title: Effect of telaprevir on the metabolism and hepatic uptake of tacrolimus (FK506).
abstract: Telaprevir, a chronic hepatitis C virus (HCV) protease inhibitor, is known to be a cytochrome P450 (CYP) 3A4/5 substrate and inhibitor. In the present study, the in vitro inhibitory effect of telaprevir on the metabolism of tacrolimus in human liver microsomes was investigated using 13-O-demethyltacrolimus (M-I) as a monitor metabolite. Telaprevir inhibited M-I formation in a time-dependent fashion with rate of enzyme inactivation (kinact ) and concentration to reach 50% of kinact (KI ) values of 0.113 min(-1) and 0.511 µm, respectively. Using the inhibition parameters generated, in vitro-in vivo extrapolations were performed to evaluate the clinical relevance of the effect of telaprevir on the area under the curve versus time (AUC) of tacrolimus. When 750 mg of telaprevir was administered orally, the intestinal wall availability (Fg ) of tacrolimus was estimated to be increased 3.7- to 7.0-fold. The hepatic intrinsic clearance (CLint ) of tacrolimus was also estimated to be decreased 4.4- to 19-fold. These results suggest that the increased AUC of tacrolimus in the presence of telaprevir was caused by intestinal and hepatic metabolism inhibition. In addition, the inhibitory effect of telaprevir on the hepatic uptake of tacrolimus was also examined using human cryopreserved hepatocytes. However, no significant inhibitory effect was noted, suggesting that the effect of telaprevir on hepatic transporters did not contribute to the increase in tacrolimus exposure.
authors: Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc., 1-6 Kashima 2-chome, Yodogawa-ku, Osaka, 532-8514, Japan.
authors: Kazuo
authors: K
authors: Oda
authors: Katsuhiro
authors: K
authors: Yamano
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D001711:Biotransformation; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D016174:Hepacivirus / Q000201:enzymology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008954:Models, Biological; D009842:Oligopeptides / Q000494:pharmacology*; D011237:Predictive Value of Tests; D011480:Protease Inhibitors / Q000494:pharmacology*; D016559:Tacrolimus / Q000378:metabolism* / Q000493:pharmacokinetics; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D009842:Oligopeptides; D011480:Protease Inhibitors; C486464:telaprevir; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: FK506; microsomes; tacrolimus; telaprevir