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，定量分析了p -糖蛋白的构效关系。将人MDRI cDNA导入猪肾上皮细胞系LLC-PK_1，采用跨细胞转运系统检测p -糖蛋白对药物的转运作用。第一个使用系列类固醇的研究表明，相对亲脂性较低的类固醇皮质醇和地塞米松被p -糖蛋白很好地转运，但对p -糖蛋白介导的药物转运不具有抑制作用。另一方面，亲脂性较高的类固醇具有较强的抑制作用，但不通过p -糖蛋白运输。p -糖蛋白的转运活性与抑制活性不一致，说明其转运机制具有多样性。下一步研究环孢素类似物对p -糖蛋白介导的几种更广泛的抗癌药物的跨细胞转运的抑制作用。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。抑癌活性排序为SDZ PSC 833 b>环孢素D、b>环孢素A b>环孢素C、双氢环孢素C。这些抗癌药物的细胞内蓄积与p糖蛋白的转运功能密切相关。抑制效果与环孢素浓度有关。对p -糖蛋白的抑制作用与免疫抑制活性无关，而与它们的亲脂性有关。我们进行了最有效药物SDZ PSC 833与阿霉素联合的I期研究，以确定这两种药物的最大耐受剂量，并研究药物在药代动力学方面的相互作用。随着SDZ PSC 833血药浓度的升高，阿霉素清除率降低，提示p -糖蛋白功能的抑制可改变药物的分布和消除。这些发现对于开发新的靶向p糖蛋白的化疗药物是有益的。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