Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy

Kunihiro Suzuki, Kosuke Doki, Masato Homma, Hirofumi Tamaki, Satoko Hori, Hisakazu Ohtani, Yasufumi Sawada, Yukinao Kohda

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

AIM: To assess whether or not co-administration of proton pump inhibitors (PPIs) is a risk factor for delayed elimination of plasma methotrexate (MTX) in high-dose MTX (HDMTX) therapy for malignant diseases. METHODS: To assess the effects of PPI co-administration on elimination of plasma MTX, we examined plasma MTX concentration data on 171 cycles of HDMTX therapy performed in 74 patients. We performed multiple logistic regression analysis to evaluate PPI co-administration as a risk factor. Inhibitory potencies of omeprazole, lansoprazole, rabeprazole and pantoprazole on MTX transport via breast cancer resistance protein (BCRP, ABCG2) were also investigated in an in vitro study using membrane vesicles expressing human BCRP. RESULTS: We identified co-administration of PPIs as a risk factor for delayed elimination (odds ratio 2.65, 95% confidence interval 1.03, 6.82) as well as renal and liver dysfunction. All four PPIs inhibited BCRP-mediated transport of MTX, with half-maximal inhibitory concentrations of 5.5-17.6 μM - considerably higher than the unbound plasma concentrations of the PPIs. CONCLUSIONS: Our results support previous findings suggesting that PPI co-administration is associated with delayed elimination of plasma MTX in patients with HDMTX therapy. This drug interaction, however, cannot be explained solely by the inhibitory effects of PPIs on BCRP-mediated MTX transport.

Original languageEnglish
Pages (from-to)44-49
Number of pages6
JournalBritish journal of clinical pharmacology
Volume67
Issue number1
DOIs
Publication statusPublished - 2009 Jan

Keywords

  • ABCG2
  • Breast cancer resistance protein
  • Delayed elimination
  • Methotrexate
  • Multiple logistic regression analysis
  • Proton pump inhibitors

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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