Drug-induced cholestasis risk assessment in sandwich-cultured human hepatocytes.
Fiche publication
Date publication
août 2016
Journal
Toxicology in vitro : an international journal published in association with BIBRA
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BACHELLIER Philippe, Pr HEYD Bruno
Tous les auteurs :
Oorts M, Baze A, Bachellier P, Heyd B, Zacharias T, Annaert P, Richert L
Lien Pubmed
Résumé
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.
Mots clés
Bile Acids and Salts, pharmacology, Cells, Cultured, Chemical and Drug Induced Liver Injury, Cholestasis, chemically induced, Cyclosporine, toxicity, Hepatocytes, drug effects, Humans, Risk Assessment, methods, Urea, metabolism
Référence
Toxicol In Vitro. 2016 Aug;34:179-86