Evaluation of possible pharmacokinetic interaction between methotrexate and proton pump inhibitors in rats
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Evaluation of possible pharmacokinetic interaction between methotrexate and proton pump inhibitors in rats Hinata Ueda1 · Katsuya Narumi1 · Yu Sato1 · Ayako Furugen1 · Masaki Kobayashi1 · Ken Iseki1 Received: 6 March 2020 / Revised: 23 June 2020 / Accepted: 7 July 2020 © Maj Institute of Pharmacology Polish Academy of Sciences 2020
Abstract Background Methotrexate (MTX), an antifolate agent, is primarily eliminated by the kidney. Organic anion transporter 3 (OAT3) contributes to renal MTX clearance. Several studies have shown an association between co-administration of proton pump inhibitors (PPIs) and delayed elimination of MTX, but the findings are conflicting. In this study, we aimed to evaluate whether the differential inhibitory effects of PPIs on the OAT3-mediated transport of MTX are associated with the risks of delayed MTX elimination. Methods We investigated the effects of PPIs on rat (r) OAT3-mediated MTX uptake using HEK293T cells expressing rOAT3. To examine whether PPIs could affect the pharmacokinetics of MTX, changes in plasma concentration–time profiles were assessed when MTX (50 mg/kg, ip) and a range of PPIs (2 mg/kg, iv) were administered to rats. Results In vitro studies demonstrated that PPIs inhibited rOAT3-mediated uptake of MTX, with estimated IC50 values of 2.1–5.2 μM, and a rank order of esomeprazole ≈ lansoprazole ≈ omeprazole > rabeprazole. When MTX and esomeprazole were co-administered to rats, the plasma concentration of MTX 6 h after administration and the t1/2 were significantly higher than those in the vehicle group. The effect of lansoprazole was not significant, but showed a tendency to prolong plasma MTX levels. Famotidine, a histamine H2-receptor antagonist, showed a weak inhibitory effect on rOAT3-mediated MTX uptake, although it did not affect plasma concentration–time profile of MTX in vivo. Conclusion Esomeprazole increases the t1/2 of MTX in rats, which may be partially attributed to the inhibition of rOAT3. Keywords Drug–drug interaction · Proton pump inhibitor · Esomeprazole · Lansoprazole · Methotrexate · Organic anion transporter 3 Abbreviations AUC Area under the plasma concentration–time curve BCRP Breast cancer resistance protein HD-MTX High-dose methotrexate IC50 Half maximal inhibitory concentration IS Internal standard Electronic supplementary material The online version of this article (https://doi.org/10.1007/s43440-020-00130-1) contains supplementary material, which is available to authorized users. * Katsuya Narumi [email protected] * Masaki Kobayashi [email protected] 1
Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita‑12‑jo, Nishi‑6‑chome, Kita‑ku, Sapporo 060‑0812, Japan
LC/MS/MS Liquid chromatography/electrospray ionization tandem mass spectrometry MRP2 Multidrug resistance-associated protein 2 MTX Methotrexate OAT Organic anion transporter PPI Proton pump inhibitor RFC1 Reduced folate carri
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