title: Bridging in vitro and in vivo metabolism and transport of faldaprevir in human using a novel cocultured human hepatocyte system, HepatoPac.
abstract: An increased appreciation of the importance of transporter and enzyme interplay in drug clearance and a desire to delineate these mechanisms necessitates the utilization of models that contain a full complement of enzymes and transporters at physiologically relevant activities. Additionally, the development of drugs with longer half-lives requires in vitro systems with extended incubation times that allow characterization of metabolic pathways for low-clearance drugs. A recently developed coculture hepatocyte model, HepatoPac, has been applied to meet these challenges. Faldaprevir is a drug in late-stage development for the treatment of hepatitis C. Faldaprevir is a low-clearance drug with the somewhat unique characteristic of being slowly metabolized, producing two abundant hydroxylated metabolites (M2a and M2b) in feces (∼40% of the dose) without exhibiting significant levels of circulating metabolites in humans. The human HepatoPac model was investigated to characterize the metabolism and transport of faldaprevir. In human HepatoPac cultures, M2a and M2b were the predominant metabolites formed, with extents of formation comparable to in vivo. Direct glucuronidation of faldaprevir was shown to be a minor metabolic pathway. HepatoPac studies also demonstrated that faldaprevir is concentrated in liver with active uptake by multiple transporters (including OATP1B1 and Na(+)-dependent transporters). Overall, human HepatoPac cultures provided valuable insights into the metabolism and disposition of faldaprevir in humans and demonstrated the importance of enzyme and transporter interplay in the clearance of the drug.
authors.affiliation: Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Diane
authors.initials: D
authors.lastname: Ramsden
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tweedie
authors.forename: Tom S
authors.initials: TS
authors.lastname: Chan
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Taub
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Li
mesh_terms: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000378:metabolism*; D001692:Biological Transport; D001711:Biotransformation; D002478:Cells, Cultured; D018920:Coculture Techniques; D015925:Cryopreservation; D003470:Culture Media; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D020719:Glucuronides / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D009842:Oligopeptides / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives; D011804:Quinolines; D012964:Sodium / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism*
chemical_list: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D003470:Culture Media; D020719:Glucuronides; D027381:Liver-Specific Organic Anion Transporter 1; D009842:Oligopeptides; D027361:Organic Anion Transporters; D011804:Quinolines; C503999:SLCO1B1 protein, human; D013844:Thiazoles; C552340:faldaprevir; D011392:Proline; D012964:Sodium; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D007930:Leucine