title: Generating an in vitro-in vivo correlation for metabolism and liver enrichment of a hepatitis C virus drug, faldaprevir, using a rat hepatocyte model (HepatoPac).
abstract: Hepatocytes provide an integrated model to study drug metabolism and disposition. As a result of a loss of polarity or a significant decrease in the expression of enzymes and transporters, suspended and sandwich-cultured hepatocytes have limitations in determining hepatocellular drug concentrations. Underprediction of the extent of glucuronidation is also a concern for these hepatocyte models. Faldaprevir is a hepatitis C virus protease inhibitor in late-stage development that has demonstrated significant liver enrichment in in vivo rat models based on quantitative whole-body autoradiography (QWBA) and liver-to-plasma area under-the-curve ratio. In bile duct cannulated rats, the primary biliary metabolite was a glucuronide. Owing to ethical concerns, it is difficult to assess liver enrichment in humans, and a lack of in vitro and in vivo correlation of glucuronidation has been reported. The current study was conducted to verify whether a hepatocyte model, rat HepatoPac, could overcome some of these limitations and provide validity for follow-up studies with human HepatoPac. With rat HepatoPac, liver enrichment values averaged 34-fold and were consistent with rat QWBA (26.8-fold) and in vivo data (42-fold). In contrast, liver enrichment in suspended hepatocytes was only 2.8-fold. Furthermore, the extent of faldaprevir glucuronidation in HepatoPac studies was in agreement with in vivo results, with glucuronidation as the major pathway (96%). Suspended rat hepatocytes did not generate the glucuronide or two key hydroxylated metabolites that were observed in vivo. Overall, our studies suggest that HepatoPac is a promising in vitro model to predict in vivo liver enrichment and metabolism, especially for glucuronidation, and has demonstrated superiority over suspended hepatocytes.
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: Roger
authors.initials: R
authors.lastname: St George
authors.forename: Lin-Zhi
authors.initials: LZ
authors.lastname: Chen
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Li
mesh_terms: D000621:Aminoisobutyric Acids; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001646:Bile / Q000378:metabolism; D001692:Biological Transport; D001711:Biotransformation; D002478:Cells, Cultured; D018920:Coculture Techniques; D015925:Cryopreservation; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005347:Fibroblasts / Q000166:cytology; D020719:Glucuronides / Q000378:metabolism*; D016174:Hepacivirus / Q000187:drug effects*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D009842:Oligopeptides / Q000378:metabolism* / Q000493:pharmacokinetics; D011392:Proline / Q000031:analogs & derivatives; D011804:Quinolines; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D003470:Culture Media; D020719:Glucuronides; D009842:Oligopeptides; D011804:Quinolines; D013844:Thiazoles; C552340:faldaprevir; D011392:Proline; D007930:Leucine