RT Journal Article
SR Electronic
T1 Metabolism and Disposition of Hepatitis C Polymerase Inhibitor Dasabuvir in Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.115.067512
DO 10.1124/dmd.115.067512
A1 Jianwei Shen
A1 Michael Serby
A1 Aimee Reed
A1 Anthony J Lee
A1 Rajeev Menon
A1 Xiaomei Zhang
A1 Kennan Marsh
A1 Xia Wan
A1 Olga Kavetskaia
A1 Volker Fischer
YR 2016
UL http://dmd.aspetjournals.org/content/early/2016/05/13/dmd.115.067512.abstract
AB Dasabuvir (also known as ABT-333), a potent non-nucleoside NS protein 5B polymerase inhibitor of the hepatitis C virus (HCV), is being developed in combination with paritaprevir / ritonavir and ombitasvir in a three direct-acting antiviral oral regimen (DAAs) for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism and disposition of dasabuvir in humans. Following the administration of a single 400-mg oral dose of [14C]dasabuvir to four healthy volunteers the mean total percentage of the administered radioactive dose recovered was 96.6%. The recovery from the individual subjects ranged from 90.8 to 103%. Dasabuvir and corresponding metabolites were predominantly eliminated in feces (94.4% of dose), and minimally through renal excretion (2.2% of dose). The biotransformation of dasabuvir primarily involves hydroxylation of the tert-butyl group to form metabolite M1, followed by glucuronidation and sulfation of M1 and subsequent secondary oxidation. Dasabuvir was the major circulating component (58% of total radioactivity) in plasma, followed by metabolite M1 (21%). Other minor metabolites represented less than 10% each of total circulating radioactivity. Dasabuvir was cleared mainly through CYP-mediated oxidation metabolism to M1. M1 and its glucuronide and sulfate conjugates were primarily eliminated in feces. Subsequent oxidation of M1 to the tert-butyl acid followed by formation of the corresponding glucuronide conjugate plays a secondary role in elimination. Cytochrome P450 profiling indicated that dasabuvir was mainly metabolized by CYP2C8 followed by CYP3A4. In summary, the biotransformation pathway and clearance routes of dasabuvir were characterized, and the structures of metabolites in circulation and excreta were elucidated.