title: Characterization of ADME properties of [(14)C]asunaprevir (BMS-650032) in humans.
abstract: 1. Asunaprevir (ASV, BMS-650032), a highly selective and potent NS3 protease inhibitor, is currently under development for the treatment of chronic hepatic C virus infection. This study describes in vivo biotransformation in humans and the identification of metabolic enzymes of ASV. 2. Following a single oral dose of [(14)C]ASV to humans, the majority of radioactivity (>73% of the dose) was excreted in feces with <1% of the dose recovered in urine. Drug-related radioactivity readily appeared in circulation and the plasma radioactivity was mainly attributed to ASV. A few minor metabolites were observed in human plasma and are not expected to contribute to the pharmacological activity because of low levels. The area under the curve (AUC) values of each circulating metabolite in humans were well below their levels in animals used in the long-term toxicological studies. In bile and feces, intact ASV was a prominent radioactive peak suggesting that both metabolism and direct excretion played important roles in ASV clearance. 3. The primary metabolic pathways of ASV were hydroxylation, sulfonamide hydrolysis and the loss of isoquinoline. In vitro studies with human cDNA expressed CYP enzymes and with human liver microsomes (HLM) in the presence of selective chemical inhibitors demonstrated that ASV was primarily catalyzed by CYP3A4 and CYP3A5.
authors.affiliation: a Department of Pharmaceutical Candidate Optimization and.
authors.forename: Jiachang
authors.initials: J
authors.lastname: Gong
authors.affiliation: b Department of Exploratory Clinical and Translational Research , Bristol-Myers Squibb , Princeton , NJ , USA .
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.affiliation: b Department of Exploratory Clinical and Translational Research , Bristol-Myers Squibb , Princeton , NJ , USA .
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.affiliation: a Department of Pharmaceutical Candidate Optimization and.
authors.forename: Vinod
authors.initials: V
authors.lastname: Arora
authors.affiliation: a Department of Pharmaceutical Candidate Optimization and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Philip
authors.affiliation: d Analytical and Bioanalytical Development, Bristol-Myers Squibb , Princeton , NJ , USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.affiliation: c Department of Chemical Synthesis , Bristol-Myers Squibb , Wallingford , CT , USA , and.
authors.forename: John
authors.initials: J
authors.lastname: Easter
authors.affiliation: a Department of Pharmaceutical Candidate Optimization and.
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
authors.affiliation: a Department of Pharmaceutical Candidate Optimization and.
authors.forename: Ramaswamy A
authors.initials: RA
authors.lastname: Iyer
authors.affiliation: a Department of Pharmaceutical Candidate Optimization and.
authors.forename: Wenying
authors.initials: W
authors.lastname: Li
mesh_terms: D065567:Absorption, Physiological; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001646:Bile / Q000378:metabolism; D002250:Carbon Radioisotopes; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D005243:Feces; D006801:Humans; D006900:Hydroxylation; D007546:Isoquinolines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D055442:Metabolome; D008875:Middle Aged; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D007546:Isoquinolines; D013449:Sulfonamides; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C571889:asunaprevir
keywords: ADME; HCV; asunaprevir; direct acting antiviral; reaction phenotyping