| Project/Area Number |
04557106
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | University of Tokyo |
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Principal Investigator |
SUGIYAMA Yuichi University of Tokyo Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (80090471)
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| Co-Investigator(Kenkyū-buntansha) |
TAKIKAWA Hajime Teikyo univ.Hospital Associate Professor, 医学部付属病院, 助教授 (70197226)
KOBAYASHI Tomoo Sankyo Co., Ltd., 生物研究所, 室長 (70085645)
INABA Makoto Cancer Chemotherapy Center, Foundation for Cancer Research,, 癌化学療法センター, 主任研究員 (60085636)
YAMAZAKI Masayo Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Research Associ, 薬学部, 助手 (40240741)
TERASAKI Tetsuya Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Associate Profe, 薬学部, 助教授 (60155463)
鈴木 洋史 東京大学, 薬学部, 助手 (80206523)
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| Project Period (FY) |
1992 – 1993
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| Project Status |
Completed (Fiscal Year 1993)
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| Budget Amount *help |
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 1993: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1992: ¥10,500,000 (Direct Cost: ¥10,500,000)
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| Keywords | Multi-drug resistance / P-glycoprotein / Monoclonal antibody / Vincristine / MRK-16 / Pharmacokinetics / Physiological pharmacokinetics / MDR / 単離脈絡叢 / 脳脊髄液関門 / 脳血液関門 / AZT / DDI / vincristine |
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| Research Abstract |
[1] Transport mechanism of peptides : Using a monoclonal antibody to transferrin as a model polypeptide, the transport mechanism for piptide in blood-brain barrier (BBB) was examined. The permeability of this antibody for blood-brain barrier was evaluated with in situ brain perfusion system, in vitro isolated and cultured bovine brain endotherial cells. As a result, the existence of receptor-mediated endocytosis pathway was suggested to be existed. By complex formation of this antibody and the polypeptide, it may possibly be improved that the net transfer of the polypeptide into the brain across the BBB.
[2] Transport mechanism for hydrophilic drugs : Using quinolone derivatives (NQs) and anti-AIDS drugs (azidothymidine and dideoxyinosine) as model drugs, the mechanism for the disposition in the central nervous system (CNS) were examined with in vivo and in vitro experimental systems. For anti-AIDS drugs, the uptake from blood to brain was suggested to be active transport. In vitro uptake studies using isolated choroid plexus revealed that NQs was pumped out from cerebrospinal fluid to the circulating blood by an active organic anion transport system which is identical with that for benzylpenicillin. In addition, not only anti-AIDS drugs but NQs are also taken up by choroid plexus in a active transport manner.
[3] Prediction of the disposition with physiological pharmacokinetics : Analysis based on the distributed model in which the ligand exchange between the plasma, brain, and cerebrospinal fluid is considered revealed that the CNS to plasma unbound concentration ratio of NQs can be predicted using the determined clearance values, which were determined with several experimental systems described above, for the transport across the barriers.
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