Interactions Between Meropenem and Renal Drug Transporters
Interactions Between Meropenem and Renal Drug Transporters
复制标题
美罗培南与肾脏药物转运蛋白之间的相互作用
DOI：
10.2174/1389200223666220428081109
复制
发表时间：
2022-01-01
影响因子：
2.3
通讯作者：
Jiao, Zheng
中科院分区：
文献类型：
--
作者：
Dong, Jing;Liu, Yanhui;Jiao, Zheng
背景：美罗培南是一种碳青霉烯类抗生素，通常与其他抗生素一起用于治疗细菌感染。美罗培南主要通过肾小球滤过和肾小管分泌经肾脏消除。目的：本研究旨在评价肾脏摄取和外排转运蛋白在美罗培南排泄中的作用以及肾脏药物转运蛋白介导的潜在药物相互作用。在用有机阴离子转运蛋白（OAT）1、OAT 3稳定转染的人胚肾293细胞中进行摄取和抑制研究，多药和毒素挤出蛋白（MATE）1和MATE 2K，以及含有乳腺癌耐药相关蛋白（BCRP）、多药耐药蛋白1（MDR 1）和多药耐药相关蛋白2（MRP 2）的膜囊泡。丙磺舒和哌拉西林被用来评估潜在的药物相互作用与美罗培南在rats.Results：我们观察到，美罗培南是一个低亲和力的底物OAT 1/3和MATE 2K有微弱的抑制作用。BCRP、MDR 1、MRP 2、MATE 1和MATE 2K不能介导美罗培南的肾排泄。此外，美罗培南不是BCRP、MDR 1、MRP 2或MATE 1的抑制剂。在5种检测的抗生素中，观察到利奈唑胺对OAT 3介导的美罗培南摄取有中度抑制作用（IC 50值为69.2 μ M），观察到哌拉西林、苄青霉素和他唑巴坦有弱抑制作用（IC 50值分别为282.2、308.0和668.1 μ M），舒巴坦无抑制作用。虽然哌拉西林有一个相对较高的药物-药物相互作用指数（最大未结合血浆浓度的IC 50比为1.42）在体外，没有有意义的影响，美罗培南在大鼠的药代动力学报告。结论：我们的研究结果表明，美罗培南和这五种抗生素之间的临床显着的相互作用是低的。
Background: Meropenem is a carbapenem antibiotic and is commonly used with other antibiotics for the treatment of bacterial infections. It is primarily eliminated renally by glomerular filtration and renal tubular secretion.Objective: This study aimed to evaluate the roles of renal uptake and efflux transporters in the excretion of meropenem and potential drug interactions mediated by renal drug transporters.Methods: Uptake and inhibition studies were conducted in human embryonic kidney 293 cells stably transfected with Organic Anion Transporter (OAT) 1, OAT3, Multidrug and Toxin Extrusion Protein (MATE) 1, and MATE2K, as well as membrane vesicles containing breast cancer resistance-related protein (BCRP), multidrug resistance protein 1 (MDR1), and Multidrug Resistance-associated Protein 2 (MRP2). Probenecid and piperacillin were used to assess potential drug interactions with meropenem in rats.Results: We observed that meropenem was a low-affinity substrate of OAT1/3 and had a weak inhibitory effect on OAT1/3 and MATE2K. BCRP, MDR1, MRP2, MATE1, and MATE2K could not mediate renal excretion of meropenem. Moreover, meropenem was not an inhibitor of BCRP, MDR1, MRP2, or MATE1. Among five tested antibiotics, moderate inhibition on OAT3-mediated meropenem uptake was observed for linezolid (IC50 value was 69.2 mu M), weak inhibition was observed for piperacillin, benzylpenicillin, and tazobactam (IC50 values were 282.2, 308.0 and 668.1 mu M, respectively), and no inhibition was observed for sulbactam. Although piperacillin had a relatively high drug-drug interaction index (ratio of maximal unbound plasma concentration to IC50 was 1.42) in vitro, no meaningful impact was reported on the pharmacokinetics of meropenem in rats.Conclusion: Our results indicated that clinically significant interactions between meropenem and these five antibiotics are low.