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Effects of proton pump inhibitors and famotidine on elimination of plasma methotrexate: Evaluation of drug-drug interactions mediated by organic anion transporter 3
Title: | Effects of proton pump inhibitors and famotidine on elimination of plasma methotrexate: Evaluation of drug-drug interactions mediated by organic anion transporter 3 |
Authors: | Narumi, Katsuya Browse this author →KAKEN DB | Sato, Yu Browse this author | Kobayashi, Masaki Browse this author →KAKEN DB | Furugen, Ayako Browse this author | Kasashi, Kumiko Browse this author | Yamada, Takehiro Browse this author | Teshima, Takanori Browse this author | Iseki, Ken Browse this author →KAKEN DB |
Keywords: | famotidine | lansoprazole | methotrexate | organic anion transporter 3 | proton pump inhibitor |
Issue Date: | Dec-2017 |
Publisher: | John Wiley & Sons |
Journal Title: | Biopharmaceutics & drug disposition |
Volume: | 38 |
Issue: | 9 |
Start Page: | 501 |
End Page: | 508 |
Publisher DOI: | 10.1002/bdd.2091 |
PMID: | 28801980 |
Abstract: | Methotrexate (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. |
Rights: | This 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. |
Type: | article (author version) |
URI: | http://hdl.handle.net/2115/72241 |
Appears in Collections: | 薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 鳴海 克哉
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