| Project/Area Number |
10044243
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Graduate School of Pharmaceutical Sciences, The University of Tokyo |
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Principal Investigator |
SUGIYAMA Yuichi Graduate School of Pharm. Sci. The Univ. of Tokyo, Professor, 大学院・薬学系研究科, 教授 (80090471)
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| Co-Investigator(Kenkyū-buntansha) |
KUSUHARA Hiroyuki Graduate School of Pharm. Sci. The Univ. of Tokyo, Research Associate, 大学院・薬学系研究科, 助手 (00302612)
KATO Yukio Graduate School of Pharm. Sci. The Univ. of Tokyo, Research Associate, 大学院・薬学系研究科, 助手 (30251440)
SUZUKI Hiroshi Graduate School of Pharm. Sci. The Univ. of Tokyo, Assistant Professor, 大学院・薬学系研究科, 助教授 (80206523)
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| Project Period (FY) |
1998 – 1999
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| Keywords | transporter / drug disposition / hepatobiliary transport / interindividual difference / species difference / gene expression system / detoxification system |
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| Research Abstract |
We attempted to establish gene expression system for several types of transporters expressed in the liver, in Which the functional analyses of the hepatobiliary transport of organic compounds can be performed. We collaborated with Dr. Peter J. Meier and investigated the contribution of organic anion transporters on the sinusoidal membrane such as oatp1 and Ntcp to the net hepatic uptake of several kinds of organic anions by comparing the transport activity between transfectant and cultured rat hepatocytes. The substrate specificity of canalicular multispecific organic anion transporter (cMOAT) which is known to play a predominant role in the biliay excretion of several anionic compounds was investigated and folates and its structural analogues as well as small peptides with anionic moiety were identified as new substrates of cMOAT. The uptake of organic anions into canalicular membrane vesicles exhibits a large interindividual difference in humans. Also, there is a large species difference in the biliary excretion of an angiotensin converting enzyme inhibitor, which is attributed to the species difference in the membrane transport via cMOAT. The present findings should be clinically important for the prediction of drug-drug interactions of these drugs via the transporters. We investigated the effect of a multidrug resistance modulator, SDZ PSC 833 on the biliary excretion of endogenous compounds and drugs. The analysis using P-glycoprotein expression system gifted from Dr. Piet Borst is being carried out. We succeeded to isolate cDNA of MRP3 from the liver of mutant rats which cMOAT is hereditarily deficient, and to characterize its substrate specificity and transport property, ・ MRP3 is reported to confer resistance to a certain type of anticancer drugs. The present results should be important to understand the detoxification system in the body and also tumors.
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