title: Mass balance, metabolite profile, and in vitro-in vivo comparison of clearance pathways of deleobuvir, a hepatitis C virus polymerase inhibitor.
abstract: The pharmacokinetics, mass balance, and metabolism of deleobuvir, a hepatitis C virus (HCV) polymerase inhibitor, were assessed in healthy subjects following a single oral dose of 800 mg of [(14)C]deleobuvir (100 μCi). The overall recovery of radioactivity was 95.2%, with 95.1% recovered from feces. Deleobuvir had moderate to high clearance, and the half-life of deleobuvir and radioactivity in plasma were ∼ 3 h, indicating that there were no metabolites with half-lives significantly longer than that of the parent. The most frequently reported adverse events (in 6 of 12 subjects) were gastrointestinal disorders. Two major metabolites of deleobuvir were identified in plasma: an acyl glucuronide and an alkene reduction metabolite formed in the gastrointestinal (GI) tract by gut bacteria (CD 6168), representing ∼ 20% and 15% of the total drug-related material, respectively. Deleobuvir and CD 6168 were the main components in the fecal samples, each representing ∼ 30 to 35% of the dose. The majority of the remaining radioactivity found in the fecal samples (∼ 21% of the dose) was accounted for by three metabolites in which deleobuvir underwent both alkene reduction and monohydroxylation. In fresh human hepatocytes that form biliary canaliculi in sandwich cultures, the biliary excretion for these excretory metabolites was markedly higher than that for deleobuvir and CD 6168, implying that rapid biliary elimination upon hepatic formation may underlie the absence of these metabolites in circulation. The low in vitro clearance was not predictive of the observed in vivo clearance, likely because major deleobuvir biotransformation occurred by non-CYP450-mediated enzymes that are not well represented in hepatocyte-based in vitro models.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
authors.forename: Lin-Zhi
authors.initials: LZ
authors.lastname: Chen
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Sabo
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
authors.forename: Elsy
authors.initials: E
authors.lastname: Philip
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
authors.forename: Lois
authors.initials: L
authors.lastname: Rowland
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
authors.forename: Bachir
authors.initials: B
authors.lastname: Latli
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Ramsden
authors.affiliation: Covance Clinical Research Unit, Inc., Madison, Wisconsin, USA.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Mandarino
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA rucha.sane@boehringer-ingelheim.com.
authors.forename: Rucha S
authors.initials: RS
authors.lastname: Sane
mesh_terms: D000179:Acrylates / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D000293:Adolescent; D000328:Adult; D001562:Benzimidazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D002250:Carbon Radioisotopes; D005243:Feces / Q000737:chemistry; D041981:Gastrointestinal Tract; D006207:Half-Life; D064368:Healthy Volunteers; D016174:Hepacivirus / Q000201:enzymology*; D006526:Hepatitis C / Q000188:drug therapy*; D065669:Hepatobiliary Elimination; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D055815:Young Adult
chemical_list: D000179:Acrylates; D001562:Benzimidazoles; D002250:Carbon Radioisotopes; C000592437:deleobuvir