distinct phenotypic and functional properties. Our results provide an assessment of human T cell compartmentalization as a new baseline for understanding human adaptive immunity. PMID:23260195

  17. Mechanism for the tissue distribution of grepafloxacin, a fluoroquinolone antibiotic, in rats.

    PubMed

    Suzuki, Takashi; Kato, Yukio; Sasabe, Hiroyuki; Itose, Minoru; Miyamoto, Gohachiro; Sugiyama, Yuichi

    2002-12-01

    This study was carried out to investigate the most important factor(s) governing the tissue distribution of grepafloxacin (GPFX), a fluoroquinolone antibiotic, in rats. The tissue-to-blood concentration ratio (K(p)) of GPFX at steady state during constant infusion was highest in the lung, followed by the pancreas, kidney, and spleen. After bolus injection, GPFX was efficiently taken up by most of the organs examined, the uptake clearance other than the lung being almost blood flow-limited. Approximately 10% of the intravenously injected dose was rapidly trapped by the lung, but GPFX distribution rapidly decreased within 30 s due to the washout by the plasma flow. Thus, the higher distribution of GPFX to the lung compared with the other organs cannot be accounted for by a difference in its uptake or efflux. Subcellular fractionation after the infusion indicated that GPFX is primarily distributed to the organelle fractions in most organs, 60% of lung-associated GPFX being recovered in the nucleus and plasma membrane fraction. Such subcellular distribution in the lung was proportional to the phosphatidylserine (PhS) content of each fraction. The steady-state K(p) value in each tissue in vivo also correlated with the tissue content of PhS. GPFX preferentially binds to PhS, compared with other phospholipids, and this binding was inhibited by weakly basic drugs, such as quinidine, imipramine, and propranolol, that have also been reported to bind to PhS. The association of GPFX with PhS synthase transformants of Chinese hamster ovary (CHO-K1) cells depends on the PhS content of each cell line, this association being also inhibited by basic drugs. These results suggest that binding of GPFX to PhS is the major determinant of the high distribution of GPFX to the lung.

  18. Topographic distribution of bcl-2 protein in feline tissues in health and neoplasia.

    PubMed

    Madewell, B R; Gandour-Edwards, R; Edwards, B F; Walls, J E; Griffey, S M

    1999-11-01

    The bcl-2 family of genes encodes proteins that influence apoptosis. In the present immunohistochemical study, the topographic distribution of bcl-2 protein was examined in healthy feline fetal, neonatal, and adult tissues, a feline renal cell line, and feline tumors obtained from a veterinary hospital. The topographic distribution of bcl-2 in healthy tissues was similar to that described in human tissues. In lymphoid tissues, follicular mantle cells strongly expressed bcl-2. In complex and differentiating epithelium, bcl-2 expression was detected in stem cell and proliferation zones. Bcl-2 expression was also detected in lower crypts of the intestine and in skin basal layers. The feline Crandell kidney cells expressed bcl-2 diffusely throughout the cytoplasm. Of 180 tumors examined, bcl-2 was expressed almost uniformly in cutaneous basal cell tumors, thyroid adenomas, and mammary carcinomas and in 50% of the lymphomas examined. Bcl-2 may play a role in blocking apoptotic cell death in a broad range of normal feline tissues, whereas dysregulated bcl-2 may extend the life of certain tumors or render certain tumors resistant to therapy because most chemotherapeutic and radiotherapeutic agents eliminate tumor cells by triggering apoptosis.

  19. 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.

  20. 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.

  1. Pharmacokinetics Application in Biophysics Experiments

    NASA Astrophysics Data System (ADS)

    Millet, Philippe; Lemoigne, Yves

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

  2. 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.

  3. 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

  4. 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

  5. Extraction of optical properties and prediction of light distribution in rat brain tissue

    NASA Astrophysics Data System (ADS)

    Azimipour, Mehdi; Baumgartner, Ryan; Liu, Yuming; Jacques, Steven L.; Eliceiri, Kevin; Pashaie, Ramin

    2014-07-01

    Predicting the distribution of light inside any turbid media, such as biological tissue, requires detailed information about the optical properties of the medium, including the absorption and scattering coefficients and the anisotropy factor. Particularly, in biophotonic applications where photons directly interact with the tissue, this information translates to system design optimization, precision in light delivery, and minimization of unintended consequences, such as phototoxicity or photobleaching. In recent years, optogenetics has opened up a new area in deep brain stimulation with light and the method is widely adapted by researchers for the study of the brain circuitries and the dynamics of neurological disorders. A key factor for a successful optogenetic stimulation is delivering an adequate amount of light to the targeted brain objects. The adequate amount of light needed to stimulate each brain object is identified by the tissue optical properties as well as the type of opsin expressed in the tissue, wavelength of the light, and the physical dimensions of the targeted area. Therefore, to implement a precise light delivery system for optogenetics, detailed information about the optical properties of the brain tissue and a mathematical model that incorporates all determining factors is needed to find a good estimation of light distribution in the brain. In general, three measurements are required to obtain the optical properties of any tissue, namely diffuse transmitted light, diffuse reflected light, and transmitted ballistic beam. In this report, these parameters were measured in vitro using intact rat brain slices of 500 μm thickness via a two-integrating spheres optical setup. Then, an inverse adding doubling method was used to extract the optical properties of the tissue from the collected data. These experiments were repeated to cover the whole brain tissue with high spatial resolution for the three different cuts (transverse, sagittal, and coronal

  6. 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.

  7. 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.

  8. [Physical and pharmacokinetic properties of anesthetics and sedatives used in neuroanesthesia and resuscitation].

    PubMed

    Egreteau, J P; Guedes, Y; L'Azou, D

    1991-01-01

    Pharmacokinetics of anesthetic drugs are widely influenced by their physical properties. Lipo-solubility is the most important characteristic. This parameter conditions tissue diffusion and subsequently potency and duration of action drugs Distribution is unequal in the different compartments of the body. The concept of effective compartment allows a best understanding of relationship between concentration, intensity and duration of action of anesthetic drugs. Constant intravenous infusion route of anesthetic drugs administration requires to be discussed.

  9. Altered distributions of bone tissue mineral and collagen properties in women with fragility fractures.

    PubMed

    Wang, Zhen Xiang; Lloyd, Ashley A; Burket, Jayme C; Gourion-Arsiquaud, Samuel; Donnelly, Eve

    2016-03-01

    Heterogeneity of bone tissue properties is emerging as a potential indicator of altered bone quality in pathologic tissue. The objective of this study was to compare the distributions of tissue properties in women with and without histories of fragility fractures using Fourier transform infrared (FTIR) imaging. We extended a prior study that examined the relationship of the mean FTIR properties to fracture risk by analyzing in detail the widths and the tails of the distributions of FTIR properties in biopsies from fracture and non-fracture cohorts. The mineral and matrix properties of cortical and trabecular iliac crest tissue were compared in biopsies from women with a history of fragility fracture (+Fx; n=21, age: mean 54±SD 15y) and with no history of fragility fracture (-Fx; n=12, age: 57±5y). A subset of the patients included in the -Fx group were taking estrogen-plus-progestin hormone replacement therapy (HRT) (-Fx+HRT n=8, age: 58±5y) and were analyzed separately from patients with no history of HRT (-Fx-HRT n=4, age: 56±7y). When the FTIR parameter mean values were examined by treatment group, the trabecular tissue of -Fx-HRT patients had a lower mineral:matrix ratio (M:M) and collagen maturity (XLR) than that of -Fx+HRT patients (-22% M:M, -18% XLR) and +Fx patients (-17% M:M, -18% XLR). Across multiple FTIR parameters, tissue from the -Fx-HRT group had smaller low-tail (5th percentile) values than that from the -Fx+HRT or +Fx groups. In trabecular collagen maturity and crystallinity (XST), the -Fx-HRT group had smaller low-tail values than those in the -Fx+HRT group (-16% XLR, -5% XST) and the +Fx group (-17% XLR, -7% XST). The relatively low values of trabecular mineral:matrix ratio and collagen maturity and smaller low-tail values of collagen maturity and crystallinity observed in the -Fx-HRT group are characteristic of younger tissue. Taken together, our data suggest that the presence of newly formed tissue that includes small/imperfect crystals

  10. Pharmacokinetics, Distribution, Metabolism, and Excretion of Omadacycline following a Single Intravenous or Oral Dose of 14C-Omadacycline in Rats

    PubMed Central

    Lin, Wen; Flarakos, Jimmy; Du, Yancy; Hu, Wenyu; He, Handan; Mangold, James; Tanaka, S. Ken

    2016-01-01

    ABSTRACT The absorption, distribution, metabolism, and excretion (ADME) of omadacycline, a first-in-class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive, Gram-negative, anaerobic, and atypical bacteria, were evaluated in rats. Tissue distribution was investigated by quantitative whole-body autoradiography in male Long-Evans Hooded (LEH) rats. Following an intravenous (i.v.) dose of 5 mg/kg of body weight, radioactivity widely and rapidly distributed into most tissues. The highest tissue-to-blood concentration ratios (t/b) were observed in bone mineral, thyroid gland, and Harderian gland at 24 h post-i.v. dose. There was no evidence of stable accumulation in uveal tract tissue, suggesting the absence of a stable binding interaction with melanin. Following a 90 mg/kg oral dose in LEH rats, the highest t/b were observed in bone mineral, Harderian gland, liver, spleen, and salivary gland. The plasma protein binding levels were 26% in the rat and 15% to 21% in other species. Omadacycline plasma clearance was 1.2 liters/h/kg, and its half-life was 4.6 h; the steady-state volume of distribution (Vss) was 6.89 liters/kg. Major circulating components in plasma were intact omadacycline and its epimer. Consistent with observations in human, approximately 80% of the dose was excreted into the feces as unchanged omadacycline after i.v. administration. Fecal excretion was primarily the result of biliary excretion (∼40%) and direct gastrointestinal secretion (∼30%). However, urinary excretion (∼30%) was equally prominent after i.v. dosing. PMID:27821446

  11. 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.

  12. Naringin Levels in Citrus Tissues : II. Quantitative Distribution of Naringin in Citrus paradisi MacFad.

    PubMed

    Jourdan, P S; McIntosh, C A; Mansell, R L

    1985-04-01

    The quantitative distribution of the flavanone-7-neohesperidoside, naringin, in seeds, seedlings, young plants, branches, flowers, and fruit of Citrus paradisi Macfad., cv ;Duncan' was analyzed by radioimmunoassay. High levels of naringin were associated with very young tissue and lower levels were found in older tissues. Seed coats of ungerminated seeds and young shoots had high naringin concentrations whereas cotyledons and roots had very low concentrations. Light-grown seedlings contained nearly twice as much naringin as etiolated seedlings and, in young plants and branches, the naringin content was highest in developing leaves and stem tissue. In flowers, the ovary had the highest levels of naringin, accounting for nearly 11% of the fresh weight. There was a net increase in the total naringin content of fruits during growth. However, due to the large increase in fruit size, there was a concomitant decrease in the naringin concentration as the fruit matured.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. [Pharmacokinetics of carbapenems].

    PubMed

    Suchánková, H; Rychlíčková, J; Urbánek, K

    2012-06-01

    Carbapenems, beta-lactam antibiotics, are ideal candidates for the treatment of serious nosocomial infections including sepsis for their exceptionally broad antibacterial spectrum and high efficiency. They are administered parenterally by intravenous infusion. Carbapenems penetrate well and rapidly into many different tissue compartments and the interstitial fluid. They are metabolized by renal dihydropeptidase-1. Therefore, imipenem must be co-administered with an inhibitor of dihydropeptidase-1. Other carbapenems registered in the Czech Republic (meropenem, ertapenem and doripenem) are more stable to this enzyme. Carbapenems are mainly eliminated via the kidneys and dose adjustment in patients with renal impairment is necessary. The elimination half-life of most carbapenems is around 1 hour with the exception of ertapenem, with 3.8-hour half-life, which allows its once-daily use. Carbapenems are a group of antibiotics with time-dependent effect. Their typical pharmaceutical property is a limited stability in solution after dilution. Administration in the prolonged infusion appears to be a convenient strategy to achieve higher efficiency. Pharmacokinetic parameters of carbapenems may vary individually, especially in critically ill patients and those treated by renal replacement therapy. Therefore, individualization of dosing regimens based on knowledge of pharmacokinetic parameters of individual patients may be useful.

  19. Tissue distribution and residue depletion of metronidazole in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Mitrowska, Kamila; Pekala, Agnieszka; Posyniak, Andrzej

    2015-01-01

    Tissue distribution and residue depletion of metronidazole (MNZ) was studied in rainbow trout (Oncorhynchus mykiss) following oral administration of MNZ in feed at the average dose of 25 mg kg(-1) body weight day(-1) for 7 days at 11 ± 2°C. The MNZ concentration in feed was 0.25% while daily feed intake was 1% of body weight. The concentrations of MNZ and its main metabolite, hydroxymetronidazole (MNZOH), in fish tissues were determined by LC-MS/MS. The drug was well distributed in tissues with maximum concentrations on day 1 post-administration. At this time, the mean MNZ concentrations in muscle, skin, kidney, liver and gill were 14,999, 20,269, 15,070, 10,102 and 16,467 µg kg(-1) respectively. MNZ was converted into MNZOH with the ratio of MNZOH:MNZ up to 7% in all fish tissues throughout the withdrawal period. This shows that MNZ itself is the main residue in rainbow trout. MNZ was detected at the level close to the decision limit (0.20 µg kg(-1)) in muscle, skin and muscle with adhering skin up to 42 days, while in kidney, liver and gill it was up to 28 days post-administration. MNZOH was eliminated more rapidly from fish tissues and it was present in muscle alone up to 21 days. The elimination half-lives of MNZ and MNZOH in rainbow trout tissues were 1.83-2.53 and 1.24-2.12 days, respectively. When muscle without skin was analysed, higher MNZ and MNZOH concentrations were detected, and for a longer period of time, than in muscle with adhering skin. Thus muscle alone could be more appropriate for the effective residue control of MNZ in rainbow trout. For the same reason, it is also essential to ensure direct cooling immediately after sampling, since MNZ and its metabolite degrade in fish muscle and skin stored in non-freezing conditions.

  20. A1 demonstrates restricted tissue distribution during embryonic development and functions to protect against cell death.

    PubMed Central

    Carrió, R.; López-Hoyos, M.; Jimeno, J.; Benedict, M. A.; Merino, R.; Benito, A.; Fernández-Luna, J. L.; Núñez, G.; García-Porrero, J. A.; Merino, J.

    1996-01-01

    Members of the bcl-2 gene family are essential regulators of cell survival in a wide range of biological processes. A1, a member of the family, is known to be expressed in certain adult tissues. However, the precise tissue distribution and function of A1 remains poorly understood. We show here that A1 is expressed in multiple tissues during murine embryonic development. In the embryo, A1 was detected first at embryonic day 11.5 in liver, brain, and limbs. At day 13.5 of gestation, A1 expression was observed in the central nervous system, liver, perichondrium, and digital zones of developing limbs in a pattern different from that of bcl-X. In the central nervous system of 15.5-day embryos, A1 was expressed at high levels in the ventricular zone and cortical plate of brain cortex. Significantly, the interdigital zones of limbs and the intermediate region of the developing brain cortex, two sites associated with extensive cell death, were devoid of A1 and bcl-X. The expression of A1 was retained in many adult tissues. To assess the ability of A1 to modulate cell death, stable transfectants expressing different amounts of A1 protein were generated in K562 cells. Expression of A1 was associated with retardation of apoptotic cell death induced by actinomycin D and cycloheximide as well as by okadaic acid. Confocal microscopy showed that the A1 protein was localized to the cytoplasm in a pattern similar to that of Bcl-2. These results demonstrate that the expression of A1 is wider than previously reported in adult tissues. Furthermore, its distribution in multiple tissues of the embryo suggests that A1 plays a role in the regulation of physiological cell death during embryonic development. Images Figure 1 Figure 2 Figure 3 Figure 5 PMID:8952545

  1. [Pharmacokinetics and biodistribution of 3H-norcantharidin in mice].

    PubMed

    Wei, Chun-Min; Wang, Ben-Jie; Ma, Ya; Sun, Zi-Ping; Li, Xiao-Li; Guo, Rui-Chen

    2007-05-01

    A single dose of 3H-norcantharidin solution was intragastrically given, blood, tissues, urine and feces were collected as scheduled, and radioactivity in these samples was determined by tritium tracing method to investigate the pharmacokinetics, tissue distribution and excretion of norcantharidin in Kunming mice. The pharmacokinetic characteristics of norcantharidin were evaluated by DAS version 2.0. The blood concentration reached to maximum 0. 5 h after intragastric administration. The radioactivity in tissues was high in small intestine, gallbladder, stomach, adrenal gland, kidney, heart and uterus 15 minutes after administration, descending with time, and high in gallbladder, adrenal gland and uterus 3 hours post dosing. The 24 h accumulative excretion ratio of urine and feces were 65.40% and 1.33% respectively. 3H-norcantharidin was easily absorbed after orally given to mice, the radioactivity was high and existed for a long-time in gallbladder, adrenal gland and uterus, and low but also existed for a long-time in large intestine, thymus and fat tissue. 3H-norcantharidin was declined quickly in small intestine, stomach, kidney and heart, and occurred rarely in brain. Norcantharidin was excreted mainly by urinary route and seldom in feces, which may be the cause of the urinary stimulation side effects observed. Because the radioactivity measured were the sum of 3H labeled norcantharidin and its metabolites, further studies on the disposition of norcantharidin in mammal animals, on the separation or identification of metabolites and, if any, on their activities, are fairly needed.

  2. 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.

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

    USGS Publications Warehouse

    May, T.W.; Wiedmeyer, Ray H.; Brown, L.D.; Casteel, S.W.

    1999-01-01

    In the United States lead is an ubiquitous environmental pollutant that is a serious human health hazard, especially for women of childbearing age, developing fetuses, and young children. Information concerning the uptake and distribution of lead to maternal and fetal tissues during pregnancy is poorly documented. A study was designed using domestic swine and lead isotope enrichment methodology to focus on maternal absorption and distribution of lead into bone and soft tissues, including the fetal compartment, under varying conditions of oral lead exposure and during altered physiological states (pregnant vs unbred). Total lead levels and Pb207/Pb206 ratios in bone (femur and vertebra), blood, and soft tissues (liver, kidney, brain) were determined by ICP-MS. Lead in fetal tissues derived from maternal bone could be differentiated from that derived from exogenous dosing. Unbred swine absorbed much less lead than pregnant females receiving the same dose. The accuracy and precision of ICP-MS at the instrumental level and for the entire method (sample collection, digestion, and analysis) were evaluated for both Pb207/Pb206 ratios and total lead. Several changes were suggested in method design to improve both instrumental and total method precision.

  4. Distribution of the feline calicivirus receptor junctional adhesion molecule a in feline tissues.

    PubMed

    Pesavento, P A; Stokol, T; Liu, H; van der List, D A; Gaffney, P M; Parker, J S

    2011-03-01

    Junctional adhesion molecule A (JAM-A) is an immunoglobulin superfamily protein that plays an important role in the assembly and maintenance of tight junctions and the establishment of epithelial cell polarity. The feline JAM-A (fJAM-A) is a functional receptor for feline calicivirus (FCV). Among natural diseases associated with FCV infection, isolates that cause oral vesicular disease are detected in epithelial cells; however, isolates that cause systemic disease are detected in multiple cell types. The distribution of an FCV receptor or receptors in feline tissues is relevant to viral pathogenesis in that it should reflect the wide latitude of clinical sequelae associated with FCV infection. The authors examined the expression of feline JAM-A in the cat by using confocal immunofluorescence localization on normal tissues, with special regard to tissue targets of naturally occurring FCV. As described in the human and the mouse, fJAM-A was widely distributed in feline tissues, where it localized at cell-cell junctions of epithelial and endothelial cells. fJAM-A was highly expressed on feline platelets, with lower levels of expression on feline peripheral blood leukocytes. Additionally, FCV infection of a feline epithelial cell monolayer causes redistribution of fJAM-A to the cytosol of infected cells. It is reasonable to propose that the spectrum of lesions caused by FCV reflects disruption of intercellular junctions that rely on fJAM-A function and tight junctional integrity.

  5. Tissue Distribution of Tungsten in Mice Following Oral Exposure to Sodium Tungstate

    DTIC Science & Technology

    2010-08-31

    1mL) solution under a pressure and temperature controlled microwave digestion system (MarsXpress, CEM Inc, Mathews, North Carolina, USA), and then... nickel and cobalt). These findings confirmed most of what has been published on tungsten tissue distribution; they also showed that the brain is...other organ or either of the other two metals that were analyzed ( nickel and cobalt). These findings confirmed most of what has been published on

  6. Clinical pharmacokinetics of levetiracetam.

    PubMed

    Patsalos, Philip N

    2004-01-01

    Since 1989, eight new antiepileptic drugs (AEDs) have been licensed for clinical use. Levetiracetam is the latest to be licensed and is used as adjunctive therapy for the treatment of adult patients with partial seizures with or without secondary generalisation that are refractory to other established first-line AEDs. Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. After oral ingestion, levetiracetam is rapidly absorbed, with peak concentration occurring after 1.3 hours, and its bioavailability is >95%. Co-ingestion of food slows the rate but not the extent of absorption. Levetiracetam is not bound to plasma proteins and has a volume of distribution of 0.5-0.7 L/kg. Plasma concentrations increase in proportion to dose over the clinically relevant dose range (500-5000 mg) and there is no evidence of accumulation during multiple administration. Steady-state blood concentrations are achieved within 24-48 hours. The elimination half-life in adult volunteers, adults with epilepsy, children with epilepsy and elderly volunteers is 6-8, 6-8, 5-7 and 10-11 hours, respectively. Approximately 34% of a levetiracetam dose is metabolised and 66% is excreted in urine unmetabolised; however, the metabolism is not hepatic but occurs primarily in blood by hydrolysis. Autoinduction is not a feature. As clearance is renal in nature it is directly dependent on creatinine clearance. Consequently, dosage adjustments are necessary for patients with moderate to severe renal impairment. To date, no clinically relevant pharmacokinetic interactions between AEDs and levetiracetam have been identified. Similarly, levetiracetam does not interact with digoxin, warfarin and the low-dose contraceptive pill; however, adverse pharmacodynamic interactions with carbamazepine and topiramate have been demonstrated. Overall, the pharmacokinetic characteristics of

  7. Tissue distribution and lipophorin transport of hydrocarbons and sex pheromones in the house fly, Musca domestica

    PubMed Central

    Schal, Coby; Sevala, Veeresh; de L.Capurro, Margareth; Snyder, Theodore E.; Blomquist, Gary J.; Bagnères, Anne–Geneviève

    2001-01-01

    We investigated the relationship between epicuticular and internal hydrocarbons in the adult house fly, Musca domestica and the distribution of hydrocarbons, including the female sex pheromone component, (Z)-9-tricosene, in tissues. Internal hydrocarbons increased dramatically in relation to sexual maturation and were found in the hemolymph, ovaries, digestive tract, and fat body. (Z)-9-Tricosene comprised a relatively large fraction of the hydrocarbons in the female carcass and hemolymph, and less so in other tissues, while other hydrocarbons were represented in greater amounts in the ovaries than in other tissues. It therefore appears that certain hydrocarbons were selectively provisioned to certain tissues such as the ovaries, from which pheromone was relatively excluded. Both KBr gradient ultracentrifugation and specific immunoprecipitation indicated that > 90% of hemolymph hydrocarbons were associated with a high-density lipophorin (density = 1.09 g ml−1), composed of two apoproteins under denaturing conditions, apolipophorin I (∼240 kD) and apolipophorin II (∼85 kD). Our results support a predicted model (Chino, 1985) that lipophorin is involved in the transport of sex pheromone in M. domestica. In addition to delivering hydrocarbons and sex pheromones to the cuticular surface, we suggest that lipophorin may play an important role in an active mechanism that selectively deposits certain subsets of hydrocarbons at specific tissues. PMID:15455072

  8. 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.

  9. Formulation, characterization and tissue distribution of a novel pH-sensitive long-circulating liposome-based theranostic suitable for molecular imaging and drug delivery

    PubMed Central

    Duan, Yin; Wei, Lihui; Petryk, Julia; Ruddy, Terrence D

    2016-01-01

    Purpose When designing liposome formulas for treatment and diagnostic purposes, two of the most common challenges are 1) the lack of a specific release mechanism for the encapsulated contents and 2) a short circulation time due to poor resistance to biological fluids. This study aimed to create a liposome formula with prolonged in vivo longevity and pH-sensitivity for cytoplasmic drug delivery. Materials and methods Liposomal particles were generated using hydrogenated soy (HS) phosphatidylcholine, cholesteryl hemisuccinate (CHEM), polyethylene glycol (PEG) and diethylenetriaminepentaacetic acid-modified phosphatidylethanolamine with film hydration and extrusion methods. The physicochemical properties of the different formulas were characterized. pH-sensitivity was evaluated through monitoring release of encapsulated calcein. Stability of the radiolabeled liposomes was assessed in vitro through incubation with human serum. The best formula was selected and injected into healthy rats to assess tissue uptake and pharmacokinetics. Results Liposomal particles were between 88 and 102 nm in diameter and negatively charged on the surface. Radiolabeling of all formulas with indium-111 was successful with good efficiency. 1%PEG-HS-CHEM not only responded to acidification very quickly but also underwent heavy degradation with serum. The 4%PEG-HS-CHEM, which exhibited both comparatively good pH-sensitivity (up to 20% release) and satisfactory stability (stability >70% after 24 h), was considered the best candidate for in vivo evaluation. Tissue distribution of 4%PEG-HS-CHEM was comparable to that of 4%PEG-HS-Chol, a long-circulating but pH-insensitive control, showing major accumulation in liver, spleen, intestine and kidneys. Analysis of blood clearance showed favorable half-life values: 0.6 and 14 h in fast and slow clearance phases, respectively. Conclusion 4%PEG-HS-CHEM showed promising results in pH-sensitivity, serum stability, tissue uptake and kinetics and is a novel

  10. EXPRESSION AND DISTRIBUTION OF THIOL-REGULATING ENZYME GLUTAREDOXIN 2 (GRX2) IN PORCINE OCULAR TISSUES*

    PubMed Central

    Upadhyaya, Bijaya; Tian, Xiaoli; Wu, Hongli; Lou, Marjorie F.

    2014-01-01

    Glutaredoxin2 (Grx2) is a mitochondrial isozyme of the cytosolic glutaredoxin1 (thioltransferase or TTase). Both belong to the large oxidoreductase family and play an important role in maintaining thiol/disulfide redox homeostasis in the cells. Grx2 is recently found in the lens where its activities of disulfide reductase and peroxidase, similar to TTase, can protect the lens against oxidative stress. Since other eye tissues are also highly sensitive to oxidative stress, and TTase’s distribution in the eye is known, we focused on this study by investigating the Grx2 distribution in the ocular tissues in comparison to the lens. Fresh porcine eyes were dissected into cornea, iris, ciliary body, the lens, vitreous humor, retina, and optic nerve. Each tissue (pooled from three eyes) was homogenized and processed for mitochondrial isolation. The mitochondrial fraction was analyzed for Grx2 protein using Western blotting with anti-Grx2 antibody, and Grx2 activity using the published procedure. The eye tissues were also measured for Grx2 mRNA expression by RT-PCR with GAPDH as the control. Grx2-rich mouse liver and purified recombinant mouse Grx2 were used as positive controls for the above analyses. It was found that Grx2 was present in all the tested ocular tissues, except vitreous humor. In comparison with the mouse liver, the protein levels of Grx2 in porcine ciliary body and the lens were 27-fold and 0.75-fold, respectively. Comparing to the lens, Grx2 protein was highest in the ciliary body (13.5-fold), followed by retina (9.2-fold), iris and optic nerve (2-fold), and cornea (1.2-fold). Enzyme activity assays showed that the retina had the highest Grx2 specific activity (3.9 mU/mg protein), followed by ciliary body (3.1 mU/mg), the lens (0.58 mU/mg), and optic nerve (0.32 mU/mg). Grx2 gene expression in these ocular tissues was further confirmed by RT-PCR analysis. Grx2 mRNA expression showed the highest in ciliary body, followed by retina, optic nerve, cornea

  11. 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

  12. Fat distribution and adipose tissue metabolism in non-obese male black African and Caucasian subjects.

    PubMed

    Ama, P F; Poehlman, E T; Simoneau, J A; Boulay, M R; Thériault, G; Tremblay, A; Bouchard, C

    1986-01-01

    Twenty-four male black African (25.5 +/- 3.0, mean +/- s.d., years of age) and 24 male Caucasian (21.5 +/- 3.6) subjects, ascertained as sedentary individuals, participated in this study designed to determine whether there were racial differences in fat distribution and adipose tissue metabolism while controlling the differences in body fat. An adipose tissue biopsy was obtained from the suprailiac region for the determination of basal (BL), epinephrine submaximal 10(-4) M (ESML) and maximal 10(-3) M (EML) stimulated lipolysis, basal (BLG) and maximal insulin 9 microU/ml (ILG) stimulated lipogenesis and heparin releasable lipoprotein lipase (LPL) activity. Body density was determined through underwater weighing procedures and body fat derived with the Siri equation. The following skinfolds were also measured: triceps, biceps, subscapular, abdomen, suprailiac, front thigh and medial calf. Caucasians were matched with the black Africans for age, body weight and body density. Results indicated that when Caucasians and black Africans of similar percentage body fat were compared, no significant differences were observed in the total amount of subcutaneous fat, fat distribution and suprailiac mean fat cell size. Moreover, no significant differences were observed between the two groups for BL, BLG, and ILG of adipose tissue. However, black Africans had higher (P less than 0.01) epinephrine stimulated lipolytic values (ESML and EML) and LPL activity (P less than 0.01) than the Caucasian subjects. These results suggest that for a comparable level of fatness and similar fat morphology and distribution, there are racial differences in adipose tissue metabolism.

  13. 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.

  14. 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.

  15. 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

  16. 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

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

    PubMed

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

    2014-07-01

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

  18. Pharmacokinetic and pharmacodynamic interactions between palifermin and heparin.

    PubMed

    Yang, Bing-Bing; Gillespie, Brad; Smith, Brian; Smith, William; Lissmats, Agneta; Rudebeck, Mattias; Kullenberg, Torbjörn; Olsson, Birgitta

    2015-10-01

    Oral mucositis, a severe complication during chemo- and/or radiotherapy, is prevented with palifermin treatment, a recombinant human keratinocyte growth factor (KGF/FGF-7). The FGF family belongs to the larger family of heparin-binding growth factors. Because it has been shown that heparin modulates binding of KGF to the KGF receptor and subsequently affects cellular proliferation induced by the KGF mitogenic signal, it is critical to understand the drug-drug interactions between palifermin and heparin, particularly because of heparin's narrow therapeutic margin. Two studies were performed in healthy subjects to characterize the effect of palifermin on the pharmacodynamics of heparin (activated partial thromboplastin time) and evaluate the impact of heparin on the pharmacokinetics and pharmacodynamics (Ki67 staining of buccal mucosal tissue) of palifermin. Results demonstrated a pronounced pharmacokinetic interaction; heparin coadministration increased the palifermin AUC 4- to 5-fold and decreased its half-life by 40%-45%, suggesting an approximate 70%-80% decrease in palifermin clearance and volume of distribution. These changes in the pharmacokinetics of palifermin during coadministration of heparin, however, did not affect the pharmacodynamic effect of palifermin, or the anticoagulant activity of heparin, and did not lead to increased safety findings. Therefore, these results suggest that dose adjustments for heparin and palifermin are not warranted when administered concurrently.

  19. 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.

  20. 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...

  1. 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.

  2. Pathogenicity, transmissibility, and tissue distribution of avian pneumovirus in turkey poults.

    PubMed

    Alkhalaf, A N; Ward, L A; Dearth, R N; Saif, Y M

    2002-01-01

    The pathogenicity, transmissibility, tissue distribution, and persistence of avian pneumovirus (APV) in turkey poults were investigated in three experiments. In the first experiment, we inoculated 2-wk-old commercial turkey poults oculonasally with APV alone or in combination with Bordetella avium. In the dually infected group, clinical signs were more severe, the virus persisted longer, the bacteria invaded more respiratory tissues, and the birds had higher antibody titer than the group exposed to APV or B. avium alone. In the second experiment, we studied the distribution of APV in different tissues in experimentally inoculated 2-wk-old commercial turkey poults. Only samples from sinuses, tracheas, and lungs were positive for APV by both reverse transcriptase-polymerase chain reaction and virus isolation. In the third experiment, we studied the ability of APV to spread among birds in 1-wk-old commercial turkey poults inoculated oculonasally. The virus was isolated and the viral RNA was detected in the inoculated and direct contact birds. The virus was not isolated, viral RNA was not detected, and no antibodies were detected in the indirect contact birds. These birds were placed in different cages in the same room where the airflow was directed from the infected toward the uninfected indirect contact group.

  3. 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

  4. 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

  5. Differences in tissue distribution of iron from various clinically used intravenous iron complexes in fetal avian heart and liver.

    PubMed

    Spicher, Karsten; Brendler-Schwaab, Susanne; Schlösser, Christoph; Catarinolo, Maria; Fütterer, Sören; Langguth, Peter; Enzmann, Harald

    2015-10-01

    Nanomedicines are more complex than most pharmacologically active substances or medicines and have been considered as non-biological complex drugs. For nanomedicines pivotal pharmacokinetic properties cannot be assessed by plasma concentration data from standard bioequivalence studies. Using intravenous iron complexes (IICs) as model we show that fetal avian tissues can be used to study time dependent tissue concentrations in heart and liver. Clear differences were found between equimolar doses of sucrose, gluconate or carboxymaltose coated iron particles. The range in tissue iron concentrations observed with these clinically widely used IICs provides an orientation as to what should be acceptable for any new IICs. Moreover, sensitivity of the experimental model was high enough to detect a 20% difference in tissue iron concentration. For the authorization of generic products under Article 10 (1) of Directive 2001/83/EC a plasma concentration of an active substance in the range of 80%-125% versus the reference product is usually considered acceptable. Based on its high discriminatory sensitivity this method was used to support a positive marketing authorization decision for a generic nanomedicine product.

  6. Tissue distributions of fluoride and its toxicity in the gills of a freshwater teleost, Cyprinus carpio.

    PubMed

    Cao, Jinling; Chen, Jianjie; Wang, Jundong; Wu, Xiangtian; Li, Yundong; Xie, Lingtian

    2013-04-15

    Fish take up fluoride directly from water and are susceptible to fluoride contamination of their environment. In this study, we examined the tissue distributions of fluoride and its toxicity in the gills of the common carp (Cyprinus carpio) chronically exposed to fluoride. Carp were exposed to a range of aqueous fluoride (35-124 mg/L) and sampled at 30, 60 and 90 days. The accumulation of fluoride in the tissues increased with the level and duration of exposure. Steady state was not achieved under the experimental conditions. The gills accumulated the highest levels of fluoride followed by the liver>brain>kidney>muscle>intestine. A dose-dependent inhibition was observed for the enzyme activities of Na(+)-K(+)-ATPase and Ca(2+)-ATPase in the gills after the fish were exposed for 90 days. Also, accumulation of fluoride was associated with the inhibition of superoxide dismutase (SOD) activities and a dose-dependent stimulation of malondialdehyde (MDA) levels in the gill tissues, suggesting that fluoride promoted oxidative stress in the fish. Microscopic examinations revealed injuries to gill tissues and chloride cells, with the severity of injury increasing with exposure concentration. These results suggest that chronic exposure to elevated concentrations of fluoride may induce toxicity in the common carp.

  7. Claudin-1, -2, -4, and -5: comparison of expression levels and distribution in equine tissues

    PubMed Central

    Lee, Bonn; Kang, Hee Young; Lee, Dong Oh; Ahn, Changhwan

    2016-01-01

    Claudins, which are known as transmembrane proteins play an essential role in tight junctions (TJs) to form physical barriers and regulate paracellular transportation. To understand equine diseases, it is helpful to measure the tissue-specific expression of TJs in horses. Major equine diseases such as colic and West Nile cause damage to TJs. In this study, the expression level and distribution of claudin-1, -2, -4, and -5 in eight tissues were assessed by Western blotting and immunohistochemistry methods. Claudin-1 was primarily identified in the lung, duodenum, and uterus, claudin-2 was evenly observed in equine tissues, claudin-4 was abundantly detected in the liver, kidney and uterus, and claudin-5 was strongly expressed in the lung, duodenum, ovary, and uterus, as determined by Western blotting method. The localization of equine claudins was observed by immunohistochemistry methods. These findings provide knowledge regarding the expression patterns and localization of equine claudins, as well as valuable information to understand tight junction-related diseases according to tissue specificity and function of claudins in horses. PMID:27030194

  8. Oral absorption and tissue distribution of a new squalenoyl anticancer nanomedicine

    NASA Astrophysics Data System (ADS)

    Harivardhan Reddy, L.; Ferreira, Humberto; Dubernet, Catherine; Mouelhi, Sinda Lepetre; Desmaële, Didier; Rousseau, Bernard; Couvreur, Patrick

    2008-05-01

    Recently, we had discovered that the linkage of nucleoside analogues to squalene, a precursor in the sterol biosynthesis, led to amphiphilic molecules, which self-organized in water as nanoassemblies of 100-300 nm in diameter, irrespective of the nucleoside analogue used. Thus, it was observed that the 4-( N)-trisnorsqualenoylgemcitabine (SQdFdC), the squalenoyl prodrug of the anticancer nucleoside analogue gemcitabine, was impressively more active than its parent compound gemcitabine, both in vitro and in vivo on experimental leukaemia. Since squalene, which is a natural constituent of shark liver and olive oil, is known to be absorbed orally, we investigated in this short note the absorption and tissue distribution of 3H-radiolabelled SQdFdC nanoassemblies comparatively to 3H-gemcitabine after oral administration to mice. Whereas gemcitabine was found to be rapidly absorbed ( t max = 1 h), this compound underwent a rapid clearance from the plasma. Conversely, the SQdFdC nanoassemblies displayed slower absorption followed by the progressive tissue accumulation, and they exhibited a lower clearance rate. The accumulation of the SQdFdC nanoassemblies in tissues such as pancreas, thymus, lung, liver and spleen (except at 1 h post-administration) was similar to that of the gemcitabine, yet exhibited significantly greater penetration and retention into the stomach and intestinal tissues comparatively to gemcitabine. Thus, the SQdFdC nanoassemblies could be of potential interest in the treatment of gastrointestinal tumours by oral route.

  9. Reconstruction of fluorescence distribution hidden in biological tissue using mesoscopic epifluorescence tomography

    NASA Astrophysics Data System (ADS)

    Björn, Saskia; Englmeier, Karl-Hans; Ntziachristos, Vasilis; Schulz, Ralf

    2011-04-01

    Mesoscopic epifluorescence tomography is a novel technique that discovers fluorescence bio-distribution in small animals by tomographic means in reflectance geometry. A collimated laser beam is scanned over the skin surface to excite fluorophores hidden within the tissue while a CCD camera acquires an image of the fluorescence emission for each source position. This configuration is highly efficient in the visible spectrum range where trans-illumination imaging of small animals is not feasible due to the high tissue absorption and scattering in biological organisms. The reconstruction algorithm is similar to the one used in fluorescence molecular tomography. However, diffusion theory cannot be employed since the source-detector separation for most image pixels is comparable to or below the scattering length of the tissue. Instead Monte Carlo simulations are utilized to predict the sensitivity functions. In a phantom study we show the effect of using enhanced source grid arrangements during the data acquisition and the reconstruction process to minimize boundary artefacts. Furthermore, we present ex vivo data that show high spatial resolution and quantitative accuracy in heterogeneous tissues using GFP-like fluorescence in B6-albino mice up to a depth of 1100 μm.

  10. Pharmacokinetic population study to describe cefepime lung concentrations.

    PubMed

    Breilh, D; Saux, M C; Delaisement, C; Fratta, A; Ducint, D; Velly, J F; Couraud, L

    2001-01-01

    Pharmacokinetic parameters of cefepime in 2 g plasma and lung tissue bid over 3 days to achieve the steady-state was studied in 16 patients (15 male, one female) subjected to lung surgery for bronchial epithelioma. The aims of this study were firstly to quantify cefepime lung diffusion with cefepime lung concentrations in comparison with cefepime serum concentrations, and secondly to estimate population pharmacokinetic parameters of cefepime in lung tissue using NONMEM. The mean characteristics of patients were: age, 60 years (range, 51-69 years), weight, 73 kg (range, 62-87 kg) and creatinine clearance, 77 ml/min (range, 62-92 ml/min). Both serum sample (two per patient) and lung sample (one per patient) cefepime concentrations were analysed by HPLC with UV detection. Five groups were made according to the time of sampling after the last cefepime intravenous infusion at the fifth infusion: 0.5 h (n=2), 2 h (n=5), 4 h (n=3), 8 h (n=3) and 12 h (n=3). The cefepime concentration ratio between lung and serum was calculated for each group and statistical analysis show no significant difference between groups. The mean concentration ratio between lung and serum was 101% (range, 70-130%). To explain this observation a two-compartment pharmacokinetic model with a population approach was used to describe pharmacokinetic parameters of cefepime both in lung and in serum. Serum was assimilated at the central compartment and lung was the peripheral compartment. NONMEM was used to estimate the mean and the variance of the pharmacokinetic parameters. Central volume of distribution (V(d)), steady-state volume of distribution (V(ss)), central clearance (CL) and transfer constants (K(cp)) from serum to lung and (K(pc)) from lung to serum were estimated. Central elimination half-life t(1/2Kbeta)was extrapolated from elimination constant beta. Results were: V(d)= 15.62 +/- 2.56 l, V(ss)= 17.58 +/- 2.58 l, CL = 3.65 +/- 1.25 l/h, beta = 0.234 h(-1), t(1/2beta)= 2.96 hours, K(cp)= 12

  11. Comparative expression and tissue distribution analyses of astacin-like squid metalloprotease in squid and cuttlefish.

    PubMed

    Kanzawa, Nobuyuki; Ogawa, Takuya; Asakura, Masanori; Okiyama, Keisuke; Honda, Michiyo; Tsuchiya, Takahide

    2008-01-01

    Astacin-like squid metalloprotease (ALSM) is a member of the astacin family of metalloproteases. In the present study, we investigated the expression and tissue distribution of ALSM in bigfin reef squid (Sepioteuthis lessoniana) and golden cuttlefish (Sepia esculenta). Myosin heavy chain hydrolysis tests showed ALSM-I-like activity in both species. We isolated partial cDNA clones showing high sequence similarity to ALSM-I and -III, suggesting that ALSM is common to squid and cuttlefish. Phylogenetic analysis showed that ALSMs are classified into two clades: ALSM-I forms one clade, and ALSM-II and -III form the other. ALSM was expressed in several tissues in bigfin reef squid, though expression was confined to the liver in cuttlefish. ALSMs are distributed in digestive organs but not in mantle muscle of squid and cuttlefish. Immunofluorescence analysis further showed that cellular localization of ALSM is evident not only in hepatic cells but also in pancreatic cells of bigfin reef squid. Thus, ALSM is commonly expressed in squid and cuttlefish, but its expression levels and distribution are distinct.

  12. Tissue distribution, synthesis stage, and ethylene induction of pineapple (Ananas comosus) chitinases.

    PubMed

    Taira, Toki; Toma, Noriko; Ichi, Marika; Takeuchi, Makoto; Ishihara, Masanobu

    2005-04-01

    We examined the tissue distribution, synthesis stage, and ethylene induction of three types of pineapple chitinase using chitinase activity gel and immunoblot analysis. Type A (acidic class III) exists in all tissues, while type B (weakly basic class I, which has strong antifungal activity) and type C (acidic class I) are localized mainly in the leaf and stem. In a pericarp, type A exists at all stages during fruit development, while type B and type C exist only at the early stage. Synthesis of type A is induced by ethylene, while that of types B and C is not affected by it. These results suggest that the physiological roles of these three types of chitinase in pineapple are different.

  13. Estimation of thermal distribution in tissue-mimicking phantom made of carrageenan gel

    NASA Astrophysics Data System (ADS)

    Kim, Jungsoon; Jung, Jihee; Kim, Moojoon; Ha, Kanglyeol

    2015-07-01

    To probe the temperature elevation effect caused by ultrasound, the use of a tissue-mimicking phantom was newly suggested. Carrageenan gel was adopted to realize not only the required transparency for visualization but also the acoustic characteristics similar to those of human tissue. To visualize the temperature elevation effect inside the phantom, thermochromic film with a critical temperature of discoloration was introduced. From the visualized image, the temperature elevation due to planar and focused ultrasound in the phantom was obtained quantitatively. To verify the suggested method, the bioheat equation was solved numerically by the Fourier transform method. The theoretical results show good agreement with experimental ones regarding the temperature distribution while plane and focused ultrasound was irradiated into the phantom.

  14. Prion-Seeding Activity Is widely Distributed in Tissues of Sporadic Creutzfeldt-Jakob Disease Patients.

    PubMed

    Takatsuki, Hanae; Fuse, Takayuki; Nakagaki, Takehiro; Mori, Tsuyoshi; Mihara, Ban; Takao, Masaki; Iwasaki, Yasushi; Yoshida, Mari; Murayama, Shigeo; Atarashi, Ryuichiro; Nishida, Noriyuki; Satoh, Katsuya

    2016-10-01

    Human prion diseases are neurodegenerative disorders caused by abnormally folded prion proteins in the central nervous system. These proteins can be detected using the quaking-induced conversion assay. Compared with other bioassays, this assay is extremely sensitive and was used in the present study to determine prion distribution in sporadic Creutzfeldt-Jakob disease patients at autopsy. Although infectivity of the sporadic form is thought to be restricted within the central nervous system, results showed that prion-seeding activities reach 10(6)/g from a 50% seeding dose in non-neuronal tissues, suggesting that prion-seeding activity exists in non-neural organs, and we suggested that non-neural tissues of 10(6)/g SD50 did not exist the infectivity.

  15. Tissue distribution comparison between healthy and fatty liver rats after oral administration of hawthorn leaf extract.

    PubMed

    Yin, Jingjing; Qu, Jianguo; Zhang, Wenjie; Lu, Dongrui; Gao, Yucong; Ying, Xixiang; Kang, Tingguo

    2014-05-01

    Hawthorn leaves, a well-known traditional Chinese medicine, have been widely used for treating cardiovascular and fatty liver diseases. The present study aimed to investigate the therapeutic basis treating fatty liver disease by comparing the tissue distribution of six compounds of hawthorn leaf extract (HLE) in fatty liver rats and healthy rats after oral administration at first day, half month and one month, separately. Therefore, a sensitive and specific HPLC method with internal standard was developed and validated to determine chlorogenic acid, vitexin-4''-O-glucoside, vitexin-2''-O-rhamnoside, vitexin, rutin and hyperoside in the tissues including heart, liver, spleen, kidney, stomach and intestine. The results indicated that the six compounds in HLE presented some bioactivity in treating rat fatty liver as the concentrations of the six compounds varied significantly in inter- and intragroup comparisons (healthy and/or fatty liver group).

  16. Tissue distribution of bovine viral diarrhea virus antigens in persistently infected cattle.

    PubMed

    Shin, T; Acland, H

    2001-08-01

    The tissue distribution and cellular localization of viral antigens in three cattle with persistent bovine viral diarrhea virus (BVDV) infection was studied. In three cases, necropsy findings of oral ulcers, abmasal ulcers and necrosis of Peyer's patches were suspected have been caused by BVDV infection. Non-cytopathic BVDV was isolated from a tissue pool of liver, kidneys and spleen. Immunohistochemical detection of BVDV showed that BVDV antigens were detected in both epithelial and nonepithelial cells in all examined organs, including the gastrointestinal tract, liver, pancreas, lung, lymphatic organs (spleen, lymph nodes), adrenal gland, ovary, uterus, and the mammary gland. These findings support the hypothesis that animals with persistent BVDV infection spread BVDV through all routes, and that infertility in BVDV infection is associated with the infection of BVDV in the ovaries and uteri.

  17. SU-E-T-388: Evaluation of Electronic Brachytherapy Dose Distributions in Tissue Equivalent Materials

    SciTech Connect

    Johnson, M; Ahmad, S; Johnson, D

    2015-06-15

    Purpose: To study the measured and calculated dose distributions for electronic brachytherapy (EBT) in various tissue equivalent homogenous materials. Methods: Calculated dose distributions in water were generated using published TG-43 parameters in Varian BrachyVision software for a 50 kVp, 50 cm Xoft source. Dose distributions were measured within a 3D-scanning tank using dosimeters including: PTW 0.125 cc, pin-point, and parallel-plate ion chambers, Sun Nuclear “Edge” diode and Gafchromic EBT3 film. Multi-channel film dosimetry was used in film analysis. EBT3 film curves were calibrated via radial dose comparison to both independently measured and published data. The resulting film calibration was utilized to measure dose distributions created by titanium filtered source utilized in clinical brachytherapy applications. Data was collected within homogenous PMMA, vinyl, polystyrene, paraffin, and water-equivalent plastic phantoms. Results: Ion-chamber data was corrected to effective points of measurement and normalized prior to comparison between calculated and measured dose distributions. Measurements made in water and water equivalent materials compared well with results from treatment planning software. The maximum percent differences (relative to water) observed between 1 cm and 3.5 cm depth from source for each of the phantom materials are as follows: PMMA 35%, polystyrene 41%, plastic-water 23%, vinyl 115%, and paraffin 46%. Conclusion: The increased probability of photoelectric interactions occurring within the patient during electronic brachytherapy will emphasize the radiological differences between varying human tissues in dose deposition. These differences can Result in clinically significant dose perturbations and it is therefore recommended to move to a model based dose calculation, as outlined in TG-186, to improve the dosimetric accuracy of low energy EBT.

  18. Tissue distribution of cells derived from the area opaca in heterospecific quail-chick blastodermal chimeras.

    PubMed

    Karagenç, Levent; Sandikci, Mustafa

    2010-01-01

    The objective of the current study was to determine the tissue distribution of cells derived from the area opaca in heterospecific quail-chick blastodermal chimeras. Quail-chick chimeras were constructed by transferring dissociated cells from the area opaca of the stage X-XII (EG&K) quail embryo into the subgerminal cavity of the unincubated chick blastoderm. The distribution of quail cells in embryonic as well as extra-embryonic tissues of the recipient embryo were examined using the QCPN monoclonal antibody after 6 days of incubation in serial sections taken at 100-mum intervals. Data gathered in the present study demonstrated that, when introduced into the subgerminal cavity of a recipient embryo, cells of the area opaca are able to populate not only extra-embryonic structures such as the amnion and the yolk sac, but also various embryonic tissues derived from the ectoderm and less frequently the mesoderm. Ectodermal chimerism was confined mainly to the head region and was observed in tissues derived from the neural ectoderm and the surface ectoderm, including the optic cup, diencephalon and lens. Although the possibility of random incorporation of transplanted cells into these embryonic structures cannot be excluded, these results would suggest that area opaca, a peripheral ring of cells in the avian embryo destined to form the extra-embryonic ectoderm and endoderm of the yolk sac, might harbor cells that have the potential to give rise to various cell types in the recipient chick embryo, including those derived from the surface ectoderm and neural ectoderm.

  19. Tissue distribution and clearance of intravenously administered titanium dioxide (TiO2) nanoparticles.

    PubMed

    Shinohara, Naohide; Danno, Nobuko; Ichinose, Takayuki; Sasaki, Takeshi; Fukui, Hiroko; Honda, Kazumasa; Gamo, Masashi

    2014-03-01

    The organ-tissue distribution and clearance of Degussa P25 TiO2 nanoparticles were determined after intravenous administration to rats (0.95 mg/kg bodyweight) using an inductively coupled plasma sector field mass spectrometer. The detection limits of Ti analysis, 0.54 and 1.4 ng/mL for blood and urine and 0.35-2.0 ng/g tissue for several organ tissues, enabled determination of tissue distribution and clearance for organs in which Ti content could not be previously determined due to low concentrations. Blood concentrations of TiO2 were 420 and 19 ng/mL at 5 and 15 min after administration, which were equivalent of only 2.8% and 0.13% of the administration dose, respectively. At 6 h, 94%, 2.0%, 0.17%, 0.023%, 0.014% and 0.026% of administered TiO2 was found in the liver, spleen, lung, kidney, heart and blood, respectively. Liver and spleen TiO2 burden was significantly higher in the administration than control group (p < 0.01) and did not decrease up to 30 days after administration, while TiO2 burden in the lung, kidney, heart and blood decreased over time. A two-step decay model was more suitable than a one-step decay model for the decay curves of pulmonary TiO2 burden but did not improve fitting to the decay curves of kidney TiO2 burden. No translocation to the brain was confirmed at a lower detection limit than was applied in previous studies. Ti content in faeces and urine in the TiO2 administration group did not differ from that in the control group.

  20. Tissue distribution of a coliphage and Escherichia coli in mussels after contamination and depuration.

    PubMed Central

    Power, U F; Collins, J K

    1990-01-01

    Experiments were undertaken to determine the tissue distribution of Escherichia coli and a coliphage after contamination of the common mussel (Mytilus edulis). Mussels were contaminated with high levels of feces-associated E. coli and a 22-nm icosahedral coliphage over a 2-day period in a flowing-seawater facility. After contamination, individual tissues were carefully dissected and assayed for E. coli and the coliphage. Contaminated mussels were also analyzed to determine the tissue distribution of the contaminants after 24- and 48-h depuration periods. The majority of each contaminant was located in the digestive tract (94 and 89% of E. coli and coliphage, respectively). Decreasing concentrations were found in the gills and labial palps, foot and muscles, mantle lobes, and hemolymph. Our results indicate that contamination above levels in water occurred only in the digestive tract. Contaminated mussels were depurated in a commercial-scale recirculating UV depuration system over a 48-h period. The percent reductions of E. coli occurred in the following order: digestive tract, hemolymph, foot and muscles, mantle lobes, and gills and labial palps. The percent reductions of the coliphage were different, occurring in the following order: hemolymph, foot and muscles, gills and labial palps, mantle lobes, and digestive tract. Our results clearly demonstrate that E. coli and the coliphage are differentially eliminated from the digestive tract. The two microorganisms are eliminated at similar rates from the remaining tissues. Our results also clearly show that the most significant coliphage retention after depuration for 48 h is in the digestive tract. Thus, conventional depuration practices are inappropriate for efficient virus elimination from mussels. PMID:2180372

  1. Tissue distribution of tungsten in mice following oral exposure to sodium tungstate.

    PubMed

    Guandalini, Gustavo S; Zhang, Lingsu; Fornero, Elisa; Centeno, Jose A; Mokashi, Vishwesh P; Ortiz, Pedro A; Stockelman, Michael D; Osterburg, Andrew R; Chapman, Gail G

    2011-04-18

    Heavy metal tungsten alloys have replaced lead and depleted uranium in many munitions applications, due to public perception of these elements as environmentally unsafe. Tungsten materials left in the environment may become bioaccessible as tungstate, which might lead to population exposure through water and soil contamination. Although tungsten had been considered a relatively inert and toxicologically safe material, recent research findings have raised concerns about possible deleterious health effects after acute and chronic exposure to this metal. This investigation describes tissue distribution of tungsten in mice following oral exposure to sodium tungstate. Twenty-four 6-9 weeks-old C57BL/6 laboratory mice were exposed to different oral doses of sodium tungstate (0, 62.5, 125, and 200 mg/kg/d) for 28 days, and after one day, six organs were harvested for trace element analysis with inductively coupled plasma mass spectrometry (ICP-MS). Kidney, liver, colon, bone, brain, and spleen were analyzed by sector-field high-resolution ICP-MS. The results showed increasing tungsten levels in all organs with increased dose of exposure, with the highest concentration found in the bones and the lowest concentration found in brain tissue. Gender differences were noticed only in the spleen (higher concentration of tungsten in female animals), and increasing tungsten levels in this organ were correlated with increased iron levels, something that was not observed for any other organ or either of the two other metals analyzed (nickel and cobalt). These findings confirmed most of what has been published on tungsten tissue distribution; they also showed that the brain is relatively protected from oral exposure. Further studies are necessary to clarify the findings in splenic tissue, focusing on possible immunological effects of tungsten exposure.

