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Pharmacokinetic Studies on Drug Excretion Mechanism Mediated by P-Glycoprotein

P-糖蛋白介导的药物排泄机制的药代动力学研究

基本信息

批准号：
06672233
负责人：
TANIGAWARA Yusuke
金额：
$ 1.41万
依托单位：
KOBE UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

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

为了研究P-糖蛋白的药物转运机制，已经对结构-活性关系进行了定量分析。将人多药耐药基因（MDRI）cDNA导入猪肾上皮细胞株LLC-PK_1，用跨细胞转运系统研究了P-糖蛋白对药物的转运。首次研究表明，脂溶性较低的皮质醇和地塞米松可被P-糖蛋白很好地转运，但对P-糖蛋白介导的药物转运无抑制作用。另一方面，具有较高亲脂性的类固醇显示出强的抑制作用，而它们不被P-糖蛋白转运。本研究进一步探讨了环孢菌素类似物对P-糖蛋白介导的七肽跨细胞转运的抑制作用。 ...更多信息其他抗癌剂。亲脂性环孢菌素类似物抑制P-糖蛋白介导的柔红霉素、阿霉素和长春碱转运。抑制活性大小顺序为SDZ PSC 833 >环孢素D、二氢环孢素D >环孢素A >环孢素C、二氢环孢素C。抑制作用与环孢素浓度有关。对P-糖蛋白的抑制作用与其免疫抑制活性无关，但与其亲脂性有关。将最有效的药物SDZ PSC 833与阿霉素联合进行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中的相互作用。随着SDZ PSC 833血药浓度的增加，阿霉素的清除率下降，表明P-糖蛋白功能的抑制可以改变药物的分布和消除。这些发现有助于开发一种新的靶向P-糖蛋白的化疗药物。少