| Project/Area Number |
09672332
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | University of Shizuoka |
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Principal Investigator |
DEGUCHI Yoshiharu University of Shizuoka, School of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (40254255)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1997: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | anion transport system / BBB efflux transport / Alzheimer's disease / ketoprofen / 6-mercaptopurine / improvement of CNS delivery / probenecid / prodrug / 血液脳関門 / 排出輸送 / モノカルボン酸輸送系 / 脳移行性改善 / ペプチド性薬物 / アセチルコリンエステラーゼ阻害薬 / 脳送達法 / 脳内代謝 / グリセロール |
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| Research Abstract |
There are increasing evidences that the drug efflux pump like P-glycoprotein in the blood- brain barrier (BBB) is actively extruded many drugs from brain to blood circulation, resulting in the limited distribution to the brain. The goal of this research was to find drugs that is recognized by the efflux transport system in the BBB, and to develop the novel drug delivery system in which the BBB efflux system is being regulated. 1) Patients with acute lymphoblastic leukemia who continuously receive 6-mercaptopurine (6-MP) are often brought about the CNS relapse. This may be caused by the restricted distribution of 6-MP in the brain. Therefore, the BBB transport of 6-MP was examined. As a result, it was found that the restricted 6-MP brain distribution may be ascribe to the active extrusion from the brain, possibly via the organic anion transport system and the monocarboxylic acid transport system. This study also suggests that the coadministration of a transport inhibitor like probenecid may improve this restricted 6-MP distribution in the brain. 2) Recently, it has been reported that nonsteroidal antiinflammatory drugs (NSAIDs) were effective to Alzheimer's disease. However, the distribution of NSAIDs into the brain is very limited. Therefore, in this study, it was examined whether a newly synthesized glyceride prodrug of ketoprofen (KT) improve the brain delivery of KT.DAKG could improve the brain uptake of KT from blood side to brain. In addition, the coadministration of probenecid with DAKG significantly improve the brain delivery of KT by inhibiting the efflux transport of KT which was metabolized from DAKG in the brain.
The findings obtained here will provide significant information for CNS drug discovery and CNS drug therapy.
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