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

Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2016/07/27/dmd.116.070722.DC1 1521-009X/44/10/1543–1549$25.00 http://dx.doi.org/10.1124/dmd.116.070722 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 44:1543–1549, October 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3 s Kenji Ikemura, Yugo Hamada, Chinatsu Kaya, Tomoyuki Enokiya, Yuichi Muraki, Hiroki Nakahara, Hajime Fujimoto, Tetsu Kobayashi, Takuya Iwamoto, and Masahiro Okuda Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine, Tsu (K.I., Y.H., T.I., M.O.); Department of Pharmacy, Mie University Hospital, Tsu (K.I., T.E., Y.M., T.I., M.O.); Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka (C.K.); Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu (H.N., H.F., T.K.), Mie, Japan Received March 30, 2016; accepted July 18, 2016 Downloaded from ABSTRACT Pemetrexed, a multitargeted antifolate, is eliminated by tubular effect of lansoprazole was much greater than those of other PPIs secretion via human organic anion transporter 3 (hOAT3). Although and the apparent IC50 value of lansoprazole against pemetrexed proton pump inhibitors (PPIs) are frequently used in cancer patients, transport via hOAT3 was 0.57 6 0.17 mM. The inhibitory type of the drug interaction between PPIs and pemetrexed remains to be lansoprazole was competitive. In a retrospective study, multivariate clarified. In this study, we examined the drug interaction between analysis revealed that coadministration of lansoprazole, but not dmd.aspetjournals.org pemetrexed and PPIs in hOAT3-expressing cultured cells, and other PPIs, with pemetrexed and carboplatin was an independent retrospectively analyzed the impact of PPIs on the development of risk factor significantly contributing to the development of hemato- hematologic toxicity in 108 patients who received pemetrexed and logic toxicity (odds ratio: 10.004, P = 0.005). These findings demon- carboplatin treatment of nonsquamous non–small cell lung cancer strated that coadministration of lansoprazole could exacerbate the for the first time between January 2011 and June 2015. We hematologic toxicity associated with pemetrexed, at least in part, by established that pemetrexed was transported via hOAT3 (Km =68.36 competitive inhibition of hOAT3. Our results would aid clinicians to 11.1 mM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, make decisions of coadministration drugs to avoid drug interaction- at ASPET Journals on October 1, 2021 omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of induced side effects for achievement of safe and appropriate pemetrexed in a concentration-dependent manner. The inhibitory chemotherapy with pemetrexed. Introduction encoded by SLC22A genes have been characterized (Sweet and Pemetrexed, a potent multitargeted antifolate, is a key drug in the Pritchard, 1999; Inui et al., 2000; Sekine et al., 2000). Both hOAT1 treatment of nonsquamous non–small cell lung cancer (NSCLC) (Adjei, (SLC22A6) and hOAT3 (SLC22A8) mediate organic anion/a-ketoglu- 2004). It is increasingly used as first-line treatment in combination with tarate exchange at the basolateral membrane of the proximal tubules platinum compounds (Scagliotti et al., 2008) and as maintenance (Sekine et al., 1997; Sweet and Pritchard, 1999). monotherapy for nonsquamous NSCLC (Hanna et al., 2004). Previous studies investigating the characteristics of pemetrexed Pemetrexed is eliminated mainly from the kidney and has a tubular transport via various solute carrier transporters revealed that pemetrexed secretion rate approximately 2.5-fold greater than the glomerular is transported primarily by hOAT3 (Kurata et al., 2014; Posada et al., filtration rate (GFR) in advanced cancer patients with normal renal 2015) and that hOAT3 substrates, such as nonsteroidal anti- function (Rinaldi et al., 1999; Mita et al., 2006). In the renal proximal inflammatory drugs (NSAIDs) and cephalosporin antibiotics, inhibit tubules, membrane transport proteins expressed specifically at the pemetrexed transport via hOAT3 (Kurata et al., 2014; Posada et al., basolateral membranes are responsible for the urinary secretion of 2015). Posada et al. (2015) reported that hOAT4 (SLC22A11) expressed various drugs. The structures and functions of human organic anion at the brush-border membrane is predominantly involved in the transport transporters (hOATs) and human organic cation transporters (hOCTs) of pemetrexed from the renal tubular cells to urine; however, inhibition of hOAT4 had no effect on the pemetrexed plasma clearance in the experiment using physiologic based pharmacokinetic models (Posada