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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

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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)

Submitter: 鳴海 克哉

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