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 language | English |
|---|---|
| Pages (from-to) | 266-271 |
| Number of pages | 6 |
| Journal | Drug metabolism and pharmacokinetics |
| Volume | 29 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2014 |
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All Science Journal Classification (ASJC) codes
- Pharmacology
- Pharmaceutical Science
- Pharmacology (medical)
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 journal › Article
}
TY - JOUR
T1 - 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
AU - Nakada, Tomohisa
AU - Kito, Tomoko
AU - Inoue, Katsuhisa
AU - Masuda, Satohiro
AU - Inui, Ken Ichi
AU - Matsubara, Kazuo
AU - Moriyama, Yoshinori
AU - Hisanaga, Noriko
AU - Adachi, Yasuhisa
AU - Suzuki, Masayuki
AU - Yamada, Ichimaro
AU - Kusuhara, Hiroyuki
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84903610226&partnerID=8YFLogxK
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U2 - 10.2133/dmpk.DMPK-13-RG-118
DO - 10.2133/dmpk.DMPK-13-RG-118
M3 - Article
C2 - 24390473
AN - SCOPUS:84903610226
VL - 29
SP - 266
EP - 271
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
SN - 1347-4367
IS - 3
ER -