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  • 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.

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.

Drug metabolism and pharmacokinetics (2014-01-07)
Tomohisa Nakada, Tomoko Kito, Katsuhisa Inoue, Satohiro Masuda, Ken-ichi Inui, Kazuo Matsubara, Yoshinori Moriyama, Noriko Hisanaga, Yasuhisa Adachi, Masayuki Suzuki, Ichimaro Yamada, Hiroyuki Kusuhara
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.

MATERIALS
Product Number
Brand
Product Description

Pyrimethamine, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Creatinine, anhydrous, ≥98%
Supelco
Pyrimethamine, VETRANAL®, analytical standard
Supelco
Creatinine, Pharmaceutical Secondary Standard; Certified Reference Material