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

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Co‐administration of proton pump inhibitors (PPIs) increases plasma methotrexate (MTX) concentration in cancer patients receiving high‐dose MTX (HDMTX) therapy. • There is controversy as to whether or not co‐administration of PPIs affects plasma MTX elimination in HDMTX therapy. • Inhibitory activity of PPIs on breast cancer resistance protein (BCRP) is a possible mechanism for the drug interaction between MTX and PPIs. WHAT THIS STUDY ADDS • Co‐administration of a PPI (omeprazole, lansoprazole, or rabeprazole) was more frequently observed in the delayed MTX elimination group than in the normal MTX elimination group. • Multiple logistic regression analysis with adjustment for significant covariates revealed that PPI co‐administration was a significant risk factor for delayed plasma MTX elimination. • The half‐maximal inhibitory concentration of each PPI in inhibiting BCRP function was much higher than the therapeutic unbound concentration in the plasma. 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.