肾脏转运体和/或代谢酶介导药物排泄及药物相互作用的研究进展

肾脏是人体最重要的排泄器官。肾单元近端小管细胞具有多种药物转运体和代谢酶,在药物及其代谢物处置中发挥关键作用。近端小管细胞中主要转运体包括有机阴离子转运体、有机阳离子转运体、有机阳离子/肉毒碱转运体、多药及毒素外排转运蛋白、P-糖蛋白、乳腺癌耐药蛋白和多药耐药相关蛋白;主要代谢酶包括细胞色素P450酶,UDP-葡萄糖醛酸基转移酶、磺酸基转移酶、谷胱甘肽S-转移酶。肾脏转运体和/或代谢酶介导药物相互作用(DDIs)是临床关注的重要问题。肾脏转运体和代谢酶存在密切协作关系,在肾脏也存在多种相互作用现象(包括转运-转运相互作用,代谢-代谢相互作用和转运-代谢相互作用),其显著影响药物肾脏处置、临床疗效和肾毒性。本文系统阐述了这些相互作用对药物及其代谢物的肾脏排泄、药动学、DDIs和肾毒性的影响。今后需要进一步阐明肾脏转运-代谢相互作用机制,将有助于研究体内药物肾脏处置和DDIs,促进临床合理用药。

Recent advances in renal drug transporter and/or drug-metabolizing enzyme interplay and its effect on drug excretion and drug-drug interactions

The kidney is the most important excretory organ of the human body. With its multitude of drug transporters and drug-metabolizing enzymes, the proximal tubule cell in the nephron plays a key role in the disposition of drugs and their metabolites. Drug transporters in PTC include organic anion transporters, organic cation transporters, organic cation/carnitine transporters, multidrug and toxic compound efflux transporters, P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated proteins. And drug-metabolizing enzymes include cytochrome P450 enzyme, UDP-glucuronyltransferase, sulfotransferases and glutathione S-transferase. Renal drug transporters and/or drug-metabolizing enzymes-mediated drug-drug interactions (DDIs) are of significant clinical concern. Renal drug transporters and drug-metabolizing enzymes have a close cooperative relationship, and there are a variety of interplay in the kidney (including transport-transport, metabolism-metabolism, and transport-metabolism interplay), which could significantly affect drug disposition in the kidney, clinical efficacy and nephrotoxicity. In this paper, the effects of the interplay on renal excretion, pharmacokinetics, DDIs and nephrotoxicity of drugs and their metabolites are systematically described. In the future, the underlying mechanism of renal transport-metabolism interplay should be further elucidated, which will contribute to the study of drug renal disposal and DDIs in vivo and promote clinical rational drug use.