聚合物辅料对P-糖蛋白抑制机制的研究进展

Recent advance in the mechanism study of polymeric inhibitors of P-glycoprotein

P-糖蛋白(P-gp)是一种能量依赖型的跨膜转运蛋白,其介导的外排效应是药物传输和癌症治疗中的一个主要障碍。近年来的研究显示,常用的聚合物辅料如Pluronic和TPGS等,都对P-gp具有良好的抑制作用。由于此类抑制剂在提高药物生物利用度的同时不良反应极低,因此研究其作用机制和构效关系对制剂研发具有重要意义。与传统小分子化合物的竞争性抑制机制不同,聚合物辅料主要通过改变细胞膜流动性、抑制P-gpATP酶活性、降低细胞内ATP水平或下调P-gp基因表达等方式影响P-gp的功能。本文综述了聚合物辅料对P-gp抑制作用的机制和构效关系,并对研究方法进行了简单介绍。

P-glycoprotein（P-gp） is an ATP-dependent multidrug efflux pump that acts as a major obstacle for oral drug delivery and cancer therapy. Recent reports have provided evidence that excipients often used in pharmaceutical formulations, such as Pluronic and TPGS, also have inhibitory effects on P-glycoprotein. Because inhibition of efflux transporters by polymeric inhibitors may dramatically increase the bioavailability of P-gp substrates with negligible side effects, identification of the mechanism and their structure activity relationship is therefore of significant importance for pharmaceutical development. Other than competitive inhibition for traditional inhibitors, polymeric inhibitors may modify P-gp function through alterations on membrane fluidity, inhibition of P-gp ATPase, depletion of intracellular ATP and down-regulating of P-gp expression. In the present review, the inhibition mechanism of potential polymeric inhibitors and their structure activity relationship will be discussed along with a brief introduction to the established methodologies.