Effects of proton pump inhibitors and famotidine on elimination of plasma methotrexate: evaluation of drug ‐drug interactions mediated by organic anion transporter 3

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 H2 receptor antagonists, are widely used among patients with cancer in clinical practice. The aim of the present study was to analyze the potential drug‐drug interactions between MTX and gastric antisecretory drugs in high‐dose MTX (HD‐MTX) therapy. We retrospectively analyzed the impact of PPIs on the plasma MTX concentration on 73 cycles of HD‐MTX therapy performed in 43 patients. We also investigated 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 48 h (0.38 vs. 0.15 μmol l‐1, respectively, P = 0.000018) and 72 h (0.13 vs. 0.05 μmol l‐1, respectively, P = 0.0002) compared to patients who did not receive a PPI (but received a 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 μM), with a rank order of lansoprazole > esomeprazole > rabeprazole > omeprazole. In contrast to PPIs, famotidine showed little inhibitory effect on hOAT3‐mediated MTX uptake. T...
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL PAPER Source Type: research