et al., 2015). Therefore, hOAT3-mediated uptake, but not hOAT4- This work was supported by a Grant-in-Aid for Scientific Research (C) [Grant 26460195 and 26460196] from the Japan Society for the Promotion of Science mediated efflux, should contribute to plasma clearance of pemetrexed. and Mie University Hospital Seed Grant Program 2015. These findings suggested that particular care should be taken during the dx.doi.org/10.1124/dmd.116.070722. coadministration of inhibitors and/or substrates of hOAT3 in patients s This article has supplemental material available at dmd.aspetjournals.org. receiving pemetrexed. ABBREVIATIONS: AST, aspartate aminotransferase; CrCl, creatinine clearance; CTCAE, Common Terminology Criteria for Adverse Events; GFR, glomerular filtration rate; Hb, hemoglobin; hOAT, human organic anion transporter; hOCT, human organic cation transporter; NSAIDs, nonsteroidal anti-inflammatory drugs; NSCLC, non-small cell lung cancer; PLT, platelet; PPI, proton pump inhibitor; WBC, white blood cell. 1543 1544 Ikemura et al. Proton pump inhibitors (PPIs) are the most commonly prescribed i.d.; Tosho, Tokyo, Japan) and a Waters 2996 photodiode array detector (Waters, drugs for the treatment of gastroesophageal hyperacidity (Targownik Milford, MA). The column temperature was set at 40°C. Pemetrexed was eluted et al., 2007). An estimated 20% of cancer patients have been treated with with 0.2% formic acid (pH 3.08 adjusted with 1 M NaOH): acetonitrile = 20: 80 at PPIs for alleviating the symptoms of gastroesophageal reflux (Smelick 1 ml/min. The detection wavelength was 254 nm. et al., 2013), highlighting the importance of investigating the drug Kinetic Analyses. Kinetic analyses were performed with GraphPad Prism version 6.0 (GraphPad Software Inc., San Diego, CA). The apparent Michaelis- interaction between PPIs and anticancer agents to provide safe and Menten constant (K ) and maximal velocity (V ) values were calculated using appropriate chemotherapy. Recent studies have reported that PPIs are m max the Michaelis-Menten equation: V = Vmax × S/(Km + S), where V is the transport inhibitors of hOATs and hOCTs (Nies et al., 2011; Chioukh et al., 2014). velocity, S is the concentration of pemetrexed, Vmax is the maximal velocity, and Since hematologic toxicity as a serious side effect of pemetrexed has Km is Michaelis-Menten constant by nonlinear regression analysis. The apparent been correlated with drug exposure (Rollins and Lindley, 2005), IC50 values were calculated from the inhibition plots according to the equation: n decreased clearance results in greater systemic exposure, which may V = Vbottom +(Vtop 2 Vbottom)/[1 + (log I/IC50) ] by nonlinear least square be associated with increased side effects. Taking these findings into regression analysis, where V is the transport velocity, Vbottom is the transport consideration, we hypothesized that coadministration of PPIs may velocity at the highest concentration of inhibitor, Vtop is the transport velocity exacerbate the hematologic toxicity of pemetrexed by inhibiting the without inhibitor, I is the concentration of the inhibitor, and n is the Hill coefficient. renal elimination of pemetrexed via hOAT3; however, the drug Patients and Data Collection. A retrospective study was conducted in 116 hospitalized patients who received combination therapy of pemetrexed and interaction between pemetrexed and PPIs and the impact of PPIs on carboplatin in the absence or presence of bevacizumab for the treatment of the development of hematologic toxicity of pemetrexed remain to be nonsquamous NSCLC for the first time at Mie University Hospital between explored in clinical situations. January 2011 and June 2015. Eligible patients received an i.v. infusion of Downloaded from In the present study, drug interaction between PPIs and pemetrexed pemetrexed (500 mg/m2) for 10 minutes, followed by a 60-minute i.v. infusion of was examined in hOAT3-expressing cultured cells, and the impact of carboplatin at a dose calculated to produce an area under the concentration-time PPIs on the development of hematologic toxicity was retrospectively curve of 5 or 6 mg×min/ml and an i.v. infusion of bevacizumab at a dose of analyzed in hospitalized patients who received combination therapy of 15 mg/kg for 90 minutes. Patients were excluded if they had missing data, pemetrexed and carboplatin for the treatment of nonsquamous NSCLC. creatinine clearance (CrCl) ,45 ml/min as estimated by the Cockcroft-Gault equation (Cockcroft and Gault, 1976), did not receive vitamin B12 and folic acid supplements for preventing the adverse

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