1993 Fiscal Year Final Research Report Summary
Analysis of drug disposition in the central nervous system based on the transport characteristics across the blood-brain barrier and blood-cerebrospinal fluid barrier : Special focus on Peptide
| Project/Area Number |
04452303
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Physical pharmacy
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| Research Institution | University of Tokyo |
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Principal Investigator |
SUGIYAMA Yuichi Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (80090471)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Hiroshi Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Research Associ, 薬学部, 助手 (80206523)
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| Project Period (FY) |
1992 – 1993
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| Keywords | Blood-Brain Barrier / Blood-CSF Barrier / Peptide / New quinolone / Anti-AIDS drug / Physiological Pharmacokinetics |
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| Research Abstract |
[1] Inhibition of active efflux of anticancer drugs from cancer cells :
The kinetic analysis of active efflux of anticancer drug, vincristine (VCR), from isolated rat hepatocytes (normal cells) and P-388 cells (cancer cells) was examined, especially focused on the effect of various inhibitors. As a results, (1)After being taken up by the cells, vincristine was either effluxed from the cells in an active transport manner or transferred into the intracellular deep pool compartment. These two roots are competitive pathway. Our study revealed that inhibitors such as verapamil and cyclosporin inhibit only the former pathway. (2) By comparing the inhibitory extent between normal and cancer cells, it has been demonstrated that many inhibitors have higher affinity for P-glycoprotein on the surface membrane of cancer cells than that for one of normal cells, suggesting that these inhibitors possibly can be used as a anticancer drug even in in vivo situation
[2]Kinetic analysis of in vivo disposition of monoclonal antibody against P-glycoprotein :
In vivo disposition and in vitro kinetics of monoclonal antibody against P-glycoprotein, MRK-16, was examined with HCT-15 cells (resistant cells) and Colo Cells (sensitive cells). The amount of surface bound, internalized, and medium were determined with time, and the obtained data were fitted to the appropriate mathematical model to calculate the kinetic parameters. Analysis based on the physiological pharmacokinetic model revealed that the distribution of this antibody after i.v.administration to mice was well-predicted using thus obtained kinetic parameters. From our findings, it is clearly demonstrated that not only expression amount of the P-glycoprotein on the surface of the cancer cells, but the permeability across the capillary endotherial cells of antibody are the important factor to determine the in vivo disposition of the antibody.
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