2024-03-28T16:45:54Zhttps://eprints.lib.hokudai.ac.jp/dspace-oai/requestoai:eprints.lib.hokudai.ac.jp:2115/722412022-11-17T02:08:08Zhdl_2115_20044hdl_2115_124Effects of proton pump inhibitors and famotidine on elimination of plasma methotrexate: Evaluation of drug-drug interactions mediated by organic anion transporter 3Narumi, KatsuyaSato, YuKobayashi, MasakiFurugen, AyakoKasashi, KumikoYamada, TakehiroTeshima, TakanoriIseki, Kenfamotidinelansoprazolemethotrexateorganic anion transporter 3proton pump inhibitor460Methotrexate (MTX) is an antifolate agent used in the treatment of numerous types of cancer, and eliminated by active tubular secretion via organic anion transporter 3 (OAT3). Gastric antisecretory drugs, such as proton pump inhibitors (PPIs) and histamine H-2 receptor antagonists, are widely used among patients with cancer in clinical practice. The aim of the present study was to analyse the potential drug-drug interactions between MTX and gastric antisecretory drugs in high-dose MTX (HD-MTX) therapy. The impact of PPIs on the plasma MTX concentration on 73cycles of HD-MTX therapy was analysed retrospectively in 43 patients. Also investigated was the involvement of OAT3 in PPI-MTX drug interaction in an in vitro study using human OAT3 expressing HEK293 cells. In a retrospective study, patients who received a PPI had significantly higher MTX levels at 48h (0.38 vs. 0.15mol l(-1), respectively, p=0.000018) and 72h (0.13 vs. 0.05mol l(-1), respectively, p=0.0002) compared with patients who did not receive a PPI (but received famotidine). Moreover, in vitro experiments demonstrated that PPIs (esomeprazole, lansoprazole, omeprazole and rabeprazole) inhibited hOAT3-mediated uptake of MTX in a concentration-dependent manner (IC50 values of 0.40-5.5 m), with a rank order of lansoprazole > esomeprazole > rabeprazole > omeprazole. In contrast to PPIs, famotidine showed little inhibitory effect on hOAT3-mediated MTX uptake. These results demonstrated that co-administration of PPI, but not famotidine, could result in a pharmacokinetic interaction that increases the plasma MTX levels, at least in part, via hOAT3 inhibition.John Wiley & SonsJournal Articleapplication/pdfhttp://hdl.handle.net/2115/72241https://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/72241/1/WoS_81576_narumi.pdf0142-2782Biopharmaceutics & drug disposition3895015082017-12enginfo:pmid/28801980info:doi/10.1002/bdd.2091This is the peer reviewed version of the following article: Katsuya Narumi et. al., Effects of proton pump inhibitors and famotidine on elimination of plasma methotrexate: Evaluation of drug–drug interactions mediated by organic anion transporter 3. Biopharm Drug Dispos. 2017;38:501–508, which has been published in final form at https://doi.org/10.1002/bdd.2091. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.author