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

[1]抗癌药物从癌细胞主动外排的抑制：检查了抗癌药物长春新碱（VCR）从分离的大鼠肝细胞（正常细胞）和P-388细胞（癌细胞）主动外排的动力学分析，特别关注各种抑制剂的作用。结果表明：（1）长春新碱被细胞摄取后，以主动转运方式从细胞外排或转移至细胞内深池隔室。这两个根是竞争途径。我们的研究表明，抑制剂如维拉帕米和环孢素只抑制前一个途径。(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-糖蛋白的亲和力高于对正常细胞的亲和力，这表明这些抑制剂甚至可以在体内情况下用作抗癌药物[2]抗P-糖蛋白单克隆抗体体内处置的动力学分析：用HCT-15细胞（耐药细胞）和科洛细胞（敏感细胞）检查了抗P-糖蛋白单克隆抗体MRK-16的体内处置和体外动力学。随时间测定表面结合、内化和介质的量，并将所得数据拟合至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显示，使用由此获得的动力学参数，可以很好地预测小鼠静脉内给药后该抗体的分布。从我们的发现中，清楚地表明，不仅癌细胞表面P-糖蛋白的表达量，而且抗体穿过毛细血管内皮细胞的渗透性是决定抗体在体内处置的重要因素。

[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.