| Project/Area Number |
08457619
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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 | Tohoku University |
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Principal Investigator |
TERASAKI Tetsuya Tohoku University, Faculty of pharmaceutical Sciences, Professor, 薬学部, 教授 (60155463)
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| Co-Investigator(Kenkyū-buntansha) |
HOSOYA Ken-ichi Tohoku University, Faculty of pharmaceutical Sciences, 薬学部, 教務職員
TAKENAKA Shoji Tohoku University, Faculty of pharmaceutical Sciences, 薬学部, 助手 (70006344)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥7,500,000 (Direct Cost: ¥7,500,000)
Fiscal Year 1997: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1996: ¥4,600,000 (Direct Cost: ¥4,600,000)
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| Keywords | blood-brain barrier / brain / membrane transport / efflux transport / drug delivery / brain efflux index method / organic anion transport / P-glycoprotein / 脳毛細血管 / 解毒 / 薬物排出輸送 / 脳排出指標 |
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| Research Abstract |
The blood-brain barrier (BBB) influx rate of BECEF-AM (Mw : 809) was determined and was very similar to that of predicted from the octanol-water partition coefficient. Quinidine (Mw : 324) was pumped out from the brain to the circulating blood via mdrla gene product at the BBB.These results suggest the lack of molecular threshold at the BBB.We have developed the brain efflux index (BEI) method to determine the efflux transport rate of drugs at the BBB.The restricted brain distribution of 3'-Azido-3'-deoxythymidine (AZT) and 2', 3'-dideoxyinosine (DDl) was analyzed using the distributed model, suggesting that both drugs are significantly effluxed from the brain via the BBB.The BBB efflux of AZT and DDI was characterized to transport via the organic anion transport system by the BEI method. Para-aminohippuric acid (PAH), an organic anion, was used to reveal the organic anion efflux transport system at the BBB.PAH was selectively effluxed from the brain to the blood. Saturable efflux of PAH was shown, suggesting the presence of the carrier-madia organic anion transport system at the BBB.B -Alanine and quinolone antibiotics were also suggested to be pumped out from the brain at the BBB via each different carrier-mediated transport system. Interestingly, in vivo evidences were obtained to suggest that the neurotranmitters such as GABA and acidic amino acid were effluxed at the BBB.
In conclusion, as shown in the above results, several efflux transport systems, including P-glycoprotein, play an important role for the regulation of normal cerebral function. Based on these findings, we have proposed a new strategy for the drug design that the lack of the affinity to the efflux transport system at the BBB would be efficient to increase the apparent influx rate of the drug to the brain.
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