RT Journal Article
SR Electronic
T1 Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1543
OP 1549
DO 10.1124/dmd.116.070722
VO 44
IS 10
A1 Kenji Ikemura
A1 Yugo Hamada
A1 Chinatsu Kaya
A1 Tomoyuki Enokiya
A1 Yuichi Muraki
A1 Hiroki Nakahara
A1 Hajime Fujimoto
A1 Tetsu Kobayashi
A1 Takuya Iwamoto
A1 Masahiro Okuda
YR 2016
UL http://dmd.aspetjournals.org/content/44/10/1543.abstract
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.