| Co-Investigator(Kenkyū-buntansha) |
KUSUHARA Hiroyuki The University of Tokyo, Graduate School of Pharmaceutical Sciences, Lecturer, 大学院・薬学系研究科, 講師 (00302612)
SUGAWARA Yasuhiko The University of Tokyo, Faculty of Medicine, Assistant Professor, 医学部附属病院, 助教授 (90313155)
YOSHIZATO Katsutoshi Hiroshima University, Graduate School of Science, Professor, 大学院・理学研究科, 教授 (20095516)
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| Budget Amount *help |
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2004: ¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 2003: ¥7,900,000 (Direct Cost: ¥7,900,000)
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| Research Abstract |
In order to establish a useful system for the prediction of drug transport in human liver, we have performed pharmacokinetic analysis using mice with humanized liver, which were transplanted with human hepatocytes. A drug for hyperlipemia, pravastatin, which is a good substrate of organic anion transporting system in liver and is eliminated mainly in bile, was used for the analysis and transport activities were estimated in each process : uptake clearance was determined by the initial hepatic uptake method and concentrations in blood, liver, bile at steady state was used for the determination of biliary clearance (biliary excretion rate/blood concentration) and bile canalicular clearance (biliary excretion rate/concentration in liver). Transplanted mice with low replacement index (approximately 1%) of human hepatocytes show higher biliary clearance and uptake clearance than highly replaced mice (more than 80%), whereas both group of mice represent similar values of bile canalicular cle
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arance. These data suggest that there is a species difference in the uptake process between human and mice, as activities in mice being higher, whereas efflux process via canalicular membrane has little difference. To reveal that transport function in chimeric mice with humanized liver could reflect the interindividual difference in human, it is necessary to demonstrate that, for example, chimeric mice transplanted with human hepatocytes of lower biliary excretion function would have lower biliary clearance of drugs. For this purpose, we have investigated the effect of single nucleotide polymorphisms of drug transporters ; uptake transporter of pravastatin from blood to liver, OATP-C/OATP1B1 and efflux transporter into bile, MRP2/ABCC2.OATP1B1 *15, whose function was suggested to be lower by in vivo analysis, was revealed to be lower transport activities by marked decrease in Vmax. One of the most common variant, V417 MRP2, was demonstrated to have no difference in the transporter function compared with wild type MRP2. Less
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