title: 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.
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.
authors.affiliation: DMPK Research Laboratories Research Division, Mitsubishi Tanabe Pharma Corporation.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Nakada
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kito
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Inoue
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Moriyama
authors.forename: Noriko
authors.initials: N
authors.lastname: Hisanaga
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Adachi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Ichimaro
authors.initials: I
authors.lastname: Yamada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003404:Creatinine / Q000378:metabolism*; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D009842:Oligopeptides / Q000378:metabolism* / Q000494:pharmacology*; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000075102:Organic Cation Transporter 2
chemical_list: D009842:Oligopeptides; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; C486464:telaprevir; D003404:Creatinine