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

    PubMed Central

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

    2014-01-01

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

  3. 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.

  4. Dermal pharmacokinetics of Terpinen-4-ol following topical administration of Zingiber cassumunar (plai) oil.

    PubMed

    Chooluck, Kotchaphan; Singh, Rajendra P; Sathirakul, Korbtham; Derendorf, Hartmut

    2012-11-01

    The purpose of this study was to investigate dermal pharmacokinetics of terpinen-4-ol in rats following topical administration of plai oil derived from the rhizomes of Zingiber cassumunar Roxb. Unbound terpinen-4-ol concentrations in dermal tissue were measured by microdialysis. The dermal pharmacokinetic study of terpinen-4-ol was performed under non-occlusive conditions. The oil was topically applied at a dose of 2, 4, and 8 mg/cm2 plai oil corresponding to the amount of 1.0, 1.9, and 3.8 mg/cm2 terpinen-4-ol, respectively. Following topical application of the oil, terpinen-4-ol rapidly distributed into the dermis and demonstrated linear pharmacokinetics with no changes in the dose-normalized area under the concentration-time curves across the investigated dosage range. The mean percentages of free terpinen-4-ol distributed in the dermis per amount of administered were 0.39 ± 0.06 %, 0.41 ± 0.08 %, and 0.30 ± 0.03 % for 2, 4, and 8 mg/cm2 doses, respectively. The dermal pharmacokinetics of terpinen-4-ol could provide information for its further formulation development and therapy schedules.

  5. 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.

  6. Automated Anatomical Interpretation of Ion Distributions in Tissue: Linking Imaging Mass Spectrometry to Curated Atlases

    PubMed Central

    2015-01-01

    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

  7. Distribution of lymphatic tissues and autonomic nerves in supporting ligaments around the cervix uteri.

    PubMed

    Zhang, Jianping; Feng, Lanlan; Lu, Yi; Guo, Dongxia; Xi, Tengteng; Wang, Xiaochun

    2013-05-01

    To investigate the distribution of lymphatic tissues and nerves in the supporting ligaments around the cervix uteri for their tomographical relationship, 9 adult female cadavers were used in this study. Following the incision of all supporting ligaments around the cervix, hematoxylin and esosin (H&E) and immunohistochemical staining of various sections of these ligaments was performed to enable the distribution of lymph tissues and autonomic nerves to be observed. Four lymph nodes were identified in three cadaver specimens. Three lymph nodes were present at a distance of 2.0 cm from the cervix in the cranial side of the cardinal ligaments (CLs), and one lymph node was located at a distance of 4.0 cm from the cervix in the cranial side of the uterosacral ligament (USL). The lymphatic vessels were dispersed in the CLs, scattered in the cervical side of the USLs, and occasionally distributed in the vesicouterine ligaments (VULs). In the CLs, parasympathetic nerves were located at the pelvic lateral wall and went downwards and medially into the cervix, while sympathetic fibers were located in the middle and lower parts of the ligaments. In the USLs, the autonomic nerves, which consisted primarily of sympathetic fibers, went downwards and laterally from the pelvic wall to the cervix. In the VULs, parasympathetic and sympathetic nerves were located in the inner sides of the vesical veins in the deep layers of the ligaments. It is concluded that there are few lymphatic tissues in the supporting ligaments around the cervix uteri, and that nerve‑sparing radical hysterectomy (NSRH) may be a safe method for the treatment of early‑stage cervical cancer.

  8. 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...

  9. 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.

  10. Tissue Iron Distribution Assessed by MRI in Patients with Iron Loading Anemias

    PubMed Central

    Gutiérrez, Lucía; House, Michael J.; Vasavda, Nisha; Drašar, Emma; Gonzalez-Gascon y Marin, Isabel; Kulasekararaj, Austin G.; St Pierre, Tim G.; Thein, Swee L.

    2015-01-01

    Bone marrow, spleen, liver and kidney proton transverse relaxation rates (R2), together with cardiac R2* from patients with sickle cell disease (SCD), paroxysmal nocturnal hemoglobinuria (PNH) and non-transfusion dependent thalassemia (NTDT) have been compared with a control group. Increased liver and bone marrow R2 values for the three groups of patients in comparison with the controls have been found. SCD and PNH patients also present an increased spleen R2 in comparison with the controls. The simultaneous measurement of R2 values for several tissue types by magnetic resonance imaging (MRI) has allowed the identification of iron distribution patterns in diseases associated with iron imbalance. Preferential liver iron loading is found in the highly transfused SCD patients, while the low transfused ones present a preferential iron loading of the spleen. Similar to the highly transfused SCD group, PNH patients preferentially accumulate iron in the liver. A reduced spleen iron accumulation in comparison with the liver and bone marrow loading has been found in NTDT patients, presumably related to the differential increased intestinal iron absorption. The correlation between serum ferritin and tissue R2 is moderate to good for the liver, spleen and bone marrow in SCD and PNH patients. However, serum ferritin does not correlate with NTDT liver R2, spleen R2 or heart R2*. As opposed to serum ferritin measurements, tissue R2 values are a more direct measurement of each tissue’s iron loading. This kind of determination will allow a better understanding of the different patterns of tissue iron biodistribution in diseases predisposed to tissue iron accumulation. PMID:26406992

  11. Distributed self-regulation of living tissue: Beyond the ideal limit

    NASA Astrophysics Data System (ADS)

    Lubashevsky, Wassily; Lubashevsky, Ihor; Mahnke, Reinhard

    2010-02-01

    The present paper is devoted to mathematical description of the vascular network response to local perturbations in the cellular tissue state, being one of the basic mechanisms controlling the inner environment of human body. Keeping in mind individual organs we propose a model for distributed self-regulation of living tissue, which is regarded as an active hierarchical system without any controlling center. This model is based on the self-processing of information about the cellular tissue state and cooperative interaction of blood vessels governing redistribution of blood flow over the vascular network. The information self-processing is implemented via mass conservation, i.e., conservation of blood flow as well as special biochemical compounds called activators transported by blood. The cooperative interaction of blood vessels stems from the response of individual vessels to activators in blood flowing through them. The general regularities are used to specify the vessel behavior. The arterial and venous beds are considered to be individually of the tree form. The constructed governing equations are analyzed numerically. In particular, first, we show that the blood perfusion rate approximately (in the analyzed case within 10% accuracy) depends only on the local concentration of activators in the cellular tissue. It is due to the hierarchical structure of the vascular network rather than the ideal behavior of individual vessels accepted previously. Second, we demonstrate the distinction between the reaction thresholds of individual vessels and that of the vascular network as a whole. The latter effect is the cause for introducing the notion of activators instead of using such quantities as temperature in describing the living tissue self-regulation.

  12. Distributed self-regulation of living tissue: beyond the ideal limit.

    PubMed

    Lubashevsky, Wassily; Lubashevsky, Ihor; Mahnke, Reinhard

    2010-02-01

    The present paper is devoted to mathematical description of the vascular network response to local perturbations in the cellular tissue state, being one of the basic mechanisms controlling the inner environment of human body. Keeping in mind individual organs we propose a model for distributed self-regulation of living tissue, which is regarded as an active hierarchical system without any controlling center. This model is based on the self-processing of information about the cellular tissue state and cooperative interaction of blood vessels governing redistribution of blood flow over the vascular network. The information self-processing is implemented via mass conservation, i.e., conservation of blood flow as well as special biochemical compounds called activators transported by blood. The cooperative interaction of blood vessels stems from the response of individual vessels to activators in blood flowing through them. The general regularities are used to specify the vessel behavior. The arterial and venous beds are considered to be individually of the tree form. The constructed governing equations are analyzed numerically. In particular, first, we show that the blood perfusion rate approximately (in the analyzed case within 10% accuracy) depends only on the local concentration of activators in the cellular tissue. It is due to the hierarchical structure of the vascular network rather than the ideal behavior of individual vessels accepted previously. Second, we demonstrate the distinction between the reaction thresholds of individual vessels and that of the vascular network as a whole. The latter effect is the cause for introducing the notion of activators instead of using such quantities as temperature in describing the living tissue self-regulation.

  13. Circulatory transport and capillary-tissue exchange as determinants of the distribution kinetics of inulin and antipyrine in dog.

    PubMed

    Weiss, Michael; Krejcie, Tom C; Avram, Michael J

    2007-04-01

    A pharmacokinetic model was developed to estimate physiologically meaningful parameters of distribution kinetics from plasma concentration-time data. The model is based on simultaneously measured disposition curves of drug and vascular marker. Employing residence time distribution theory, a recirculatory model with two subsystems, the pulmonary and systemic circulation, was constructed. In addition to intravascular mixing, the axially distributed model of the systemic circulation accounts for transcapillary transport of solutes, quantified by permeability-surface area product (PS) and diffusional equilibration time. Parameters of ICG, inulin, and antipyrine were estimated from disposition data obtained in awake dogs under control conditions and during an isoproterenol infusion or moderate hypovolemia. Results suggest that distribution kinetics is (1) governed by extravascular diffusion and (2) its dependency on cardiac output decreases with increasing diffusional resistance. Hemorrhage decreased the effective PS of inulin. In conclusion, this novel mechanistic model effectively described both the permeability-limited distribution of inulin into interstitial fluid and the flow-limited distribution of antipyrine into total body water and might be useful for other drugs.

  14. 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

  15. Distribution of monocarboxylate transporters MCT1-MCT8 in rat tissues and human skeletal muscle.

    PubMed

    Bonen, Arend; Heynen, Miriam; Hatta, Hideo

    2006-02-01

    In the past decade, a family of monocarboxylate transporters (MCTs) have been identified that can potentially transport lactate, pyruvate, ketone bodies, and branched-chain ketoacids. Currently, 14 such MCTs are known. However, many orphan transporters exist that have transport capacities that remain to be determined. In addition, the tissue distribution of many of these MCTs is not well defined. Such a cataloging can, at times, begin to suggest the metabolic role of a particular MCT. Recently, a number of antibodies against selected MCTs (MCT1, -2, -4, and -5 to -8) have become commercially available. Therefore, we examined the protein expression of these MCTs in a large number of rat tissues (heart, skeletal muscle, skin, brain, testes, vas deferens, adipose tissue, liver, kidney, spleen, and pancreas), as well as in human skeletal muscle. Unexpectedly, many tissues coexpressed 4-5 MCTs. In particular, in rat skeletal muscle MCT1, MCT2, MCT4, MCT5, and MCT6 were observed. In human muscle, these same MCTs were present. We also observed a pronounced MCT7 signal in human muscle, whereas a very faint signal occurred for MCT8. In rat heart, which is an important metabolic sink for lactate, we confirmed that MCT1 and -2 were expressed. In addition, MCT6 and -8 were also prominently expressed in this tissue, although it is known that MCT8 does not transport aromatic amino acids or lactate. This catalog of MCTs in skeletal muscle and other tissues has revealed an unexpected complexity of coexpression, which makes it difficult to associate changes in monocarboxylate transport with the expression of a particular MCT. The differences in transport kinetics for lactate and pyruvate are only known for MCT1, -2 and -4. Transport kinetics remain to be established for many other MCTs. In conclusion, this study suggests that in skeletal muscle, as well as other tissues, lactate and pyruvate transport rates may not only involve MCT1 and -4, as other monocarboxylate transporters are

  16. [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.

  17. 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...

  18. 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

  19. 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.

  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. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  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. 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

  8. Clinical pharmacokinetics and pharmacodynamics of linagliptin.

    PubMed

    Graefe-Mody, Ulrike; Retlich, Silke; Friedrich, Christian

    2012-07-01

    Linagliptin is an orally active small-molecule inhibitor of dipeptidyl peptidase (DPP)-4, which was first licensed in the US, Europe, Japan and other territories in 2011 to improve glycaemic control in adults with type 2 diabetes mellitus. Linagliptin is the first and thus far the only DPP-4 inhibitor, and oral antihyperglycaemic drug in general, to be approved as a single-strength once-daily dose (5 mg). Compared with other available DPP-4 inhibitors, linagliptin has a unique pharmacokinetic/pharmacodynamic profile that is characterized by target-mediated nonlinear pharmacokinetics, concentration-dependent protein binding, minimal renal clearance and no requirements for dose adjustment for any intrinsic or extrinsic factor. After single or multiple oral doses of 1-10 mg, linagliptin displays less than dose-proportional increases in maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC). Linagliptin is rapidly absorbed after oral administration, with C(max) occurring after approximately 90 minutes, and reaches steady-state concentrations within 4 days. With the therapeutic dose, steady-state C(max) (11-12 nmol/L) and AUC (∼150 nmol · h/L) are approximately 1.3-fold greater than after a single dose, indicating little drug accumulation with repeat dosing. Linagliptin exhibits concentration-dependent protein binding in human plasma in vitro (99% at 1 nmol/L to 75-89% at >30 nmol/L) and has a large apparent volume of distribution, demonstrating extensive distribution into tissues. The nonlinear pharmacokinetics of linagliptin are best described by a two-compartmental model that incorporates target-mediated drug disposition resulting from high-affinity, saturable binding to DPP-4. The oral bioavailability of linagliptin estimated with this model is approximately 30%. Linagliptin has a long terminal half-life (>100 hours); however, its accumulation half-life is much shorter (approximately 10 hours), accounting for the rapid

  9. 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. 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

  2. A comparison of the ganglioside distributions of fat tissues in various animals by two-dimensional thin layer chromatography.

    PubMed

    Ohashi, M

    1979-01-01

    The ganglioside distributions of various fat tissues from human, rabbit, rat, mouse, chicken and frog were compared with pig adipose gangliosides by two-dimensional thin layer chromatography. It was found that there is a remarkable species variation in ganglioside distribution, especially in the composition and relative concentration of complex gangliosides. Differing from pig adipose tissues, those of human, rabbit, rat, mouse, chicken, but not frog, contained GM3 as a most abundant ganglioside. The data for human, rabbit and chicken indicated a simple distribution of only NeuAc-type gangliosides, while those for rat and mouse indicated a rather complicated pattern containing both NeuAc- and NeuGc-type gangliosides. The ganglioside pattern of the frog fat body differed markedly from those of mammalian fat tissues because of the presence of three different, unusual monosialosylgangliosides as major components. In other respects, a substantial amount of disialosylgangliosides was commonly found in all animal fat tissues.

  3. Bimodal distribution of RNA expression levels in human skeletal muscle tissue

    PubMed Central

    2011-01-01

    Background Many human diseases and phenotypes are related to RNA expression, levels of which are influenced by a wide spectrum of genetic and exposure-related factors. In a large genome-wide study of muscle tissue expression, we found that some genes exhibited a bimodal distribution of RNA expression, in contrast to what is usually assumed in studies of a single healthy tissue. As bimodality has classically been considered a hallmark of genetic control, we assessed the genome-wide prevalence, cause, and association of this phenomenon with diabetes-related phenotypes in skeletal muscle tissue from 225 healthy Pima Indians using exon array expression chips. Results Two independent batches of microarrays were used for bimodal assessment and comparison. Of the 17,881 genes analyzed, eight (GSTM1, HLA-DRB1, ERAP2, HLA-DRB5, MAOA, ACTN3, NR4A2, and THNSL2) were found to have bimodal expression replicated in the separate batch groups, while 24 other genes had evidence of bimodality in only one group. Some bimodally expressed genes had modest associations with pre-diabetic phenotypes, of note ACTN3 with insulin resistance. Most of the other bimodal genes have been reported to be involved with various other diseases and characteristics. Association of expression with cis genetic variation in a subset of 149 individuals found all but one of the confirmed bimodal genes and nearly half of all potential ones to be highly significant expression quantitative trait loci (eQTL). The rare prevalence of these bimodally expressed genes found after controlling for batch effects was much lower than the prevalence reported in other studies. Additional validation in data from separate muscle expression studies confirmed the low prevalence of bimodality we observed. Conclusions We conclude that the prevalence of bimodal gene expression is quite rare in healthy muscle tissue (<0.2%), and is much lower than limited reports from other studies. The major cause of these clearly bimodal

  4. 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

  5. Dose-Dependent Pharmacokinetics of Amphotericin B Lipid Complex in Rabbits

    PubMed Central

    Walsh, Thomas J.; Jackson, Andre J.; Lee, James W.; Amantea, Michael; Sein, Tin; Bacher, John; Zech, Loren

    2000-01-01

    Amphotericin B lipid complex (ABLC) was recently approved by the Food and Drug Administration for treatment of patients with invasive fungal infections who are intolerant of or refractory to conventional amphotericin B therapy. Little is known, however, about the pharmacokinetics of this new antifungal compound. We therefore investigated the pharmacokinetics of ABLC in comparison with those of conventional desoxycholate amphotericin B (DAmB) in rabbits. The pharmacokinetics of DAmB in a rabbit model were similar to those previously reported in humans. The pharmacokinetics of ABLC differed substantially from those of DAmB. Plasma amphotericin B levels following ABLC administration were 10 times lower than those following administration of an equal dosage of DAmB. The levels of ABLC in whole blood were approximately 40 times greater than those in plasma. The ABLC model differed from the DAmB model by (i) a dose- and time-dependent uptake and return between the plasma compartment and apparent cellular components of the blood-sediment compartment and (ii) time-dependent tissue uptake and return to plasma from serially connected compartments. Following infusion of ABLC, there was a nonlinear uptake into the apparent cellular components of the blood-sediment compartment. This uptake was related to the reciprocal of the integral of the total amount of drug infused (i.e., the more drug infused the greater the fractional uptake between 0.5 and 5 mg/kg of body weight for ABLC). The transfer of drug from plasma to the cellular components of the blood-sediment compartment resulted in initial uptake followed by rapid redistribution back to the plasma. The study describes a detailed model of the pharmacokinetics of ABLC and characterizes a potential role of the cellular components of the blood-sediment compartment in the distribution of this new antifungal compound in tissue. PMID:10898677

  6. 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.

