Evaluation of the Potency of Telaprevir and Its Metabolites as Inhibitors of Renal Organic Cation Transporters, a Potential Mechanism for the Elevation of Serum Creatinine
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- NAKADA Tomohisa
- DMPK Research Laboratories Research Division, Mitsubishi Tanabe Pharma Corporation
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- KITO Tomoko
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo
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- INOUE Katsuhisa
- Tokyo University of Pharmacy and Life Sciences
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- MASUDA Satohiro
- Department of Pharmacy, Kyoto University Hospital
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- INUI Ken-ichi
- Kyoto Pharmaceutical University
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- MATSUBARA Kazuo
- Department of Pharmacy, Kyoto University Hospital
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- MORIYAMA Yoshinori
- Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, & Pharmaceutical Sciences
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- HISANAGA Noriko
- DMPK Research Laboratories Research Division, Mitsubishi Tanabe Pharma Corporation
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- ADACHI Yasuhisa
- Research Institute, Sekisui Medical Company, Ltd.
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- SUZUKI Masayuki
- Development Division, Mitsubishi Tanabe Pharma Corporation
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- YAMADA Ichimaro
- Development Division, Mitsubishi Tanabe Pharma Corporation
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- KUSUHARA Hiroyuki
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo
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Abstract
Telaprevir-based triple therapy is a highly effective treatment for chronic hepatitis C. However, adverse reactions include reversible and dose-dependent elevation of serum creatinine levels. We speculated that this effect reflects inhibition of the renal organic cation transporters hOCT2, hMATE1, and hMATE2-K by telaprevir or its metabolites (VRT-127394 and VRT-0922061). Telaprevir, VRT-127394, and VRT-0922061 showed negligible or weak effects on hOCT2 at concentrations of ≥20 µM, but inhibited hMATE1 by 35, 38, and 53% and hMATE2-K by 47, 45, and 61% at 100 µM, respectively. Telaprevir or its metabolites (10 µM) did not affect basal-to-apical transport of MPP+ across monolayers of hOCT2-hMATE1 double-transfected MDCKII cells, whereas pyrimethamine, a potent inhibitor of hMATE1, markedly inhibited MPP+ transport. Taken together, inhibition of hOCT2, hMATE1, and hMATE2-K is unlikely to be clinically relevant because unbound plasma concentrations of telaprevir and its metabolites reach only 2 µM following oral administration of a dose of 750 mg telaprevir. Hence, elevated serum creatinine during telaprevir therapy may not be related to direct inhibition of renal organic cation transporters.
Journal
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- Drug Metabolism and Pharmacokinetics
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Drug Metabolism and Pharmacokinetics 29 (3), 266-271, 2014
The Japanese Society for the Study of Xenobiotics