Huang Lei-ming, Zhao Jin-hua, Wang Guo-cheng, Zhou Jian-ping
Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
Yao Xue Xue Bao. 2010 Oct;45(10):1224-31.
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.
P-糖蛋白（P-gp）是一种依赖ATP的多药外排泵，它是口服药物递送和癌症治疗的主要障碍。最近的报告提供了证据表明，药物制剂中常用的辅料，如普朗尼克和TPGS，对P-糖蛋白也有抑制作用。由于聚合物抑制剂对转运体的抑制作用可能会显著提高P-gp底物的生物利用度，且副作用可忽略不计，因此确定其作用机制及其构效关系对于药物开发具有重要意义。除了对传统抑制剂的竞争性抑制外，聚合物抑制剂还可能通过改变膜流动性、抑制P-gp ATP酶、消耗细胞内ATP以及下调P-gp表达来改变P-gp功能。在本综述中，将讨论潜在聚合物抑制剂的抑制机制及其构效关系，并简要介绍已建立的方法。