  7. Clearance and tissue distribution of intravenously injected Salmonella typhi polysaccharide in rabbits.

    PubMed Central

    Isibasi, A; Jimenez, E; Kumate, J

    1983-01-01

    The interaction of Freeman polysaccharide of Salmonella typhi with blood and tissues of rabbits was studied by radioimmunoassay. After intravenous injection of 1.0 mg of S. typhi Freeman polysaccharide, a rapid clearance phase (t1/2, 6.0 min) was followed by a slower clearance period (t1/2, 55.2 min). These results suggest first, that the distribution of whole lipopolysaccharide is a function of how the polysaccharides are handled by the host; further, that the O side chain determines how and where lipopolysaccharide is cleared from the circulatory system; and finally, that Freeman polysaccharide regulates the toxicity of lipopolysaccharide by influencing its clearance from blood. PMID:6642672

  8. Using microfluidics to understand the effect of spatial distribution of tissue factor on blood coagulation.

    PubMed

    Shen, Feng; Kastrup, Christian J; Ismagilov, Rustem F

    2008-01-01

    Initiation of blood coagulation by tissue factor (TF) is a robust, highly regulated process. Both the spatial distribution of TF and the geometry of the vasculature may play important roles in regulating coagulation. As this review describes, microfluidic systems provide a unique opportunity for investigating the spatiotemporal dynamics of blood coagulation in vitro. Microfluidic systems with surfaces of phospholipid bilayers patterned with TF have been used to demonstrate experimentally the threshold responses of initiation of coagulation to the size and shape of surfaces presenting TF. These systems have also been used to demonstrate experimentally that propagation of coagulation is regulated by the shear rate of blood flow in microcapillaries and microchannels. By understanding these and other aspects of the spatial dynamics that regulate blood coagulation, many new methods for treating clotting disorders, such as venous thromboembolism (VTE) and sepsis, could arise.

  9. Pharmacokinetics of melamine in pigs following intravenous administration.

    PubMed

    Baynes, Ronald E; Smith, Geof; Mason, Sharon E; Barrett, Erica; Barlow, Beth M; Riviere, Jim E

    2008-03-01

    Melamine-contaminated pet food was recently added as a supplement to livestock feed. There is little or no information concerning the pharmacokinetics of melamine in livestock, and the aim of this study was to obtain pharmacokinetic parameters for this contaminant in pigs. Melamine was administered intravenously to five weanling pigs at a dose of 6.13 mg/kg and plasma samples were collected over 24 h, extracted for melamine, and then analyzed by HPLC-UV. The data was shown to best fit a one-compartment model with melamine's half-life of 4.04 (+/- 0.37) h, clearance of 0.11 (+/- 0.01) L/h/kg, and volume of distribution of 0.61 (+/- 0.04) L/kg. These data are comparable to the only mammalian study in rats and suggests that melamine is readily cleared by the kidney and there is unlikely to be significant tissue binding. Further tissue residue studies are required to assess the depletion kinetics of this contaminant in the pig which will determine whether residue levels in the kidney should be of public health concern if pigs were exposed to a similar dose.

  10. Molecular cloning, tissue distribution, and immune function of goose TLR7.

    PubMed

    Qi, Yulin; Chen, Shun; Zhao, Qiurong; Wang, Mingshu; Jia, Renyong; Zhu, Dekang; Liu, Mafeng; Liu, Fei; Chen, Xiaoyue; Cheng, Anchun

    2015-02-01

    TLR7 is a transmembrane endosomal protein that plays an essential role in innate antiviral responses via the recognition of conserved viral molecular patterns. Here, we cloned the full-length cDNA of goose TLR7 and carried out a molecular characterization of goose TLR7. The goose TLR7 gene is 3900 bp and encodes a 1045 amino acid protein with high homology to poultry (93% to duck and 83% to chicken). Similar conclusions were made by phylogenetic analysis. The predicted protein secondary structure of goose TLR7 contained a conserved Toll/interleukin-1 receptor domain and characteristic leucine-rich repeat regions, which has also been reported for duck TLR7. Additionally, the tissue distribution of goose TLR7 suggests that immune-associated tissues, especially the cecal tonsil and bursa of Fabricius, have high goose TLR7 expression levels. Goose TLR7 is abundantly expressed in lung tissues, which is distinct from its expression in chickens. Similar to duck TLR7, goose spleen mononuclear cells (MNCs) exposed to the mammalian TLR7 agonists R848 and Imiquimod showed significant induction of the production of proinflammatory cytokines and IFN-α. New type gosling viral enteritis virus (NGVEV) infection resulted in high mRNA expression levels of goose TLR7 in the spleen. By contrast, no direct interaction between NGVEV and goose TLR7 was detected after infecting goose spleen MNCs with NGVEV in vitro. However, triggering of goose TLR7 resulted in the rapid up-regulation of proinflammatory cytokines and anti-viral molecules, suggesting that goose TLR7 plays an important role in anti-viral defense.

  11. 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.

  12. First isolation of Toxoplasma gondii from cats of Colima, Mexico: tissue distribution and genetic characterization.

    PubMed

    Rico-Torres, Claudia Patricia; Del Viento-Camacho, Alejandra; Caballero-Ortega, Heriberto; Besné-Mérida, Alejandro; Luna-Pastén, Héctor; Correa, Dolores; Palma-García, José Manuel

    2015-04-15

    Toxoplasma gondii is among the commonest zoonotic infectious agents worldwide. It infects many warm-blooded animals, including felines, the definitive hosts. This parasite is now classified in 15 haplogroups spread out around the world. Few reports reveal a predominance of genotypes I and III in Mexico, although recombinant and atypical variants have also been found in humans and animals. The aim of this study was to detect, isolate and genotype T. gondii from cats of Colima Mexico, and to analyze tissue distribution of the parasite. IgG specific antibodies were investigated in 48 serum samples from unwanted and stray cats by indirect ELISA. Isolation in mice and molecular characterization by PCR-RFLP and sequencing were attempted using pools of brain, heart, liver, lung, spleen and brachiocephalic muscle samples of seropositive cats. Fourteen animals (29.2%) were seropositive, the frequency ranged between 27.3 and 40% among the different localities. Ten seropositive animals were euthanized, eight of them were positive for the B1 gene by conventional PCR. More frequently infected tissues were the brachiocephalic muscle (75.0%) the brain (63.0%) and the spleen (63.0%). Genotype III was determined for the SAG3 locus of the parasite infecting an unwanted cat. Tachyzoites were isolated from the peritoneal cavity of two mice inoculated with the tissue pool of one kitten. Type I alleles were found in SAG1, SAG2, SAG3, BTUB, GRA6, c29-2 and PK1 loci, while c22-8 was type II, and L358 and Apico were type III. This genotype corresponds to ToxoDB genotype #28. This is the first T. gondii isolate genetically characterized in Colima, Mexico and is different to other isolations of the country.

  13. Brevetoxin: tissue distribution and effect on cytochrome P450 enzymes in fish.

    PubMed

    Washburn, B S; Baden, D G; Gassman, N J; Walsh, P J

    1994-07-01

    As part of our investigation of the metabolism of brevetoxin (PbTx) in fish, we initiated a two-part study to determine the toxin's tissue distribution and its ability to induce xenobiotic metabolizing enzymes. In the first study, gulf toadfish (Opsanus beta) were administered 14C-PbTx-3 orally in a fishmeal slurry and sacrificed 72 hr later. Radioactivity was greatest in the hepatobiliary system (40% of body burden), representing the key role this system plays in the detoxification and elimination of brevetoxin. Muscle tissue contained 27%, followed by gastrointestinal tract (25%). To investigate the effects of PbTx on xenobiotic metabolizing enzymes, immature redfish (Scianops ocellatus) were given two doses of brevetoxin (1.5 or 2.5 micrograms/100 g body weight) or cod liver oil in a fishmeal slurry by gavage. The activities of two hepatic P450 enzymes, ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-depentylase (PROD), as well as the cytosolic enzyme, glutathione S-transferase (GST), were measured. At the higher dose, PbTx significantly increased EROD activity. These results suggest that brevetoxin is capable of inducing an important xenobiotic metabolizing enzyme (EROD).

  14. A Nanostructured Matrices Assessment to Study Drug Distribution in Solid Tumor Tissues by Mass Spectrometry Imaging

    PubMed Central

    Giordano, Silvia; Pifferi, Valentina; Morosi, Lavinia; Morelli, Melinda; Falciola, Luigi; Cappelletti, Giuseppe; Visentin, Sonja; Licandro, Simonetta A.; Frapolli, Roberta; Zucchetti, Massimo; Pastorelli, Roberta; Brunelli, Laura; D’Incalci, Maurizio; Davoli, Enrico

    2017-01-01

    The imaging of drugs inside tissues is pivotal in oncology to assess whether a drug reaches all cells in an adequate enough concentration to eradicate the tumor. Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging (MALDI-MSI) is one of the most promising imaging techniques that enables the simultaneous visualization of multiple compounds inside tissues. The choice of a suitable matrix constitutes a critical aspect during the development of a MALDI-MSI protocol since the matrix ionization efficiency changes depending on the analyte structure and its physico-chemical properties. The objective of this study is the improvement of the MALDI-MSI technique in the field of pharmacology; developing specifically designed nanostructured surfaces that allow the imaging of different drugs with high sensitivity and reproducibility. Among several nanomaterials, we tested the behavior of gold and titanium nanoparticles, and halloysites and carbon nanotubes as possible matrices. All nanomaterials were firstly screened by co-spotting them with drugs on a MALDI plate, evaluating the drug signal intensity and the signal-to-noise ratio. The best performing matrices were tested on control tumor slices, and were spotted with drugs to check the ion suppression effect of the biological matrix. Finally; the best nanomaterials were employed in a preliminary drug distribution study inside tumors from treated mice. PMID:28336905

  15. Expression and subcellular distribution of gephyrin in non-neuronal tissues and cells.

    PubMed

    Nawrotzki, Ralph; Islinger, Markus; Vogel, Ingeborg; Völkl, Alfred; Kirsch, Joachim

    2012-04-01

    Gephyrin is a scaffolding protein required for the accumulation of inhibitory neurotransmitter receptors at neuronal postsynaptic membranes. In non-neuronal tissues, gephyrin is indispensible for the biosynthesis of molybdenum cofactor, the prosthetic group of oxidoreductases including sulfite oxidase and xanthine oxidase. However, the molecular and cellular basis of gephyrin's non-neuronal function is poorly understood; in particular, the roles of its splice variants remain enigmatic. Here, we used cDNA screening as well as Northern and immunoblot analyses to show that mammalian liver contains only a limited number of gephyrin splice variants, with the C3-containing variant being the predominant isoform. Using new and established anti-gephyrin antibodies in immunofluorescence and subcellular fractionation studies, we report that gephyrin localizes to the cytoplasm of both tissue hepatocytes and cultured immortalized cells. These findings were corroborated by RNA interference studies in which the cytosolic distribution was found to be abolished. Finally, by blue-native PAGE we show that cytoplasmic gephyrin is part of a ~600 kDa protein complex of yet unknown composition. Our data suggest that the expression pattern of non-neuronal gephyrin is simpler than indicated by previous evidence. In addition, gephyrin's presence in a cytosolic 600 kDa protein complex suggests that its metabolic and/or other non-neuronal functions are exerted in the cytoplasm and are not confined to a particular subcellular compartment.

  16. 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.

  17. Differential tissue distribution of various polybrominated biphenyls of Firemaster FF-1 in male rats.

    PubMed

    Domino, E F; Fivenson, D P; Domino, S E

    1980-01-01

    Gas chromatography with an electron-capture detector was used to identify the major components of the polybrominated biphenyls (PBB's) in Firemaster FF-1. The distribution and clearance of the PBB's in rat whole blood, grey and white matter, cerebellum, heart, kidney, liver, spleen, lung, jejunum, testes, and subcutaneous fat from the inguinal region were determined at various times after a single dose of 10 mg/kg of Firemaster FF-1 given orally. Peak blood levels of PBB occurred within 4 hr whereas levels in inguinal subcutaneous fat peaked 7--14 days after the single oral dose. Concentrations in other tissues peaked usually within 12 hr and showed complex logarithmic decline over time. 2,2',4,5,5'-Pentabromobiphenyl (PnBBa) was cleared much more rapidly from the rat than 2,3',4,4',5-pentabromobiphenyl (PnBBb) or any of the higher molecular weight analogs. Furthermore, PnBBa penetrated the brain more rapidly. Each of the PBB analogs was found in all tissues examined but varied in both rate of absorption and clearance.

  18. 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

  19. QSAR analysis of blood-brain distribution: the influence of plasma and brain tissue binding.

    PubMed

    Lanevskij, Kiril; Dapkunas, Justas; Juska, Liutauras; Japertas, Pranas; Didziapetris, Remigijus

    2011-06-01

    The extent of brain delivery expressed as steady-state brain/blood distribution ratio (log BB) is the most frequently used parameter for characterizing central nervous system exposure of drugs and drug candidates. The aim of the current study was to propose a physicochemical QSAR model for log BB prediction. Model development involved the following steps: (i) A data set consisting of 470 experimental log BB values determined in rodents was compiled and verified to ensure that selected data represented drug disposition governed by passive diffusion across blood-brain barrier. (ii) Available log BB values were corrected for unbound fraction in plasma to separate the influence of drug binding to brain and plasma constituents. (iii) The resulting ratios of total brain to unbound plasma concentrations reflecting brain tissue binding were described by a nonlinear ionization-specific model in terms of octanol/water log P and pK(a). The results of internal and external validation demonstrated good predictive power of the obtained model as both log BB and brain tissue binding strength were predicted with residual mean square error of 0.4 log units. The statistical parameters were similar among training and validation sets, indicating that the model is not likely to be overfitted.

  20. Distribution of Lipid Formulations of Amphotericin B into Bone Marrow and Fat Tissue in Rabbits

    PubMed Central

    Groll, Andreas H.; Mickiene, Diana; Piscitelli, Stephen C.; Walsh, Thomas J.

    2000-01-01

    The distribution of the three currently available lipid formulations of amphotericin B (AmB) into bone marrow and fat tissue was evaluated in noninfected rabbits. Groups of four animals each received either 1 mg of AmB deoxycholate (D-AmB) per kg of body weight per day or 5 mg of AmB colloidal dispersion, AmB lipid complex, or liposomal AmB per kg per day for seven doses. Plasma, bone marrow, fat, and liver were collected at autopsy, and AmB concentrations were determined by high-performance liquid chromatography. At the investigated dosages of 5 mg/kg/day, all AmB lipid formulations achieved at least fourfold-higher concentrations in bone marrow than did standard D-AmB at a dosage of 1 mg/kg/day. Concentrations in bone marrow were 62 to 76% of concurrent AmB concentrations in the liver. In contrast, all AmB formulations accumulated comparatively poorly in fat tissue. The results of this study show that high concentrations of AmB can be achieved in the bone marrow after administration of lipid formulations, suggesting their particular usefulness against disseminated fungal infections involving the bone marrow and against visceral leishmaniasis. PMID:10639371

  1. Tissue distribution of nitrazepam and 7-aminonitrazepam in a case of nitrazepam intoxication.

    PubMed

    Moriya, Fumio; Hashimoto, Yoshiaki

    2003-01-28

    We report a case of nitrazepam poisoning in which the distribution of nitrazepam and 7-aminonitrazepam was determined in body fluids and tissues. A 52-year-old woman was found dead in a shallow ditch (approximately 5 cm in depth), in the winter. Ambient temperature was 2-8 degrees C. The postmortem interval was estimated to be approximately 1 day and no putrefaction was observed. The cause of death was thought to be drowning due to nitrazepam overdose and cold exposure. Blood concentrations of nitrazepam and 7-aminonitrazepam were very site dependent (0.400-0.973 microg/ml and 0.418-1.82 microg/ml). In addition, the concentration of the same analytes in the bile were 4.08 and 1.67 microg/ml, respectively, and in the urine: 0.580 and 1.09 microg/ml, respectively. A high accumulation of both substances was observed in various types of brain tissue (2.17-6.22 microg/g and 2.49-5.11 microg/g). Only small amounts of nitrazepam and 7-aminonitrazepam were detected in the liver (0.059 and 0.113 microg/g, respectively). Large differences in the observed concentrations of nitrazepam and 7-aminonitrazepam among arterial and venous blood samples were thought to be mainly due to dilution of arterial blood by water entering the circulation through lungs at the time of death. Bacterial metabolism of nitrazepam may also have contributed to the observed differences.

  2. Biomagnification and tissue distribution of perfluoroalkyl substances (PFASs) in market-size rainbow trout (Oncorhynchus mykiss).

    PubMed

    Goeritz, Ina; Falk, Sandy; Stahl, Thorsten; Schäfers, Christoph; Schlechtriem, Christian

    2013-09-01

    The present study investigated the biomagnification potential as well as the substance and tissue-specific distribution of perfluoroalkyl substances (PFASs) in market-size rainbow trout (Oncorhynchus mykiss). Rainbow trout with an average body weight of 314 ± 21 g were exposed to perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) in the diet for 28 d. The accumulation phase was followed by a 28-d depuration phase, in which the test animals were fed with nonspiked trout feed. On days 0, 7, 14, 28, 31, 35, 42, and 56 of the present study, fish were sampled from the test basin for PFAS analysis. Biomagnification factors (BMFs) for all test compounds were determined based on a kinetic approach. Distribution factors were calculated for each test compound to illustrate the disposition of PFASs in rainbow trout after 28 d of exposure. Dietary exposure of market-size rainbow trout to PFASs did not result in biomagnification; BMF values were calculated as 0.42 for PFOS, >0.23 for PFNA, >0.18 for PFHxS, >0.04 for PFOA, and >0.02 for PFBS, which are below the biomagnification threshold of 1. Liver, blood, kidney, and skin were identified as the main target tissues for PFASs in market-size rainbow trout. Evidence was shown that despite relative low PFAS contamination, the edible parts of the fish (the fillet and skin) can significantly contribute to the whole-body burden.

  3. Mercury and methylmercury distribution in tissues of sculpins from the Bering Sea

    PubMed Central

    Lieske, Camilla; Bhojwani, Shaina; Castellini, J. Margaret; López, J. Andrés; O’Hara, Todd M.

    2017-01-01

    Fish skeletal muscle is often used to monitor mercury concentrations and is used by regulatory agencies to develop fish consumption advisories. However, the distribution of mercury species (MeHg+ and THg) in muscle tissue and other organs is not well understood in a number of fish species. Here we evaluate the spatial distribution of THg and MeHg+ in skeletal muscle and internal organs (heart, liver, and kidney) of 19 sculpin representing three species: Myoxocephalus scorpius (shorthorn sculpin n = 13), Myoxocephalus jaok (plain sculpin, n = 4), and Megalocottus platycephalus (belligerent sculpin, n = 2). Four subsamples of muscle were taken along the lateral aspect of each fish, from muscle A (cranial) to muscle D (caudal). Using Games–Howell post hoc procedure to compare mean concentrations of all tissues, muscle samples were significantly different from internal organs, although there was no difference between muscle-sampling locations. THg concentrations (ww) were higher in muscle (muscle A through D mean ± SD, 0.30 ± 0.19 mg/kg) than that in heart (0.06 ± 0.05 mg/kg), kidney (0.08 ± 0.06 mg/kg), and liver (0.09 ± 0.08 mg/kg). Percent MeHg+ decreased with age in both skeletal muscle and organs (p < 0.05). In contrast to some previous reports for other fish species, this study found significantly higher THg concentrations in muscle than in the liver. This study highlights the importance of using muscle samples when evaluating potential Hg exposure in risk assessments for piscivorous wildlife and human populations, and assumptions related to organ mercury concentrations should be examined with care. PMID:28154451

  4. Modeling metal bioaccumulation and tissue distribution in killifish (Fundulus heteroclitus) in three contaminated estuaries.

    PubMed

    Dutton, Jessica; Fisher, Nicholas S

    2014-01-01

    The present study experimentally assessed the uptake, loss, and resulting tissue distribution of As(V), Cd, Cr(III), Hg(II), and methylmercury (MeHg) in killifish (Fundulus heteroclitus) following aqueous exposure in water collected from 3 contaminated field sites-Baltimore Harbor and Elizabeth River (Chesapeake Bay), and Mare Island (San Francisco Bay)-using a radiotracer technique. Uptake rate constants (L g-1 d-1) were highest for MeHg (0.370-0.781) and lowest for As (0.00028-0.00065). Loss rate constants (d-1) were highest for As (0.046-0.096) and lowest for MeHg (0.006-0.009). Tissue distribution data showed that MeHg was redistributed around the body throughout the 9-d depuration period, and drinking may be an uptake mechanism for Cd from the aqueous phase in higher-salinity water. The kinetic parameters calculated in the present study were entered into a bioaccumulation model to calculate the predicted body burden of each metal at steady state and the percentage body burden attributable to dietary exposure on a site-specific basis. Calculated body burdens varied between field sites for all metals except Cr. The predicted values for Cd, Hg(II), and MeHg matched independent field data from contaminated estuaries, indicating that the model can account for the major processes governing metal concentration in killifish. The diet accounted for >97% of the body burden of Cd and MeHg and was the predominant exposure route for As and Cr.

  5. Identification, tissue distribution and orexigenic activity of neuropeptide F (NPF) in penaeid shrimp.

    PubMed

    Christie, Andrew E; Chapline, M Christine; Jackson, James M; Dowda, Jenilee K; Hartline, Niko; Malecha, Spencer R; Lenz, Petra H

    2011-04-15

    The neuropeptide Fs (NPFs) are an invertebrate subgroup of the FMRFamide-like peptides, and are proposed by some to be the homologs of vertebrate neuropeptide Y. Although there is some information about the identity, tissue distribution and function of NPFs in insects, essentially nothing is known about them in crustaceans. We have identified and characterized NPF-encoding transcripts from the penaeid shrimp Litopenaeus vannamei and Melicertus marginatus. Two transcripts were identified from each species. For each shrimp species, the two transcripts differed from one another by the presence or absence of an insert in the portion of the open reading frame that encodes the NPF peptide. The two NPF isoforms are identical in L. vannamei and M. marginatus, with their predicted structures being KPDPSQLANMAEALKYLQELDKYYSQVSRPRFamide and KPDPSQLANMAEALKYLQELDKYYSQVSRPSPRSAPGPASQIQALENTLKFLQLQELGKLYSLRARPRFamide. RT-PCR tissue profiling showed both transcripts are broadly distributed within the nervous system of each species. The transcript encoding the shorter NPF was detected in some, but not all, midgut samples. The transcript encoding the longer NPF was absent in the midgut of both species, and neither transcript was detected in their skeletal muscle. Juvenile L. vannamei fed on a diet supplemented with the shorter NPF exhibited a marked increase in food intake relative to control individuals that did not receive the supplement; the NPF-fed shrimp also showed a significant increase in growth relative to the control group. Our data suggest that NPF is present in both the nervous system and midgut of penaeid shrimp, functioning, at least in part, as a powerful orexigenic agent.

  6. Postmortem distribution of α-pyrrolidinobutiophenone in body fluids and solid tissues of a human cadaver.

    PubMed

    Wurita, Amin; Hasegawa, Koutaro; Minakata, Kayoko; Gonmori, Kunio; Nozawa, Hideki; Yamagishi, Itaru; Suzuki, Osamu; Watanabe, Kanako

    2014-09-01

    We experienced an autopsy case of a 21-year-old male Caucasian, in which the direct cause of his death was judged as subarachnoid hemorrhage. There was cerebral arteriovenous malformation, which seemed related to the subarachnoid hemorrhage. The postmortem interval was estimated to be about 2days. By our drug screening test using gas chromatography-mass spectrometry, we could identify α-pyrrolidinobutiophenone (α-PBP) in his urine specimen, which led us to investigate the postmortem distribution of α-PBP in this deceased. The specimens dealt with were right heart blood, left heart blood, femoral vein blood, cerebrospinal fluid, urine, stomach contents and five solid tissues. The extraction of α-PBP and α-pyrrolidinovalerophenone (α-PVP, internal standard) was performed by a modified QuEChERS (quick, easy, cheap, effective, rugged and safe) method, followed by the analysis by liquid chromatography-tandem mass spectrometry. Because this study included various kinds of human matrices, we used the standard addition method to overcome the matrix effects. The highest concentration was found in urine, followed by stomach contents, the kidney, lung, spleen, pancreas and liver. The blood concentrations were about halves of those of the solid tissues. The high concentrations of α-PBP in urine and the kidney suggest that the drug tends to be rapidly excreted into urine via the kidney after its absorption into the blood stream. The urine specimen is of the best choice for analysis. This is the first report describing the postmortem distribution of α-PBP in a human to our knowledge.

  7. 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

  8. Tissue distribution of teneligliptin in rats and comparisons with data reported for other dipeptidyl peptidase‐4 inhibitors

    PubMed Central

    Akahoshi, Fumihiko; Iijima, Hiroaki; Hisanaga, Noriko; Kume, Toshiyuki

    2016-01-01

    Abstract The tissue distribution of teneligliptin, a dipeptidyl peptidase (DPP)‐4 inhibitor, was investigated in rats, and compared with tissue distributions previously reported for other DPP‐4 inhibitors. Following the oral administration of [14C]teneligliptin to Sprague–Dawley rats, it was predominantly distributed to the kidney and liver, followed by the lung, spleen and pituitary gland. The elimination half‐life (t 1/2) of [14C]teneligliptin was 68.3 and 69.0 h in the kidney and liver, respectively; these values were about 10 times greater than the plasma t 1/2. Of note, the elimination of [14C]teneligliptin from tissues with high DPP‐4 activity (kidney, liver and lung) was slower in wild‐type rats than in DPP‐4‐deficient rats, especially in the kidney. By contrast, in the heart and pancreas, which weakly express DPP‐4, no difference was observed in [14C]teneligliptin concentrations between the two animal strains. In the kidney, most radioactivity was attributable to unchanged teneligliptin from 0.5 to 72 h after administration. The marked difference in the distribution of [14C]teneligliptin between the two strains suggests that the high binding affinity of teneligliptin for DPP‐4 is involved in its tissue distribution. The currently marketed DPP‐4 inhibitors are highly distributed to the liver, kidney and lung, but the extent of tissue distribution varies greatly among the drugs. The differences in the tissue distributions of DPP‐4 inhibitors might be related to differences in their pleiotropic effects. © 2016 The Authors Biopharmaceutics & Drug Disposition Published by John Wiley & Sons Ltd. PMID:26749565

  9. Ex Vivo and In Silico Feasibility Study of Monitoring Electric Field Distribution in Tissue during Electroporation Based Treatments

    PubMed Central

    Kranjc, Matej; Bajd, Franci; Sersa, Igor; Woo, Eung Je; Miklavcic, Damijan

    2012-01-01

    Magnetic resonance electrical impedance tomography (MREIT) was recently proposed for determining electric field distribution during electroporation in which cell membrane permeability is temporary increased by application of an external high electric field. The method was already successfully applied for reconstruction of electric field distribution in agar phantoms. Before the next step towards in vivo experiments is taken, monitoring of electric field distribution during electroporation of ex vivo tissue ex vivo and feasibility for its use in electroporation based treatments needed to be evaluated. Sequences of high voltage pulses were applied to chicken liver tissue in order to expose it to electric field which was measured by means of MREIT. MREIT was also evaluated for its use in electroporation based treatments by calculating electric field distribution for two regions, the tumor and the tumor-liver region, in a numerical model based on data obtained from clinical study on electrochemotherapy treatment of deep-seated tumors. Electric field distribution inside tissue was successfully measured ex vivo using MREIT and significant changes of tissue electrical conductivity were observed in the region of the highest electric field. A good agreement was obtained between the electric field distribution obtained by MREIT and the actual electric field distribution in evaluated regions of a numerical model, suggesting that implementation of MREIT could thus enable efficient detection of areas with insufficient electric field coverage during electroporation based treatments, thus assuring the effectiveness of the treatment. PMID:23029212

  10. 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

  11. Differences in tissue distribution of HBCD alpha and gamma between adult and developing mice.

    PubMed

    Szabo, David T; Diliberto, Janet J; Huwe, Janice K; Birnbaum, Linda S

    2011-09-01

    Hexabromocyclododecane (HBCD) is a mixture of three stereoisomers alpha (α), beta (β), and gamma (γ). γ-HBCD dominates the mixture (∼70%), and despite α-HBCD's minor contribution to global HBCD production and usage (∼10%), it is the dominant congener found in most biotic samples worldwide. Evidence of toxicity and lack of stereoisomer studies drives the importance of understanding HBCD toxicokinetics in potentially susceptible populations. The majority of public health concern has focused on hazardous effects resulting from exposure of infants and young children to HBCD due to reports on adverse developmental effects in rodent studies, in combination with human exposure estimates suggesting that nursing infants and young children have the highest exposure to HBCD. This study was designed to investigate differences in the disposition of both γ-HBCD and α-HBCD in infantile mice reported to be susceptible to the HBCD commercial mixture. The tissue distribution of α-[(14)C]HBCD- and γ-[(14)C]HBCD-derived radioactivity was monitored in C57BL/6 mice following a single oral dose of either compound (3 mg/kg) after direct gavage at postnatal day 10. Mice were held up to 7 days in shoebox cages after which pups were sacrificed, tissue collected, and internal dosimetry was measured. Developing mice exposed to α-HBCD had an overall higher body burden than γ-HBCD at every time point measured; at 4 days postexposure, they retained 22% of the α-HBCD administered dose, whereas pups exposed to γ-HBCD retained 10%. Total body burden in infantile mice after exposure to γ-HBCD was increased 10-fold as compared with adults. Similarly, after exposure to α-HBCD, infantile mice contained 2.5-fold higher levels than adult. These differences lead to higher concentrations of the HBCD diastereomers at target tissues during critical windows of development. The results indicate that the toxicokinetics of the two HBCD diastereomers differ between developing and adult mice

  12. Analysis of Algorithms Predicting Blood: Air and Tissue: Blood Partition Coefficient from Solvent Partition Coefficients for Use in Complex Mixture Physiological Based Pharmacokinetic/Pharmacodynamic Modeling

    DTIC Science & Technology

    2004-03-01

    coefficients have been found to vary with changes in hematocrit, blood lipids (fasted versus postprandial sampling) and organ lipids (Fiserova-Bergerova...assumed that blood was taken in various fasted or postprandial states depending on the individual. The one to two hour postprandial value (Fiserova...being made up of tissue water, neutral lipids (non-polar lipids including triglycerides and cholesterol ) and phospholipids (lipids with a phosphoric acid

  13. Effect of methacholine induced bronchoconstriction on the pulmonary distribution and plasma pharmacokinetics of inhaled sodium cromoglycate in subjects with normal and hyperreactive airways.

    PubMed Central

    Richards, R; Haas, A; Simpson, S; Britten, A; Renwick, A; Holgate, S

    1988-01-01

    Inhalation treatment may be less effective in the presence of bronchoconstriction because of the reduced penetration of drugs into the airways. The effect of bronchoconstriction on the lung deposition and plasma pharmacokinetics of inhaled sodium cromoglycate was examined. Ten subjects attended the laboratory on three occasions. On the first occasion a bronchial provocation test was performed to determine the concentration of methacholine required to reduce the forced expiratory volume in one second (FEV1) by 20% (PC20). On the two subsequent occasions subjects inhaled either saline or their PC20 methacholine, followed five minutes later by an aerosol containing sodium cromoglycate and stannous phytate labelled with technetium-99m. Twenty minutes later a gamma emission lung scan was performed to determine the intrathoracic deposition of the nebulised aerosol. The central:peripheral (C:P) ratio of lung deposition was then calculated. Measurements of FEV1 were made and blood samples taken for analysis of plasma sodium cromoglycate concentration at intervals for four hours. Methacholine led to a 23.4% (SEM 0.6%) lower FEV1 and a 2.8 times higher C:P ratio than those observed after saline. There was a direct correlation between log PC20 methacholine and the increase in the C:P ratio (r = 0.81). Despite these changes with methacholine, the plasma pharmacokinetics of inhaled sodium cromoglycate were not significantly different after methacholine and after saline, except that the maximum concentration achieved (Cmax) was increased. These observations suggest that the area of cromoglycate deposition and the anatomical site are less important in determining the plasma pharmacokinetics of cromoglycate than is the total dose delivered to the lung. PMID:3140407

  14. Distribution, isomerization and enantiomer selectivity of hexabromocyclododecane (HBCD) diastereoisomers in different tissue and subcellular fractions of earthworms.

    PubMed

    Li, Bing; Chen, Hao; Sun, Hongwen; Lan, Zhonghui

    2017-05-01

    In this study, earthworms Eisenia fetida (E. fetida) were exposed to a soil artificially contaminated with individual hexabromocyclododecane (HBCD) diastereoisomers (α-, β- and γ-HBCDs) to investigate the distribution, isomerization and enantiomer selectivity of HBCDs at tissue and subcellular levels. At the tissue level, the concentrations of HBCDs all followed the order of gut>bodyfluid>body wall, which suggested that earthworms accumulated HBCDs mainly via ingesting soil particles. At the subcellular level, the concentrations of HBCDs in an extracellular fraction consisting of granules, tissue fragment, cell membrane and intact cells (fraction A) were higher than those in an intracellular fractions consisting of the microsomal and cytosol (fraction B+C). This confirmed the passive diffusion during the distribution of HBCDs into the intracellular compartment. The distribution proportions of HBCDs varied among different tissue and subcellular fractions, and all changed over time within 14 days. The variable distributions of HBCDs in different fractions were a result of the comprehensive effects of dynamics and thermodynamics processes. The β- and γ-HBCDs were isomerized to α-HBCD in all tissue and subcellular fractions except for fraction C, and the isomerization ratios varied a lot, which seemed to be related to HBCDs residence time. The selective enrichment of (-) α-, (-) β and (-) γ-HBCDs was found in all fractions and this is consistent with that in the whole earthworm. Besides, the extents of enantio-selectivity did not change significantly among different tissue and subcellular fractions.

  15. Semi-quantitative immunohistochemical detection of 5-hydroxymethyl-cytosine reveals conservation of its tissue distribution between amphibians and mammals.

    PubMed

    Almeida, Rimple D; Sottile, Virginie; Loose, Matthew; De Sousa, Paul A; Johnson, Andrew D; Ruzov, Alexey

    2012-02-01

    5-Hydroxymethyl-cytosine (5-hmC) is a form of modified cytosine, which has recently attracted a considerable attention due to its potential role in transcriptional regulation. According to several reports 5-hydroxymethyl-cytosine distribution is tissue-specific in mammals. Thus, 5-hmC is enriched in embryonic cell populations and in adult neuronal tissue. Here, we describe a novel method of semi-quantitative immunohistochemical detection of 5-hmC and utilize it to assess the levels of this modification in amphibian tissues. We show that, similar to mammalian embryos, 5-hmC is enriched in axolotl tadpoles compared with adult tissues. Our data demonstrate that 5-hmC distribution is tissue-specific in amphibians, and that strong 5-hmC enrichment in neuronal cells is conserved between amphibians and mammals. In addition, we identify 5-hmC-enriched cell populations that are distributed in amphibian skin and connective tissue in a mosaic manner. Our results illustrate that immunochemistry can be successfully used not only for spatial identification of cells enriched with 5-hmC, but also for the semi-quantitative assessment of the levels of this epigenetic modification in single cells of different tissues.

  16. 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

    2011-12-05

    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.

  17. 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.

  18. Tissue distribution and differential expression of melanocortin 1 receptor, a malignant melanoma marker

    PubMed Central

    Salazar-Onfray, F; López, M; Lundqvist, A; Aguirre, A; Escobar, A; Serrano, A; Korenblit, C; Petersson, M; Chhajlani, V; Larsson, O; Kiessling, R

    2002-01-01

    The melanocortin 1 receptor is a G-protein-coupled receptor, described to be expressed on melanomas and melanocytes. Subsequent RT–PCR studies demonstrated the presence of melanocortin 1 receptor mRNA in other tissues such as pituitary gland and testis. Previously, we have demonstrated that three HLA-A2 binding nonamer peptides derived from melanocortin 1 receptor can elicit peptide-specific CTL which can recognize target cells transfected with the melanocortin 1 receptor gene and MHC class I matched melanoma lines. The potential of targeting melanocortin 1 receptor in therapy and diagnosis will depend on a preferential expression of this receptor in the majority of primary and metastatic melanomas vs normal tissues. We tested a panel of melanomas, carcinomas and other cell lines for the presence of melanocortin 1 receptor, using two monoclonal antibodies. The receptor was detected in 83% of the tested melanoma cell lines but not in other carcinoma lines. Immunohistochemistry revealed a strong expression of melanocortin 1 receptor in all tested primary and metastatic melanomas, but also demonstrated low levels of expression in adrenal medulla, cerebellum, liver and keratinocytes. Flow cytometry studies showed that melanocortin 1 receptor was expressed in in vitro activated monocytes/macrophages and in the THP-1 monocytic leukaemia line at levels of about 1 in 3 to 1 in 5 of that found in melanomas. Peripheral blood-derived dendritic cells, also express melanocortin 1 receptor in vitro. This extensive analysis of melanocortin 1 receptor tissue distribution may be of relevance not only for melanoma immunology, but also for research on the pathogenicity of inflammatory conditions in the skin and neurologic tissues. It remains to be seen if the over-expression of melanocortin 1 receptor in melanomas is sufficiently high to allow a ‘therapeutic window’ to be exploited in cancer immunotherapy. British Journal of Cancer (2002) 87, 414–422. doi:10.1038/sj

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. Endopeptidase 24-16 in murines: tissue distribution, cerebral regionalization, and ontogeny.

