The inhibitory effects of eighteen front-line antibiotics on the substrate uptake mediated by human Organic anion/cation transporters, Organic anion transporting polypeptides and Oligopeptide transporters in in vitro models

Publication date: 30 March 2018
Source:European Journal of Pharmaceutical Sciences, Volume 115
Author(s): Xiaoxi Lu, Ting Chan, Ling Zhu, Xiaofeng Bao, Tony Velkov, Qi Tony Zhou, Jian Li, Hak-Kim Chan, Fanfan Zhou
Human Organic anion/cation transporters (OATs/OCTs), Organic anion transporting polypeptides (OATPs) and proton-coupled Oligopeptide transporters (PepTs) are important membrane transporters responsible of the cellular influx of drugs in many human key tissues. Inhibitor(s) impacting on the cellular uptake of transporter drug substrates is one of the primary causes of drug-drug interactions that lead to unsatisfied therapeutic outcomes and/or unwanted side effects. In the current study, we selected eighteen antibiotic agents used in infectious disease treatment and comprehensively evaluated their inhibitory effects on the substrate uptake mediated through the essential OATs/OCTs, OATPs and PepTs isoforms. Transport functional assay, dose-response curve and kinetic analysis were performed on the HEK293 cells over-expressing each of these transporter genes. Our data revealed that nitrofurantoin, sulfadiazine and metronidazole significantly inhibited the transport activity of OAT3 (IC50 values of 6.23±1.33μM, 6.65±1.30μM and 6.51±0.99μM; Ki values of 5.86μM, 3.98μM and 6.48μM, respectively). Trimethoprim and ciprofloxacin potently decreased the substrate uptake mediated via OATP1A2 (IC50 values of 9.35±1.10μM and 9.25±1.18μM; Ki values of 8.19μM and 7.64μM, respectively). In addition, these antibiotic agents consistently decreased methotrexate influx via OAT3 and OATP1A2. In summary, our study is the first to show that nitrofurantoin, sulfadiazine and metronidazole are potent inhibitors of OAT3 and trimethoprim is a novel inhibitor of OATP1A2. Our study also provides new evidence for the drug-drug interactions of ciprofloxacin with OATP1A2 drug substrates like methotrexate. Therefore, precautions are required when co-administering these antibiotics with OAT3 or OATP1A2 drug substrates.

Graphical abstract

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