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

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

研究成果: ジャーナルへの寄稿学術誌査読

7 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)266-271
ページ数6
ジャーナルDrug metabolism and pharmacokinetics
29
3
DOI
出版ステータス出版済み - 2014

!!!All Science Journal Classification (ASJC) codes

  • 薬理学
  • 薬科学
  • 薬理学(医学)

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