    PubMed

    Dauch, P; Masuo, Y; Vincent, J P; Checler, F

    1992-11-01

    The tissue distribution, cerebral regionalization, and ontogeny of endopeptidase 24-16 were established in murines by means of its quenched fluorimetric substrate, Mcc-Pro-Leu-Gly-Pro-D-Lys-Dnp, and its selective dipeptide blocker, Pro-Ile. Endopeptidase 24-16 was particularly abundant in the liver and kidney, and the lowest specific activity was detected in the heart. In the brain, a 16-fold difference in specific activity was observed between the poorest and the richest cerebral areas. Endopeptidase 24-16 appeared in high concentrations in the olfactory bulb and tubercule, cingulate cortex, medial striatum, and globus pallidus, and was particularly weak in the CA1, CA2, and CA3 parts of the hippocampal formation and in the cerebellum. Endopeptidase 24-16 content in thirteen thalamic nuclei indicated a rather homogeneous distribution. This homogeneity was not observed in the hypothalamus, where pronounced variations occurred between enriched zones such as suprachiasmatic and arcuate nuclei and relatively poor areas such as periventricular and supraoptic nuclei. Endopeptidase 24-16 appeared to be developmentally regulated in the mouse brain; it was already detected at the fetal stage, increased transiently after birth, then regularly declined until adulthood.

  4. Effect of tissue and atmosphere's parameters on human eye temperature distribution.

    PubMed

    Firoozan, Mohammad Sadegh; Porkhial, Soheil; Nejad, Ali Salmani

    2015-01-01

    A three dimensional finite element method analysis was employed to investigate the effect of tissue and atmosphere parameters namely, ambient temperature, ambient convection coefficient, local blood temperature, and blood convection coefficient upon temperature distribution of human eyes. As a matter of simplification, only eye ball and skull bone are considered as the system of eye modeling. Decreasing the local blood temperature and keeping it cool is one of the most important ways to control bleeding during surgeries. By lower temperature of body organs such as the eye, the need for oxygenated blood is reduced, allowing for an extension in time for surgery. With this in mind, this study is done to see which one of parameters, such as ambient temperature, ambient convection coefficient, local blood temperature, and blood convection coefficient, has an effective role in decreasing the temperature of the eye. To this end, 3 different paths were employed to find out about the temperature distribution through the eye. The analysis of the three paths demonstrates the interaction of ambient and blood temperature in modeling temperature changes in specific locations of the eye. These data will be important in applications such as eye surgery, relaxation, and sleep therapy.

  5. Heterogeneous distribution of a basement membrane heparan sulfate proteoglycan in rat tissues

    PubMed Central

    1987-01-01

    A heparan sulfate proteoglycan (HSPG) synthesized by murine parietal yolk sac (PYS-2) cells has been characterized and purified from culture supernatants. A monospecific polyclonal antiserum was raised against it which showed activity against the HSPG core protein and basement membrane specificity in immunohistochemical studies on frozen tissue sections from many rat organs. However, there was no reactivity with some basement membranes, notably those of several smooth muscle types and cardiac muscle. In addition, it was found that pancreatic acinar basement membranes also lacked the HSPG type recognized by this antiserum. Those basement membranes that lacked the HSPG strongly stained with antisera against laminin and type IV collagen. The striking distribution pattern is possibly indicative of multiple species of basement membrane HSPGs of which one type is recognized by this antiserum. Further evidence for multiple HSPGs was derived from the finding that skeletal neuromuscular junction and liver epithelia also did not contain this type of HSPG, though previous reports have indicated the presence of HSPGs at these sites. The PYS-2 HSPG was shown to be antigenically related to the large, low buoyant density HSPG from the murine Engelbreth-Holm swarm tumor. It was, however, confirmed that only a single population of antibodies was present in the serum. Despite the presence of similar epitopes on these two proteoglycans of different hydrodynamic properties, it was apparent that the PYS-2 HSPG represents a basement membrane proteoglycan of distinct properties reflected in its restricted distribution in vivo. PMID:2959669

  6. 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

  7. 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.

  8. 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.

  9. 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.

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

    PubMed

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

    2016-11-01

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

  11. Transmitting Tissue ECM Distribution and Composition, and Pollen Germinability in Sarcandra glabra and Chloranthus japonicus (Chloranthaceae)

    PubMed Central

    HRISTOVA, KATERINA; LAM, MATTHEW; FEILD, TAYLOR; SAGE, TAMMY L.

    2005-01-01

    • Background and Aims Free-flowing surface exudates at the stigmatic (wet versus dry stigma) and adaxial epidermis at the site of angiospermy in carpels of Chloranthaceous species have been proposed to comprise a continuous extracellular matrix (ECM) operating in pollen tube transmission to the ovary. The aim of this research was to establish the spatial distribution and histo/immunochemical composition of the ECM involved in pollen tube growth in Sarcandra glabra and Chloranthus japonicus (Chloranthaceae). • Methods Following confirmation of the pollen tube pathway, the histo/immunochemical make-up of the ECM was determined with histochemistry on fresh tissue to detect cuticle, esterase, proteins, pectins, and lipids and immunolocalization at the level of the TEM on sections from cryofixed/freeze-substituted tissue to detect molecules recognized by antibodies to homogalacturonans (JIM7, 5), arabinogalactan-proteins (JIM13) and cysteine-rich adhesion (SCA). • Key Results Pollen germinability is low in both species. When grains germinate, they do so on an ECM comprised of an esterase-positive cuticle proper (dry versus wet stigma). Pollen tubes do not track the surface ECM of stigma or adaxial epidermal cells at the site of angiospermy. Instead, tubes grow between stigmatic cells and subsequently along the inner tangential walls of the stigmatic and adaxial carpel cells at the site of angiospermy. Pollen tubes enter the ovary locule at the base of the funiculus. The stigmatic ECM is distinct by virtue of the presence of anti-JIM5 aggregates, lipids, and a protein recognized by anti-SCA. • Conclusions The Chloranthaceae joins a growing number of basal angiosperm taxa whereby pollen tubes germinate on a dry versus wet stigma to subsequently grow intercellularly en route to the ovary thereby challenging traditional views that the archetype pollen tube pathway was composed of the surface of stigma and adaxial epidermal cells covered with a free-flowing exudate

  12. Molecular cloning, tissue distribution, and pharmacological characterization of melanocortin-4 receptor in grass carp (Ctenopharyngodon idella).

    PubMed

    Li, L; Yang, Z; Zhang, Y-P; He, S; Liang, X-F; Tao, Y-X

    2017-04-01

    Melanocortin-4 receptor (MC4R) plays a pivotal role in the mediation of leptin action on food intake and energy expenditure in mammals. The MC4R has also been identified in several teleosts, and its importance in the regulation of fish energy homeostasis is emerging. We herein reported on the molecular cloning, tissue distribution, and pharmacological characterization of MC4R in grass carp (Ctenopharyngodon idella), an economically and ecologically important fish. We showed that grass carp MC4R (ciMC4R) consisted of a 981 bp open reading frame encoding a protein of 326 amino acids, highly homologous (>95%) to several teleost MC4Rs. Phylogenetic and synteny analysis further indicated ciMC4R was closely related to piscine MC4Rs. Using reverse transcription PCR, we found that mc4r messenger RNA was expressed in the brain as well as various peripheral tissues in grass carp. The pharmacological properties of ciMC4R were investigated using 4 agonists, including α-melanocyte stimulating hormone (α-MSH), β-MSH, [Nle(4), D-Phe(7)]-MSH (NDP-MSH), and adrenocorticotropic hormone (ACTH). We showed that all 4 ligands could bind to ciMC4R and initiate dose-dependent intracellular cyclic adenosine monophosphate (cAMP) accumulation. Grass carp MC4R had the highest affinity for NDP-MSH. Both NDP-MSH and ACTH (1-24) exhibited higher potencies compared to the other 2 endogenous agonists. The ciMC4R was constitutively active, with significantly increased basal cAMP level compared with that of human MC4R (P < 0.01). The availability of ciMC4R and its pharmacologic characteristics provide a basis for future investigation of its functional roles in regulating diverse physiological processes and novel insights into understanding the mechanism of food habit transition in grass carp.

  13. Calculation of dose distribution in compressible breast tissues using finite element modeling, Monte Carlo simulation and thermoluminescence dosimeters.

    PubMed

    Mohammadyari, Parvin; Faghihi, Reza; Mosleh-Shirazi, Mohammad Amin; Lotfi, Mehrzad; Hematiyan, Mohammad Rahim; Koontz, Craig; Meigooni, Ali S

    2015-12-07

    Compression is a technique to immobilize the target or improve the dose distribution within the treatment volume during different irradiation techniques such as AccuBoost(®) brachytherapy. However, there is no systematic method for determination of dose distribution for uncompressed tissue after irradiation under compression. In this study, the mechanical behavior of breast tissue between compressed and uncompressed states was investigated. With that, a novel method was developed to determine the dose distribution in uncompressed tissue after irradiation of compressed breast tissue. Dosimetry was performed using two different methods, namely, Monte Carlo simulations using the MCNP5 code and measurements using thermoluminescent dosimeters (TLD). The displacement of the breast elements was simulated using a finite element model and calculated using ABAQUS software. From these results, the 3D dose distribution in uncompressed tissue was determined. The geometry of the model was constructed from magnetic resonance images of six different women volunteers. The mechanical properties were modeled by using the Mooney-Rivlin hyperelastic material model. Experimental dosimetry was performed by placing the TLD chips into the polyvinyl alcohol breast equivalent phantom. The results determined that the nodal displacements, due to the gravitational force and the 60 Newton compression forces (with 43% contraction in the loading direction and 37% expansion in the orthogonal direction) were determined. Finally, a comparison of the experimental data and the simulated data showed agreement within 11.5%  ±  5.9%.

  14. Identification and distribution of mercury species in rat tissues following administration of thimerosal or methylmercury.

    PubMed

    Rodrigues, Jairo L; Serpeloni, Juliana M; Batista, Bruno L; Souza, Samuel S; Barbosa, Fernando

    2010-11-01

    Methylmercury (Met-Hg) is one the most toxic forms of Hg, with a considerable range of harmful effects on humans. Sodium ethyl mercury thiosalicylate, thimerosal (TM) is an ethylmercury (Et-Hg)-containing preservative that has been used in manufacturing vaccines in many countries. Whereas the behavior of Met-Hg in humans is relatively well known, that of ethylmercury (Et-Hg) is poorly understood. The present study describes the distribution of mercury as (-methyl, -ethyl and inorganic mercury) in rat tissues (brain, heart, kidney and liver) and blood following administration of TM or Met-Hg. Animals received one dose/day of Met-Hg or TM by gavage (0.5 mg Hg/kg). Blood samples were collected after 6, 12, 24, 48, 96 and 120 h of exposure. After 5 days, the animals were killed, and their tissues were collected. Total blood mercury (THg) levels were determined by ICP-MS, and methylmercury (Met-Hg), ethylmercury (Et-Hg) and inorganic mercury (Ino-Hg) levels were determined by speciation analysis with LC-ICP-MS. Mercury remains longer in the blood of rats treated with Met-Hg compared to that of TM-exposed rats. Moreover, after 48 h of the TM treatment, most of the Hg found in blood was inorganic. Of the total mercury found in the brain after TM exposure, 63% was in the form of Ino-Hg, with 13.5% as Et-Hg and 23.7% as Met-Hg. In general, mercury in tissues and blood following TM treatment was predominantly found as Ino-Hg, but a considerable amount of Et-Hg was also found in the liver and brain. Taken together, our data demonstrated that the toxicokinetics of TM is completely different from that of Met-Hg. Thus, Met-Hg is not an appropriate reference for assessing the risk from exposure to TM-derived Hg. It also adds new data for further studies in the evaluation of TM toxicity.

  15. Lung tissue distribution after intravenous administration of grepafloxacin: comparative study with levofloxacin.

    PubMed

    Yamamoto, Hiroshi; Koizumi, Tomonobu; Hirota, Masao; Kaneki, Toshimichi; Ogasawara, Hitoshi; Yamazaki, Yoshitaka; Fujimoto, Keisaku; Kubo, Keishi

    2002-01-01

    The aim of the present study is to study the pharmacokinetics in plasma, lung lymph and bronchial washing fluid after intravenous infusion of grepafloxacin (GPFX), in comparison with those of levofloxacin (LVFX). Four conscious sheep with chronically instrumented lung lymph fistulas and tracheotomy were prepared. GPFX and LVFX concentrations in plasma and lung lymph after intravenous infusion of the drugs (10 mg/kg) for over 10 min were measured. In addition serial bronchial washing with 50 mL normal saline was performed to obtain epithelial lining fluid (ELF) at 2, 4, 6, 8, 12, 24 h after the intravenous administration. The time courses of lung lymph concentration were almost identical to those of the concomitant levels of both GPFX and LVFX in plasma, suggesting that both GPFX and LVFX could be easily moved from plasma to pulmonary interstitium and/or lung lymph circulation. However, GPFX concentrations of ELF were significantly higher than LVFX concentrations over time after the administration. In addition, intracellular concentrations in ELF of GPFX were also extremely high compared with those of LVFX. These results demonstrated that penetration of GPFX in bronchial wall, bronchial epithelium and/or phagocytic cells was superior to that of LVFX. These observations suggest that the pharmacokinetic characteristics of GPFX in the lung may provide a new insight into the strategy for clinical treatment of various pulmonary infections, especially cytotropic bacterial infections.

  16. Tissomics: two- and three-dimensional distribution of nuclei in brain tissue using laser scanning cytometry (LSC)

    NASA Astrophysics Data System (ADS)

    Lenz, Domnik; Mittag, Anja; Mosch, Birgit; Bocsi, Jozsef; Arendt, Thomas; Tarnok, Attila

    2005-03-01

    Automated quantitative (i.e. stochiometric) analysis of tissues is of eminent importance in the understanding of all interactions between cells in their natural environment. In tissue cytometry a solid trigger is necessary in order to unequivocally differentiate between cellular and non-cellular events. This can be best performed by nuclear staining. Aim of this study was to analyze a brain tissue section by laser scanning cytometry (LSC) in order to depict the threedimensional distribution of nuclei in the tissue. To this end the section was measured in several foci and different nuclei detected in several depths of the tissue were assigned to the respective layer. Frozen sections of formalin-fixed rat or human brain tissue (120μm thickness) were incubated with propidiumiodide (PI) (50μg/ml) and covered on slides. For analysis by the LSC propidiumiodide was used as trigger. After a first analysis focussed on the top of the tissue, the focus was adjusted in 30μm steps deeper into the tissue. Per analysis data of at least 50,000 cells were acquired. After finishing measurements from all depths of the field were merged, i.e. data were combined into a composite data file. With the special features of the LSC it was possible to develop a method depicting the threedimensional distribution of the nuclei in solid tissue sections. LSC can be useful tool for this relatively new field of solid tissue cytometry termed tissomics. After evaluation of methods like this, so far not available data can be analysed for diagnostic purposes. By these studies we intend to demonstrate the power of the LSC for the routine pathological use. This should add up to the bright versatility of applications for the LSC as a cytometric instrument suitable for high throughput and high content analysis.

  17. Distribution of Fatal Vibrio Vulnificus Necrotizing Skin and Soft-Tissue Infections

    PubMed Central

    Huang, Kuo-Chin; Weng, Hsu-Huei; Yang, Tien-Yu; Chang, Te-Sheng; Huang, Tsan-Wen; Lee, Mel S.

    2016-01-01

    Abstract Vibrio vulnificus necrotizing skin and soft tissue infections (VNSSTIs), which have increased significantly over the past few decades, are still highly lethal and disabling diseases despite advancing antibiotic and infection control practices. We, therefore, examined the spatiotemporal distribution of worldwide reported episodes and associated mortality rates of VNSSTIs between 1966 and 2014. The PubMed and Cochrane Library databases were systematically searched for observational studies on patients with VNSSTIs. The primary outcome was all-cause mortality. We did random-effects meta-analysis to obtain estimates for primary outcomes; the estimates are presented as means plus a 95% confidence interval (CI). Data from the selected studies were also extracted and pooled for correlation analyses. Nineteen studies of 2227 total patients with VNSSTIs were analyzed. More than 95% of the episodes occurred in the subtropical western Pacific and Atlantic coastal regions of the northern hemisphere. While the number of cases and the number of deaths were not correlated with the study period (rs = 0.476 and 0.310, P = 0.233 and 0.456, respectively), the 5-year mortality rate was significantly negatively correlated with them (rs = −0.905, P = 0.002). Even so, the pooled estimate of total mortality rates from the random-effects meta-analysis was as high as 37.2% (95% CI: 0.265–0.479). These data suggest that VNSSTIs are always an important public health problem and will become more critical and urgent because of global warming. Knowing the current distribution of VNSSTIs will help focus education, policy measures, early clinical diagnosis, and appropriate medical and surgical treatment for them. PMID:26844475

  18. Tissue distribution and histopathological effects of dietary methylmercury in benthic grubby Myoxocephalus aenaeus

    SciTech Connect

    Pelletier, E.; Audet, C.

    1995-05-01

    There is a need to test deterministic models predicting the behavior and effects of chemicals on aquatic systems by conducting experiments with more than one trophic step at a time. This approach requires the set-up of an experimental food chain in pounds or mesocosm facilities which can be used for dietary uptake studies and assessment of sublethal stress induced by contaminated food. In the course of our current research program at the INRS marine mesocosms facilities, a model benthic food chain including inter- and sub-tidal species such as the mussel (Mytilus edulis), clam (Mya arenaria), starfish (Leptasterias polaris), polychaete (Nereis virens), amphipod (Gammarus sp.), gastropod (Buccinum undatum), and fishes (Pleuronectec americanus, Myoxocephalus aenaeus), is used for testing food uptake models and for the development of sublethal toxicity tests which could be used in the environmental assessment of coastal and estuarine waters. Among these test organisms, the grubby (M. aenaeus) is a small coastal fish (12-15 cm) characterized by a broad head. The grubby is tolerant of water temperature and salinity variations and lives on a wide variety of bottom strata at low depths. The grubby is carnivorous and consumes a wide variety of molluscs and the young of many species of fish. Because of its size, its estuarine and coastal distribution and its large spectrum of prey, this species was seen as an ideal fish to fit into our experimental food chain model. This paper reports a preliminary experiment designed to measure distribution of mercury in tissues and to test the response of various histopathological and biochemical stress indicators in grubby exposed to dietary contamination by methylmercury (MeHg) for a 20-day exposure period. MeHg was chosen because it is rapidly bioaccumulated by most living organisms and its toxicity has been studied for decades in numerous aquatic ecosystems. 17 refs., 2 tabs.

