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

NAKADA Tomohisa, KITO Tomoko, INOUE Katsuhisa, MASUDA Satohiro, INUI Ken-ichi, MATSUBARA Kazuo, MORIYAMA Yoshinori, HISANAGA Noriko, ADACHI Yasuhisa, SUZUKI Masayuki, YAMADA Ichimaro, KUSUHARA Hiroyuki

doi:10.2133/dmpk.dmpk-13-rg-118

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.

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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