TY - JOUR T1 - Bridging <em>In Vitro</em> and <em>In Vivo</em> Metabolism and Transport of Faldaprevir in Human Using a Novel Co-cultured Human Hepatocyte System, Hepatopacâ„¢ JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.113.055897 SP - dmd.113.055897 AU - Diane Ramsden AU - Donald J. Tweedie AU - Tom S. Chan AU - Mitchell E Taub AU - Yongmei Li Y1 - 2013/12/23 UR - http://dmd.aspetjournals.org/content/early/2013/12/23/dmd.113.055897.abstract N2 - 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 which 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 co-culture 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 (approximately 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+-dependant 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 on the clearance of the drug. ER -