Abstract

Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, the drug interaction between pemetrexed and PPIs was examined in hOAT3-expressing cultured cells, and the impact of PPIs on the development of hematological toxicity was retrospectively analyzed in 108 patients who received pemetrexed and carboplatin treatment for non-squamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 ± 11.1 μM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much higher than those of other PPIs, and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 μM. Inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that co-administration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematological toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that co-administration of lansoprazole could exacerbate the hematological toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of co-administration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed.