外排型转运体与CYP450酶所介导的药物相互作用

The drug-drug interaction mediated by efflux transporters and CYP450 enzymes

多种药物同时给药后药物间相互作用能引发许多不良反应和治疗上的困难。引起这种药物相互作用的主要因素包括药物外排型转运体:P-糖蛋白(P-glycoprotein,P-gp,MDR1)、多药耐药相关蛋白(multidrug resistance associated protein,MRP)以及乳腺癌耐药蛋白(breast cancer resistance protein,BCRP)3种ABC转运体以及药物代谢酶细胞色素P450(CYP450)。近年来,大量研究发现决定口服药物生物利用度的主要因素是肠道细胞中CYP3A对已吸收药物的生物转化作用和肠道细胞中P-gp对已吸收药物的主动外排作用。同为CYP3A和(或)P-gp底物的药物,当其与CYP3A和(或)P-gp的抑制剂同时服用后,药物的口服生物利用度可能升高。MRP、BCRP与P-gp同属药物的外排泵,与P-gp有重叠的底物特异性。MRP及BCRP与代谢酶CYP3A之间也存在着相似于P-gp的药物相互作用。本文从外排型转运体的类型、参与药物代谢的主要CYP450酶家族CYP3A、临床上由外排型转运体及代谢酶共同介导的药物相互作用和体外研究方法等方面进行综述。

Multidrug regimens and corresponding drug interactions cause many adverse reactions and treatment failures. Drug efflux transporters： P-glycoprotein （P-gp）, multidrug resistance associated protein （MRP） and breast cancer resistance protein （BCRP） in conjunction with metabolizing enzymes （cytochrome P450, CYP450） are major factors in such interaction. In recent years, a large number of studies have shown that P-gp plays a role in the oxidative metabolism of its substrates that are also substrates of CYP3A4. Combined actions of P-gp and CYP3A could account in some part for the low oral bioavailability determined for many of these dual substrates. P-gp along with efflux transporters （MRP and BCRP） having overlapping substrate specificity plays critical role in drug disposition. The relationship between MRP or BCRP and CYP3A is similar to that between P-gp and CYP3A. In this paper, we summarize the classification of efflux transporters, the main metabolizing enzymes CYP3A, clinical significance interactions mediated by efflux transporters and CYP450 enzymes and in vitro studies.