title: Drug-induced cholestasis risk assessment in sandwich-cultured human hepatocytes.
abstract: Drug-induced cholestasis (DIC) is recognized as one of the prime mechanisms for DILI. Hence, earlier detection of drug candidates with cholestatic signature is crucial. Recently, we introduced an in vitro model for DIC and evaluated its performance with several cholestatic drugs. We presently expand on the validation of this model by 14 training compounds (TCs) of the EU-EFPIA IMI project MIP-DILI. Several batches of human hepatocytes in sandwich-culture were qualified for DIC assessment by verifying the bile acid-dependent increase in sensitivity to the toxic effects of cyclosporin A. The cholestatic potential of the TCs was expressed by determining the drug-induced cholestasis index (DICI). A safety margin (SM) was calculated as the ratio of the lowest TC concentration with a DICI≤0.80 to the Cmax,total. Nefazodone, bosentan, perhexiline and troglitazone were flagged for cholestasis (SM<30). The hepatotoxic (but non-cholestatic) compounds, amiodarone, diclofenac, fialuridine and ximelagatran, and all non-hepatotoxic compounds were cleared as "safe" for DIC. Tolcapone and paracetamol yielded DICI-based SM values equal to or higher than those based on cytotoxicity, thus excluding DIC as a DILI mechanism. This hepatocyte-based in vitro assay provides a unique tool for early and reliable identification of drug candidates with cholestasis risk.
authors.affiliation: Drug Delivery and Disposition, KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, O&N2, Herestraat 49, box 921, 3000 Leuven, Belgium; KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim, France. Electronic address: Marlies.Oorts@pharm.kuleuven.be.
authors.forename: Marlies
authors.initials: M
authors.lastname: Oorts
authors.affiliation: KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim, France. Electronic address: a.baze@kaly-cell.com.
authors.forename: Audrey
authors.initials: A
authors.lastname: Baze
authors.affiliation: Université de Franche-Comté, EA4267, 25030 Besançon, France; Centre de Chirurgie Viscérale et de Transplantation, Hôpital de Hautepierre, 67098 Strasbourg, France. Electronic address: philippe.bachellier@chru-strasbourg.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bachellier
authors.affiliation: Université de Franche-Comté, EA4267, 25030 Besançon, France; Service de Chirurgie Digestive et Viscérale, Centre de Transplantation Hépatique, Hôpital Jean Minjoz, 25000 Besançon, France. Electronic address: bruno.heyd@univ-fcomte.fr.
authors.forename: Bruno
authors.initials: B
authors.lastname: Heyd
authors.affiliation: Service de Chirurgie Viscérale et Digestive, Centre hospitalier Emile Muller, Moenchsberg, 68100 Mulhouse, France. Electronic address: zachariast@ch-mulhouse.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zacharias
authors.affiliation: Drug Delivery and Disposition, KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, O&N2, Herestraat 49, box 921, 3000 Leuven, Belgium. Electronic address: Pieter.Annaert@pharm.kuleuven.be.
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
authors.affiliation: KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim, France; Université de Franche-Comté, EA4267, 25030 Besançon, France. Electronic address: l.richert@kaly-cell.com.
authors.forename: Lysiane
authors.initials: L
authors.lastname: Richert
mesh_terms: D001647:Bile Acids and Salts / Q000494:pharmacology; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis / Q000139:chemically induced*; D016572:Cyclosporine / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018570:Risk Assessment / Q000379:methods; D014508:Urea / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D016572:Cyclosporine; D014508:Urea
keywords: Bile acids; Drug-induced cholestasis; Hepatotoxicity; In vitro model; MIP-DILI set of training compounds; Sandwich-cultured human hepatocytes