title: Metabolism and Disposition of the Hepatitis C Protease Inhibitor Paritaprevir in Humans.
abstract: Paritaprevir (also known as ABT-450), a potent NS3-4A serine protease inhibitor [identified by AbbVie (North Chicago, IL) and Enanta Pharmaceuticals (Watertown, MA)] of the hepatitis C virus (HCV), has been developed in combination with ombitasvir and dasabuvir in a three-direct-acting antiviral agent (DAA) oral regimen for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of paritaprevir in humans. After the administration of a single 200-mg oral dose of [(14)C]paritaprevir coadministered with 100 mg of ritonavir to four male healthy volunteers, the mean total percentage of the administered radioactive dose recovered was 96.5%, with recovery in individual subjects ranging from 96.0% to 96.9%. Radioactivity derived from [(14)C]paritaprevir was primarily eliminated in feces (87.8% of the dose). Radioactivity recovered in urine accounted for 8.8% of the dose. The biotransformation of paritaprevir in humans involves: 1) P450-mediated oxidation on the olefinic linker, the phenanthridine group, the methylpyrazinyl group, or combinations thereof; and 2) amide hydrolysis at the acyl cyclopropane-sulfonamide moiety and the pyrazine-2-carboxamide moiety. Paritaprevir was the major component in plasma [90.1% of total radioactivity in plasma, AUC from time 0 to 12 hours (AUC0-12hours) pool]. Five minor metabolites were identified in plasma, including the metabolites M2, M29, M3, M13, and M6; none of the metabolites accounted for greater than 10% of the total radioactivity. Paritaprevir was primarily eliminated through the biliary-fecal route followed by microflora-mediated sulfonamide hydrolysis to M29 as a major component in feces (approximately 60% of dose). In summary, the biotransformation and clearance pathways of paritaprevir 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.), Drug Analysis (O.K.), Exploratory Science (K.M.), CPPM-Clinical PK/PD (A.K., R.M.), AbbVie, North Chicago, Illinois 60064 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.), Drug Analysis (O.K.), Exploratory Science (K.M.), CPPM-Clinical PK/PD (A.K., R.M.), AbbVie, North Chicago, Illinois 60064.
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.), Drug Analysis (O.K.), Exploratory Science (K.M.), CPPM-Clinical PK/PD (A.K., R.M.), AbbVie, North Chicago, Illinois 60064.
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.), Drug Analysis (O.K.), Exploratory Science (K.M.), CPPM-Clinical PK/PD (A.K., R.M.), AbbVie, North Chicago, Illinois 60064.
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.), Drug Analysis (O.K.), Exploratory Science (K.M.), CPPM-Clinical PK/PD (A.K., R.M.), AbbVie, North Chicago, Illinois 60064.
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.), Drug Analysis (O.K.), Exploratory Science (K.M.), CPPM-Clinical PK/PD (A.K., R.M.), AbbVie, North Chicago, Illinois 60064.
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.), Drug Analysis (O.K.), Exploratory Science (K.M.), CPPM-Clinical PK/PD (A.K., R.M.), AbbVie, North Chicago, Illinois 60064.
authors.forename: Amit
authors.initials: A
authors.lastname: Khatri
authors.affiliation: Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Drug Analysis (O.K.), Exploratory Science (K.M.), CPPM-Clinical PK/PD (A.K., R.M.), AbbVie, North Chicago, Illinois 60064.
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.), Drug Analysis (O.K.), Exploratory Science (K.M.), CPPM-Clinical PK/PD (A.K., R.M.), AbbVie, North Chicago, Illinois 60064.
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.), Drug Analysis (O.K.), Exploratory Science (K.M.), CPPM-Clinical PK/PD (A.K., R.M.), AbbVie, North Chicago, Illinois 60064.
authors.forename: Volker
authors.initials: V
authors.lastname: Fischer
mesh_terms: D000284:Administration, Oral; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D003521:Cyclopropanes; D005243:Feces / Q000737:chemistry; D064368:Healthy Volunteers; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D065669:Hepatobiliary Elimination; D006801:Humans; D006868:Hydrolysis; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D057057:Serine Proteases / Q000378:metabolism; D013449:Sulfonamides; D014018:Tissue Distribution; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; D011392:Proline; C000614516:NS3-4A serine protease, Hepatitis C virus; D057057:Serine Proteases; C585405:paritaprevir