| Project/Area Number |
11470493
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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 |
医薬分子機能学
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| Research Institution | Graduate School of Pharmaceutical Sciences, The University of Tokyo |
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Principal Investigator |
SUZUKI Hiroshi The Univ.of Tokyo Graduate School of Pharm.Sci.Research Associate, 大学院・薬学系研究科, 助教授 (80206523)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIMURA Kenji Sankyu Co., Ltd Procudt Development Laboratories Director, 分析代謝研究所, 所長(研究職)
KATO Yukio The Univ.of Tokyo Graduate School of Pharm.Sci.Research Associate, 大学院・薬学系研究科, 助手 (30251440)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥9,300,000 (Direct Cost: ¥9,300,000)
Fiscal Year 2000: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1999: ¥6,100,000 (Direct Cost: ¥6,100,000)
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| Keywords | MDR1 / MRP2 / MRP3 / intestinal absorption / intestinal excretion / CYP enzymes / enterocytes / Caco-2細胞 / ABCトランスポーター / 有機アニオン系化合物 / MDR1 P-糖タンパク / CYP3A4 / MRP / 有機アニオン |
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| Research Abstract |
One of the most important factors to determine the oral bioavailability is the small intestinal absorption. Since the substrate specificity of CYP3A and MDR1 P-glycoprotein resembles each other, the oral absorption of many drugs is prohibited by the synergistic role of these proteins. In order to determine the relative role of CYP enzymes and P-glycoprotein, an effort was made to determine the selective inhibitors. It was demonstrated that L754,394 and PSC 833 are selective for CYP3A4 and MDR1 P-glycoprotein, respectively. The contribution of these proteins may be determined by using human small intestine in vivo.
In addition, it is possible that many anionic drugs can be eliminated by efflux transporters located in the small intestine. We have particularly focused on the function of multidrug resistance associated protein (MRP) family proteins. MRP2 is expressed on the apical membrane. By comparing the intestinal excretion between normal and MRP2-deficient rats, it was demonstrated that MRP2 prohibits the absorption of anionic drugs. In contrast, MRP3 is located on the basolateral membrane of enterocytes. It was found that MRP3 accepts glucuronide conjugates, sulfated bile acids, non-conjugated organic anions, and monovalent bile salts. Furthermore, by using the basolateral membrane from the small intestine, it was revealed that un-identified MRP family protein (s) is responsible for the ATP-dependent transport of glucuronide conjugates. By regulating the function of these efflux transporters, it is possible to enhance the oral bioavailability.
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