  19. Tissue distribution of PEBBLE RNA and pebble protein during Drosophila embryonic development.

    PubMed

    Prokopenko, S N; Saint, R; Bellen, H J

    2000-02-01

    pebble (pbl) is required for cytokinesis during postblastoderm mitoses (Hime, G., Saint, R., 1992. Zygotic expression of the pebble locus is required for cytokinesis during the postblastoderm mitoses of Drosophila. Development 114, 165-171; Lehner, C.F., 1992. The pebble gene is required for cytokinesis in Drosophila. J. Cell Sci. 103, 1021-1030) and encodes a putative guanine nucleotide exchange factor (RhoGEF) for Rho1 GTPase (Prokopenko, S.N., Brumby, A., O'Keefe, L., Prior, L., He, Y., Saint, R., Bellen, H.J., 1999. A putative exchange factor for Rho1 GTPase is required for initiation of cytokinesis in Drosophila. Genes Dev. 13, 2301-2314). Mutations in pbl result in the absence of a contractile ring leading to a failure of cytokinesis and formation of polyploid multinucleate cells. Analysis of the subcellular distribution of PBL demonstrated that during mitosis, PBL accumulates at the cleavage furrow at the anaphase to telophase transition when assembly of a contractile ring is initiated (Prokopenko, S.N., Brumby, A., O'Keefe, L., Prior, L., He, Y., Saint, R., Bellen, H.J., 1999. A putative exchange factor for Rho1 GTPase is required for initiation of cytokinesis in Drosophila. Genes Dev. 13, 2301-2314). In addition, levels of PBL protein cycle during each round of cell division with the highest levels of PBL found in telophase and interphase nuclei. Here, we report the expression pattern of pbl during embryonic development. We show that PEBBLE RNA and PBL protein have a similar tissue distribution and are expressed in a highly dynamic pattern throughout embryogenesis. We show that PBL is strongly enriched in dividing nuclei in syncytial embryos and in pole cells as well as in nuclei of dividing cells in postblastoderm embryos. Our expression data correlate well with the phenotypes observed in pole cells and, particularly, with the absence of cytokinesis after cellular blastoderm formation in pbl mutants.

  20. Quantitative structure-pharmacokinetic relationship (QSPkP) analysis of the volume of distribution values of anti-infective agents from J group of the ATC classification in humans.

    PubMed

    Louis, Bruno; Agrawal, Vijay K

    2012-11-01

    In this study, a quantitative structure-pharmacokinetic relationship (QSPkR) model for the volume of distribution (Vd) values of 126 anti-infective drugs in humans was developed employing multiple linear regression (MLR), artificial neural network (ANN) and support vector regression (SVM) using theoretical molecular structural descriptors. A correlation-based feature selection (CFS) was employed to select the relevant descriptors for modeling. The model results show that the main factors governing Vd of anti-infective drugs are 3D molecular representations of atomic van der Waals volumes and Sanderson electronegativities, number of aliphatic and aromatic amino groups, number of beta-lactam rings and topological 2D shape of the molecule. Model predictivity was evaluated by external validation, using a variety of statistical tests and the SVM model demonstrated better performance compared to other models. The developed models can be used to predict the Vd values of anti-infective drugs.

  1. 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.

  2. Tissue distribution of borneol-modified ganciclovir-loaded solid lipid nanoparticles in mice after intravenous administration.

    PubMed

    Ren, Jungang; Zou, Meijuan; Gao, Ping; Wang, Yue; Cheng, Gang

    2013-02-01

    The main purpose of this research was to prepare borneol-modified and non-borneol ganciclovir-loaded solid lipid nanoparticles (SLNs) to study whether borneol could enhance the transport of ganciclovir (GCV) incorporated in SLN to the brain in mice after their intravenous administration. Ganciclovir injection (GCV-inj) was selected as a control. The SLNs were prepared using a modified microemulsion method. Pharmacokinetic and biodistribution studies were conducted in kunming mice after intravenous administration of GCV-inj, GCV solid lipid nanoparticles without borneol (GCV-SLN), and three types of GCV solid lipid nanoparticles containing different ratios of borneol (GCVb-SLN). It was found that, in plasma, the area under the concentration-time curve (AUC 0 ∼ t) for GCVb-SLN and GCV-SLN was greater than that for the GCV-inj. In the brain, the AUC 0 ∼ t of GCVb-SLN was significantly increased compared with that of a GCV-inj and GCV-SLN. In the other mouse tissues, the peak concentration of GCV achieved was always lower after the injection of any of the four types of SLN than after the commercial injection. These results indicate that GCV-SLN modified with borneol enhances the transport of ganciclovir to the brain. Therefore, SLN modified with borneol is a potential delivery system for transporting drugs to the central nervous system (CNS).

  3. Dietary pyrrolizidine (Senecio) alkaloids and tissue distribution of copper and vitamin A in broiler chickens.

    PubMed

    Huan, J; Cheeke, P R; Lowry, R R; Nakaue, H S; Snyder, S P; Whanger, P D

    1992-09-01

    The effect of feeding a diet containing 5% tansy ragwort (TR) (Senecio jacobaea), a poisonous plant containing pyrrolizidine alkaloids (PA), on the blood and liver levels of copper, zinc, iron and vitamin A in broiler chicks was examined. Serum and liver copper and liver iron concentrations were increased in chicks fed a diet with 5% TR, while serum and liver zinc and vitamin A decreased. When PA were removed from the diet, partial restoration of normal serum vitamin A level occurred, indicating that the ability to mobilize liver vitamin A is not irreversibly inhibited by PA. The decline in serum vitamin A occurred by 8 days of TR feeding with a concurrent decline in growth rate. When chicks were fed a diet high in vitamin A (25,000 IU/kg), followed by a basal diet containing TR, serum vitamin A levels were significantly (P < 0.01) decreased, while liver vitamin A level increased. This indicates that mobilization of previously stored vitamin A from the liver is impaired by PA. Prior feeding of a high vitamin A level resulted in protective effects against PA toxicity, as assessed by histopathology. This study shows that a dietary source of PA modifies metabolism and tissue distribution of minerals and vitamin A.

  4. Population pharmacokinetics of daptomycin.

    PubMed

    Dvorchik, Barry; Arbeit, Robert D; Chung, Julia; Liu, Susan; Knebel, William; Kastrissios, Helen

    2004-08-01

    Data from subjects in nine phase 1 (n = 153) and six phase 2/3 (n = 129) clinical trials were combined to identify factors contributing to interindividual variability in daptomycin pharmacokinetics (PK). Over 30 covariates were considered. A two-compartment model with first-order elimination provided the best fit for data on daptomycin concentrations in plasma over time. In the final population PK model, daptomycin plasma clearance (CL) was a function of renal function, body temperature, and sex. Of these factors, renal function contributed most significantly to interindividual variability. CL varied linearly with the estimated creatinine clearance. CL among dialysis subjects was approximately one-third that of healthy subjects (0.27 versus 0.81 liter/h). CL in females was 80% that in males; however, in clinical trials, the outcome was not affected by sex and therefore this effect is not considered clinically meaningful. The relationship with body temperature should be interpreted cautiously since the analysis included only a limited number of subjects who were hyperthermic. The volume of distribution of the peripheral compartment (V2) and intercompartmental clearance (Q) were linearly related to body weight. V2 increased approximately twofold in the presence of an acute infection. No factors were identified that significantly impacted V1. This analysis supports the dosing of daptomycin on a milligram-per-kilogram-of-body-weight basis and suggests that modified dosing regimens are indicated for patients with severe renal disease and for those undergoing dialysis.

  5. Distribution pattern of bovine viral diarrhoea virus type 1 genome in lymphoid tissues of experimentally infected sheep.

    PubMed

    Karikalan, M; Rajukumar, K; Mishra, N; Kumar, M; Kalaiyarasu, S; Rajesh, K; Gavade, V; Behera, S P; Dubey, S C

    2016-06-01

    In this study, cellular localization and the distribution pattern of BVDV genome in lymphoid tissues during the course of experimental acute BVDV-1 infection of sheep was investigated. Tonsils, mesenteric lymph nodes (MLN) and spleen were collected on 3, 6, 9, 12 and 15 days post infection (dpi) from twenty 4-month-old lambs, experimentally inoculated intra-nasally with 5 × 10(5) TCID50 of a non-cytopathic (ncp) BVDV-1 isolate, Ind-17555. Tissues collected from ten mock-infected lambs served as controls. In situ hybridization (ISH) was carried out in paraformaldehyde fixed paraffin embedded tissue sections using digoxigenin labelled riboprobe targeting 5'-UTR of BVDV-1. BVDV genome was detected at all the intervals from 3 dpi to 15 dpi in the lymphoid tissues with variations between the intervals and also amongst the infected sheep. During the early phase of acute infection, presence of viral genome was more in tonsils than MLN and spleen, whereas the distribution was higher in MLN during later stages. BVDV-1 genome positive cells included lymphocytes, macrophages, plasma cells, reticular cells and sometimes crypt epithelial cells. Genome distribution was frequently observed in the lymphoid follicles of tonsils, MLN and spleen, besides the crypt epithelium in tonsils, paracortex and medullary sinus and cords of MLN. Most abundant and widespread distribution of BVDV-1 genome was observed on 6 dpi while there was a reduction in number and intensity of positive signals by 15 dpi in most of the infected animals. This is the first attempt made to study the localisation of BVDV-1 in lymphoid tissues of acutely infected sheep by in situ hybridization. The results show that the kinetics of BVDV-1 distribution in lymphoid tissues of experimentally infected non-pregnant sheep follows almost a similar pattern to that demonstrated in BVDV infected cattle.

  6. Simultaneous determination of multiple bioactive components of Bu-zhong-yi-qi-tang in rat tissues by LC-MS/MS: Application to a tissue distribution study.

    PubMed

    He, Min; Chen, Wenwen; Wang, Mengmeng; Wu, Yu; Zeng, Jin; Zhang, Zhirong; Shen, Shujiao; Jiang, Jian

    2017-02-15

    A liquid chromatography coupled with electrospray ionization mass spectrometry method was developed and validated for simultaneous determination of seven bioactive constituents including astragaloside IV, calycosin, glycyrrhizic acid, enoxolone, saikosaponin D, ferulic acid and hesperiden in rats' various tissues using diclofenac as the internal standard (IS). Biological samples were pretreated by protein precipitation with acetonitrile. The chromatographic separation was carried out on a C18 column with a gradient mobile phase consisting of acetonitrile and water (containing 0.1% formic acid and 4mM ammonium acetate). All analytes and IS were quantitated through electrospray ionization in negative ion multiple reaction monitoring mode. The mass transitions were as follows: m/z 829.7→783.3 for astragaloside IV, m/z 283.3→267.7 for calycosin, m/z 821.6→350.0 for glycyrrhizic acid, m/z 469.9→425.2 for enoxolone, m/z 825.7→779.6 for saikosaponin D, m/z 192.5→133.9 for ferulic acid, m/z 609.1→301.0 for hesperiden and m/z 293.6→249.9 for the IS, respectively. The lower limits of quantification for the seven analytes in different rat tissues were 0.2-20ng/mL. Bu-zhong-yi-qi-tang (Hochuekkito in Japan, Bojungikki-tang in Korea) is one of the most frequently prescribed traditional herbal formulas used in Korea, Japan, and China to treat gastrointestinal diseases, cancer and chronic fatigue syndrome. The validated method was successfully applied to a tissue distribution study of the seven components in rat tissue after oral administration of Bu-zhong-yi-qi-tang concentrated granule. The results of the tissue distribution study showed that the high concentration of seven components were mainly in the gastrointestinal tract.

  7. Pharmacokinetics of a novel amoxicillin/colistin suspension after intramuscular administration in pigs.

    PubMed

    He, J; Tang, S; Li, L; Zhang, C; Li, X; Xia, X; Xiao, X

    2011-02-01

    An amoxicillin (AMO) or colistin (COS) oil suspension was developed and corresponding pharmacokinetics studies were conducted in pigs after i.m. injection. The combination product is a white- to cream-colored oil suspension which is easy to be re-dispersed. Settling volume ratio, syringeability and flowability of the product is well consistent with the technical standards set by the Ministry of Agriculture of People's Republic of China. Two studies were conducted to investigate the pharmacokinetics of the combination product in swine. First, the pharmacokinetics of the combination product was compared with those of the same products merely removing either AMO or COS. No significant change in the major pharmacokinetic parameters (C(max) , T(max) , MRT, t(1/2λ) , AUC and AUMC) was observed when either component was removed from the combination product, indicating that AMO and COS do not interfere with each other in their absorption and distribution in the tissue when used as a combination. Second, the pharmacokinetics of the combination product was compared with that of their respective single products. It was found that the apparent elimination half-lives (t(1/2λ) ) of AMO and COS in combination product were 6.38 and 8.09 h, which were 2.40 and 2.38 times longer than the single products, respectively. Thus, the novel AMO/COS suspension extended significantly the half-life of both drugs to maintain a longer drug residence time in pigs when compared to their single products.

  8. 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 thrombolytic potency (clot lysis in percent versus dose administered in mg/kg) and of specific thrombolytic activity (clot lysis in percent versus steady state plasma level in microgram/ml) were fitted with an exponentially transformed sigmoidal function y = 100 c/(1 + e-a(ax-eh] and the maximal percent lysis (c), the dose or plasma level at which maximal rate of lysis is achieved (b) and the maximal rate of lysis (z = 1/4 ac.eb) were determined. With rt-PA, these parameters were c = 72 +/- 6% (mean +/- SEM), b = 0.19 +/- 0.08 mg/kg, z = 68 +/- 25% lysis per mg/kg, with corresponding values of 87 +/- 5%, 0.07 +/- 0.03 mg/kg and 150 +/- 38% lysis per mg/kg for Activase (p = NS). Deletion of the finger and growth factor domains in rt-PA (rt-PA-delta FE) was not associated with marked alteration of the thrombolytic potency (c = 90 +/- 30%, b = 0.34 +/- 0.35 mg/kg, and z = 54 +/- 14% per mg/kg), but was associated with a significant reduction of the specific thrombolytic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Tissue distribution study of salvianolic acid B long-circulating liposomes in mice by UPLC-MS/MS determination.

    PubMed

    Pi, Jiaxin; Liu, Zhidong; Shu, Lexin; Li, Lin; Wang, Ying; Li, Nan; Li, Jiawei

    2015-01-01

    In targeting delivery system research on salvianolic acid B, it's vital but hard to evaluate the tissue distribution for its low concentrations in tissues. So the simple, rapid, selective and sensitive UPLC-MS/MS method was provided hereby to determine the concentration of salvianolic acid B in mice tissues after intravenous administration of salvianolic acid B injections, conventional liposomes and long-circulating liposomes. The UPLC was conducted by a C(18) column with a gradient mobile phase consisting of acetonitrile and water containing 0.1% formic acid. The tandem mass spectrometry was operated in negative-electrospray ionization selected-reaction-monitoring mode, and the optimized characteristic precursor to product ion transition m/z 717.3→519.1 was selected. The biosamples were homogenized and treated with a protein precipitation, which led to an acceptable matrix effect and extraction recovery. The linear calibration curves were plotted in the given concentration ranges. The intra-day and inter-day precisions were less than 13.9% and the accuracies were in the range of 86.3-109.2%. The tissue distribution results determined by UPLC-MS/MS we developed showed that the conventional and long-circulating liposomes we made had succeeded in prolonging the retention time and increasing the level of salvianolic acid B in certain distribution tissues such as liver, kidney and brain.

  10. Halogenated flame retardants during egg formation and chicken embryo development: maternal transfer, possible biotransformation, and tissue distribution.

    PubMed

    Zheng, Xiao-Bo; Luo, Xiao-Jun; Zeng, Yan-Hong; Wu, Jiang-Ping; Chen, She-Jun; Mai, Bi-Xian

    2014-08-01

    Hen muscle, eggs, and newborn chick tissues (muscle and liver) were collected from an electronic waste recycling site in southern China. The authors examined the maternal transfer, potential metabolism, and tissue distribution of several halogenated flame retardants (HFRs) during egg formation and chicken embryo development. The pollutant composition changes significantly from hen muscle to eggs and from eggs to tissues of newborn chicks. Higher-halogenated chemicals, such as octa- to deca-polybrominated diphenyl ether (PBDE) congeners, deca-polybrominated biphenyl (PBB209), and dechlorane plus (DP), are less readily transferred to eggs compared with lower-halogenated chemicals. During embryo development, PBDEs are the most likely to be metabolized, whereas decabromodiphenyl ethane (DBDPE) is the least. The authors also observed selective maternal transfer of anti-DP and stereoselective metabolism of syn-DP during chicken embryo development. During tissue development, liver has greater affinity than the muscle for chemcials with a high log octanol-water partition coefficient, with the exception of DBDPE. The differences in metabolism potential of different chemicals in chicken embryos cause pollutant composition alterations. Halogenated flame retardant from maternal transfer and tissue distribution also exhibited chemical specificity, especially for DBDPE. Levels of DBDPE were elevated along with the full process from hen muscle to eggs and from eggs to chick tissues. More attention should be paid to the selective accumulation and biotransformation of HFRs in the early development stage of birds.

  11. Determining the pharmacokinetics and long-term biodistribution of SiO2 nanoparticles in vivo using accelerator mass spectrometry.

    PubMed

    Malfatti, Michael A; Palko, Heather A; Kuhn, Edward A; Turteltaub, Kenneth W

    2012-11-14

    Biodistribution is an important factor in better understanding silica dioxide nanoparticle (SiNP) safety. Currently, comprehensive studies on biodistribution are lacking, most likely due to the lack of suitable analytical methods. Accelerator mass spectrometry was used to investigate the relationship between administered dose, pharmacokinetics (PK), and long-term biodistribution of (14)C-SiNPs in vivo. PK analysis showed that SiNPs were rapidly cleared from the central compartment, were distributed to tissues of the reticuloendothelial system, and persisted in the tissue over the 8 week time course, raising questions about the potential for bioaccumulation and associated long-term effects.