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

基于跨血脑屏障和血脑脊液屏障的转运特性分析中枢神经系统的药物分布：特别关注肽

基本信息

批准号：
04452303
负责人：
SUGIYAMA Yuichi
金额：
$ 3.14万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

项目摘要

[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.

[1] 抑制癌细胞中抗癌药物的主动流出：对离体大鼠肝细胞（正常细胞）和 P-388 细胞（癌细胞）中的抗癌药物长春新碱（VCR）的主动流出进行了动力学分析，特别是重点关注各种抑制剂的作用。结果：(1)长春新碱被细胞摄取后，要么以主动转运的方式从细胞中流出，要么转移到细胞内的深池室中。这两个根源是竞争途径。我们的研究表明，维拉帕米和环孢菌素等抑制剂仅抑制前一种途径。 (2)通过比较正常细胞和癌细胞之间的抑制程度，已经证明许多抑制剂对癌细胞表面膜上的P-糖蛋白的亲和力比对正常细胞之一的亲和力高，这表明这些抑制剂可能可以即使在体内也可用作抗癌药物[2]抗P-糖蛋白单克隆抗体体内分布的动力学分析：检查了抗P-糖蛋白单克隆抗体MRK-16的体内分布和体外动力学与 HCT-15 细胞（耐药细胞）和 Colo 细胞（敏感细胞）。随着时间的推移测定表面结合量、内化量和介质量，并将获得的数据拟合到适当的数学模型以计算动力学参数。基于生理药代动力学模型的分析表明，使用由此获得的动力学参数可以很好地预测对小鼠静脉注射后该抗体的分布。我们的研究结果清楚地表明，不仅癌细胞表面上P-糖蛋白的表达量，抗体穿过毛细血管内皮细胞的渗透性也是决定抗体体内分布的重要因素。