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

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)266-271
Number of pages6
JournalDrug Metabolism and Pharmacokinetics
Volume29
Issue number3
DOIs
Publication statusPublished - 2014

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Cations
Creatinine
Kidney
Serum
Pyrimethamine
Chronic Hepatitis C
telaprevir
Oral Administration
Therapeutics

Keywords

  • Creatinine
  • MATE1
  • MATE2-K
  • OCT2
  • Renal transporter
  • Telaprevir

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Pharmaceutical Science
  • Medicine(all)

Cite this

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.

In: Drug Metabolism and Pharmacokinetics, Vol. 29, No. 3, 2014, p. 266-271.

Research output: Contribution to journalArticle

Nakada, T, Kito, T, Inoue, K, Masuda, S, Inui, KI, Matsubara, K, Moriyama, Y, Hisanaga, N, Adachi, Y, Suzuki, M, Yamada, I & Kusuhara, H 2014, '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, vol. 29, no. 3, pp. 266-271. https://doi.org/10.2133/dmpk.DMPK-13-RG-118
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. / 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. In: Drug Metabolism and Pharmacokinetics. 2014 ; Vol. 29, No. 3. pp. 266-271.
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