Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3

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, 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 (K m = 68.3 6 11.1 mM). 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 IC 50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 6 0.17 mM. 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 interactioninduced side effects for achievement of safe and appropriate chemotherapy with pemetrexed.

Stereoselective Inhibition of Renal Basolateral Human Organic Anion Transporter 3 by Lansoprazole Enantiomers

“…Lansoprazole is known to be a potent inhibitor of hOAT3 [11, 15]. However, little is known about the stereoselective inhibitory potencies of lansoprazole against hOAT1 and hOAT3.…”

“…Similarly, our recent study demonstrated that lansoprazole competitively inhibited hOAT3-mediated transport of pemetrexed, which has a structure and pharmacokinetics similar to those of methotrexate [15]. In addition, our retrospective clinical study demonstrated that co-administration of lansoprazole should increase the risk for the development of side effects (hematological toxicity) of pemetrexed [15]. These findings indicate that drug interaction between lansoprazole and hOAT3 substrates could be a cause of clinical problem.…”

“…Drug interactions between methotrexate and PPIs, including lansoprazole, have been reported in various clinical trials [12-14]. Similarly, our recent study demonstrated that lansoprazole competitively inhibited hOAT3-mediated transport of pemetrexed, which has a structure and pharmacokinetics similar to those of methotrexate [15]. In addition, our retrospective clinical study demonstrated that co-administration of lansoprazole should increase the risk for the development of side effects (hematological toxicity) of pemetrexed [15].…”

“…Cellular uptake of [ 14 C]PAH and [ 3 H]ES (well-established substrates of hOAT1 and hOAT3 [27], respectively), pemetrexed, and methotrexate was determined using monolayer cultures of HEK-hOAT1, HEK-hOAT3, and HEK-pBK cells at 37°C for 2 min, with confirmation of the linearity in uptake of each substrate up to 5 min in HEK-hOAT1 and HEK-hOAT3 cells. For the inhibition study of lansoprazole enantiomers against hOAT3-mediated transport of pemetrexed and methotrexate, the concentration of each substrate was set at 25 µmol/L based on K m values of pemetrexed (68.3 ± 11.1 µmol/L) and methotrexate (76.6 ± 10.1 µmol/L) estimated in our previous studies [15, 28]. The composition of the incubation medium was as follows: 145 mmol/L NaCl, 3 mmol/L KCl, 1 mmol/L CaCl 2 , 0.5 mmol/L MgCl 2 , 5 mmol/L D-glucose, and 5 mmol/L HEPES (pH 7.4).…”

“…The apparent Michaelis-Menten constant (K m ) and maximal velocity (V max ) values were calculated using the following equation: V = V max S/(K m + S), where V is the transport velocity, V max is the maximum transport velocity, S is the concentration of substrate, and K m is the Michaelis-Menten constant by nonlinear regression analysis. The apparent 50% inhibitory concentration (IC 50 ) values of inhibitor against substrate transport via hOATs were calculated from the inhibition plots using the following equation by nonlinear least square regression analysis [15]: V = V bottom + (V top – ­V bottom )/(1 + [I/IC 50 ] n ), where V is the transport velocity, V bottom is the transport velocity at the highest concentration of inhibitor, V top is the transport velocity without inhibitor, I is the concentration of the inhibitor, and n is the Hill coefficient.…”