Pharmacokinetic Studies on Drug Excretion Mechanism Mediated by P-Glycoprotein

为了研究P-糖蛋白转运药物的机制，对其构效关系进行了定量研究。将人MDRI基因导入猪肾上皮细胞系LLC-PK_1，用跨细胞转运系统测定了P-糖蛋白对药物转运的影响。首次用一系列类固醇进行的研究表明，皮质醇和地塞米松是亲脂性相对较低的类固醇，它们能很好地被P-糖蛋白转运，但对P-糖蛋白介导的药物转运没有抑制作用。而亲脂性较强的类固醇则表现出较强的抑制作用，但它们不通过P-糖蛋白转运。其转运活性与抑制活性不一致，提示P-糖蛋白的转运机制具有多样性。下一步研究环孢素类似物对P-糖蛋白介导的SEV-…跨细胞转运的抑制作用更多的外周抗癌药物。亲脂性环孢素类似物抑制P-糖蛋白介导的柔红霉素、阿霉素和长春花碱的转运。抑制活性排序为SDZ PSC 833&GT、环孢素D、二氢环孢素D&GT、环孢素A&GT、环孢素C、二氢环孢素C。抗癌药物在细胞内的积累与P-糖蛋白的转运功能密切相关。抑制作用依赖于环孢素的浓度。对P-糖蛋白的抑制作用与其免疫抑制活性无关，而与其亲脂性有关。采用最强的药物SDZ PSC 833与阿霉素联合的I期研究，确定两种药物的最大耐受量，并研究药物在药代动力学中的相互作用。阿霉素清除量随SDZ PSC 833血药浓度升高而降低，提示抑制P-糖蛋白功能可改变药物的分布和消除。这些发现对于开发以P-糖蛋白为靶点的新的化疗药物是有用的。较少

To investigate a mechanism of drug transport by P-glycoprotein, a quantitative analysis has been performed for structure-activity relationships. The drug transport by P-glycoprotein was measured by a transcellular transport system by introducing human MDRI cDNA into a porcine kidney epithelial cell line, LLC-PK_1.The first study using a series of steroids showed that cortisol and dexamethasone, which are relatively lower lipophilic steroids, were well transported by P-glycoprotein, but that they did not possess an inhibitory effect on P-glycoprotein-mediated transport of drugs. On the other hand, steroids with higher lipophilicity showed a strong inhibitory effect, while they were not transported by P-glycoprotein. The transporting activity was not consistent with the inhibitory activity, suggesting a multiplicity of transporting mechanism of P-glycoprotein.The next study investigated the inhibitory effect of cyclosporin analogs on P-glycoprotein-mediated transcellular transport of sev … More eral anticancer agents. The lipophilic cyclosporin analogs inhibited P-glycoprotein-mediated transport of daunorubicin, doxorubicin and vinblastine. The rank order of the inhibitory activity was SDZ PSC 833 > cyclosporin D,dihydrocyclosporin D > cyclosporin A > cyclosporin C,dihydrocyclosporin C.The intracellular accumulation of the anticancer agents was highly associated with the transporting function of P-glycoprotein. The inhibitory effect depended on the concentration of cyclosporins. The inhibitory effect on P-glycoprotein was not correlated with the immunosuppressive activity, but was correlated with their lipophilicity.The phase I study of the combination of the most potent agent, SDZ PSC 833 and doxorubicin was conducted to determine the maximum tolerated dose of these two agents as well as to investigate the drug interaction in pharmacokinetics. The doxorubicin clearance was decreased with increased blood concentration of SDZ PSC 833, indicating that the inhibition of P-glycoprotein function could change drug distribution and elimination. These findings are useful for developing a new chemotherapy to target P-glycoprotein. Less