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. Method: 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 μM), weak inhibition was observed for piperacillin, benzylpenicillin, and tazobactam (IC50 values were 282.2, 308.0 and 668.1 μM, 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.

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美罗培南与肾脏药物转运体的相互作用

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。它主要通过肾小球滤过和肾小管分泌从肾脏清除。目的：本研究旨在评估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。方法：在稳定转染有机阴离子转运蛋白（OAT）1、OAT3、多药和毒素排出蛋白（MATE）1、MATE2K的人胚肾293细胞，以及含有乳腺癌耐药性的膜囊泡中进行摄取和抑制研究。相关蛋白 (BCRP)、多药耐药蛋白 1 (MDR1) 和多药耐药相关蛋白 2 (MRP2)。丙磺舒和哌拉西林用于评估大鼠与美罗培南的潜在药物相互作用。结果：我们观察到美罗培南是一种低亲和力的 OAT1/3 底物，对 OAT1/3 和 MATE2K 具有较弱的抑制作用。BCRP、MDR1、MRP2、MATE1 和 MATE2K 不能介导美罗培南的肾脏排泄。此外，美罗培南不是 BCRP、MDR1、MRP2 或 MATE1 的抑制剂。在五种受试抗生素中，观察到利奈唑胺对 OAT3 介导的美罗培南摄取有中度抑制作用（IC50 值为 69.2 μM），观察到哌拉西林、苄青霉素和他唑巴坦的抑制作用较弱（IC50 值分别为 282.2、308.0 和 668.1 μM），并且没有观察到舒巴坦的抑制作用。尽管哌拉西林在体外具有相对较高的药物相互作用指数（最大游离血浆浓度与 IC50 之比为 1.42），美罗培南在大鼠体内的药代动力学没有有意义的影响。结论：我们的结果表明，美罗培南与这五种抗生素之间具有临床意义的相互作用很低。