| Project/Area Number |
12557228
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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 | 展開研究 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | The University of Tokyo |
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Principal Investigator |
SUZUKI Hiroshi Graduate School of Pharmaceutical Sciences, The University of Tokyo, Associate Professor, 大学院・薬学系研究科, 助教授 (80206523)
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| Co-Investigator(Kenkyū-buntansha) |
SHODA Jun-ichi School of Medicine, Tsukuba University, Lecturer, 臨床医学系, 講師 (90241827)
KATO Yukio Graduate School of Pharmaceutical Sciences, The University of Tokyo, Assistant Professor, 大学院・薬学系研究科, 助手 (30251440)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥10,200,000 (Direct Cost: ¥10,200,000)
Fiscal Year 2001: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2000: ¥6,400,000 (Direct Cost: ¥6,400,000)
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| Keywords | genetic polymorpnism / xenobiotic detoxification / transporters / OATP2 / MRP / organic anions / biliary excretion / vectorial transport / プラバスタチン / SNPs / 薬物動態 / ABCトランスポーター |
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| Research Abstract |
We have investigated the function of transporters responsible for the Hepatic uptake (organic anion transporting polypeptide 2 ; OATP2/SLC21A6) and biliary excretion (multidrug resistance associated protein 2 ; MRP2/ABCC2). Concerning OATP2/SLC21A6 we have examined the transport properties of several substrates by using HEK 293 cells Stably expressing the single nucleotide polymorphisms (SNPs) mutants. It was suggested that the OATP2/SLC21A6 SNPs which are frequently observed in Orientals may be associated with the alterations in the kinetic parameters for the transport of certain kinds of ligands. Concerning MRP2/ABCC2, we could suggest the amino acid residues which are important in the substrate transport by using the site-directed mutagenesis method. A novel MRP2/ABCC2 mutation was found in Orientals. In addition, by using the cell lines established from the Japanese cancer patients, we found many kinds of novel mutations, along with the linkage of the mutations in MRP2/ABCC2. Moreover, by using an Madin-Darby canine kidney (MDCK) cell line which stably expresses OATP2/SLC21A6 and MRP2/ABCC2 on the basal and apical membranes, respectively, we have performed the precise kinetic analysis for the transcellular transport, the basal uptake, and the apical efflux, and could suggest that it may be possible for us to predict the drug disposition in mutated subjects by examining the in vitro disposition of ligands in MDCK cell monolayer expressing the mutated transporters.
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