Interactions Between Meropenem and Renal Drug Transporters

Abstract

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.