PT  - JOURNAL ARTICLE
AU  - Ikemura, Kenji
AU  - Hamada, Yugo
AU  - Kaya, Chinatsu
AU  - Enokiya, Tomoyuki
AU  - Muraki, Yuichi
AU  - Nakahara, Hiroki
AU  - Fujimoto, Hajime
AU  - Kobayashi, Tetsu
AU  - Iwamoto, Takuya
AU  - Okuda, Masahiro
TI  - Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3
AID  - 10.1124/dmd.116.070722
DP  - 2016 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 1543--1549
VI  - 44
IP  - 10
4099  - http://dmd.aspetjournals.org/content/44/10/1543.short
4100  - http://dmd.aspetjournals.org/content/44/10/1543.full
SO  - Drug Metab Dispos2016 Oct 01; 44
AB  - 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, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous 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 greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 µM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed.