title: Metabolism and Disposition of Hepatitis C Polymerase Inhibitor Dasabuvir in Humans.
abstract: Dasabuvir [also known as ABT-333 or N-(6-(3-(tert-butyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide] is a potent non-nucleoside NS protein 5B polymerase inhibitor of the hepatitis C virus (HCV) and is being developed in combination with paritaprevir/ritonavir and ombitasvir in an oral regimen with three direct-acting antivirals for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of dasabuvir in humans. After administration of a single oral dose of 400-mg [(14)C]dasabuvir (without coadministration of paritaprevir/ritonavir and ombitasvir) to four healthy male 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 the dose) and minimally through renal excretion (2.2% of the dose). The biotransformation of dasabuvir primarily involves hydroxylation of the tert-butyl group to form active metabolite M1 [N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide], 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 < 10% each of total circulating radioactivity. Dasabuvir was cleared mainly through cytochrome P450-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.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics-Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois jianwei.shen@abbvie.com.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Shen
authors.affiliation: Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics-Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois.
authors.forename: Michael
authors.initials: M
authors.lastname: Serby
authors.affiliation: Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics-Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois.
authors.forename: Aimee
authors.initials: A
authors.lastname: Reed
authors.affiliation: Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics-Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Lee
authors.affiliation: Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics-Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Menon
authors.affiliation: Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics-Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics-Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois.
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.affiliation: Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics-Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois.
authors.forename: Xia
authors.initials: X
authors.lastname: Wan
authors.affiliation: Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics-Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois.
authors.forename: Olga
authors.initials: O
authors.lastname: Kavetskaia
authors.affiliation: Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics-Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois.
authors.forename: Volker
authors.initials: V
authors.lastname: Fischer
mesh_terms: D015081:2-Naphthylamine; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000493:pharmacokinetics; D064368:Healthy Volunteers; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006900:Hydroxylation; D008297:Male; D010084:Oxidation-Reduction; D013431:Sulfates / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D015081:2-Naphthylamine; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D020719:Glucuronides; D013431:Sulfates; D013449:Sulfonamides; D014498:Uracil; D017361:Viral Nonstructural Proteins; C588260:dasabuvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase