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.
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Authors | 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 |
Journal | Drug metabolism and pharmacokinetics
(Drug Metab Pharmacokinet)
Vol. 29
Issue 3
Pg. 266-71
( 2014)
ISSN: 1880-0920 [Electronic] England |
PMID | 24390473
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Oligopeptides
- Organic Cation Transport Proteins
- Organic Cation Transporter 2
- SLC22A2 protein, human
- SLC47A1 protein, human
- SLC47A2 protein, human
- telaprevir
- Creatinine
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Topics |
- Animals
- Biological Transport
(drug effects, physiology)
- Cell Line
- Creatinine
(metabolism)
- Dogs
- HEK293 Cells
- Humans
- Kidney
(drug effects, metabolism)
- Madin Darby Canine Kidney Cells
- Oligopeptides
(metabolism, pharmacology)
- Organic Cation Transport Proteins
(antagonists & inhibitors, metabolism)
- Organic Cation Transporter 2
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