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糖尿病导致的药物转运体与细胞色素P450酶相互作用失衡及其临床意义

Imbalance of Drug Transporter-CYP450s Interplay by Diabetes and Its Clinical Significance.

作者信息

Yang Yiting, Liu Xiaodong

机构信息

Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.

出版信息

Pharmaceutics. 2020 Apr 11;12(4):348. doi: 10.3390/pharmaceutics12040348.

DOI:10.3390/pharmaceutics12040348
PMID:32290519
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7238081/
Abstract

The pharmacokinetics of a drug is dependent upon the coordinate work of influx transporters, enzymes and efflux transporters (i.e., transporter-enzyme interplay). The transporter-enzyme interplay may occur in liver, kidney and intestine. The influx transporters involving drug transport are organic anion transporting polypeptides (OATPs), peptide transporters (PepTs), organic anion transporters (OATs), monocarboxylate transporters (MCTs) and organic cation transporters (OCTs). The efflux transporters are P-glycoprotein (P-gp), multidrug/toxin extrusions (MATEs), multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). The enzymes related to drug metabolism are mainly cytochrome P450 enzymes (CYP450s) and UDP-glucuronosyltransferases (UGTs). Accumulating evidence has demonstrated that diabetes alters the expression and functions of CYP450s and transporters in a different manner, disordering the transporter-enzyme interplay, in turn affecting the pharmacokinetics of some drugs. We aimed to focus on (1) the imbalance of transporter-CYP450 interplay in the liver, intestine and kidney due to altered expressions of influx transporters (OATPs, OCTs, OATs, PepTs and MCT6), efflux transporters (P-gp, BCRP and MRP2) and CYP450s (CYP3As, CYP1A2, CYP2E1 and CYP2Cs) under diabetic status; (2) the net contributions of these alterations in the expression and functions of transporters and CYP450s to drug disposition, therapeutic efficacy and drug toxicity; (3) application of a physiologically-based pharmacokinetic model in transporter-enzyme interplay.

摘要

药物的药代动力学取决于摄取转运体、酶和外排转运体的协同作用（即转运体 - 酶相互作用）。转运体 - 酶相互作用可能发生在肝脏、肾脏和肠道。参与药物转运的摄取转运体有有机阴离子转运多肽（OATP）、肽转运体（PepT）、有机阴离子转运体（OAT）、单羧酸转运体（MCT）和有机阳离子转运体（OCT）。外排转运体有P - 糖蛋白（P - gp）、多药/毒素外排蛋白（MATE）、多药耐药相关蛋白（MRP）和乳腺癌耐药蛋白（BCRP）。与药物代谢相关的酶主要是细胞色素P450酶（CYP450）和尿苷二磷酸葡萄糖醛酸转移酶（UGT）。越来越多的证据表明，糖尿病以不同方式改变CYP450和转运体的表达及功能，扰乱转运体 - 酶相互作用，进而影响某些药物的药代动力学。我们旨在关注：（1）糖尿病状态下，由于摄取转运体（OATP、OCT、OAT、PepT和MCT6）、外排转运体（P - gp、BCRP和MRP2）以及CYP450（CYP3A、CYP1A2、CYP2E1和CYP2C）表达改变，导致肝脏、肠道和肾脏中转运体 - CYP450相互作用失衡；（2）这些转运体和CYP450表达及功能改变对药物处置、治疗效果和药物毒性的净贡献；（3）基于生理学的药代动力学模型在转运体 - 酶相互作用中的应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/7238081/6753a759c6fa/pharmaceutics-12-00348-g006.jpg
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