TY - JOUR
T1 - 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
AU - Nakada, Tomohisa
AU - Kito, Tomoko
AU - Inoue, Katsuhisa
AU - Masuda, Satohiro
AU - Inui, Ken Ichi
AU - Matsubara, Kazuo
AU - Moriyama, Yoshinori
AU - Hisanaga, Noriko
AU - Adachi, Yasuhisa
AU - Suzuki, Masayuki
AU - Yamada, Ichimaro
AU - Kusuhara, Hiroyuki
N1 - Funding Information:
†Tomohisa Nakada and Tomoko Kito contributed equally to this work. ††Present address: Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Tomohisa Nakada, Noriko Hisanaga, Masayuki Suzuki, and Ichimaro Yamada are employees of Mitsubishi Tanabe Pharma Corporation. Yasuhisa Adachi is an employee of Sekisui Medical Co., Ltd. This study was conducted at the University of Tokyo and sponsored by Mitsubishi Tanabe Pharma Corporation.
PY - 2014
Y1 - 2014
N2 - 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 doubletransfected 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.
AB - 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 doubletransfected 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.
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U2 - 10.2133/dmpk.DMPK-13-RG-118
DO - 10.2133/dmpk.DMPK-13-RG-118
M3 - Article
C2 - 24390473
AN - SCOPUS:84903610226
VL - 29
SP - 266
EP - 271
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
SN - 1347-4367
IS - 3
ER -