Human hepatocytes as a key in vitro model to improve preclinical drug development.
Over past decades, numerous in vitro and/or ex vivo models have been developed to investigate drug metabolism. In the order of complexity we found the isolated perfused liver, hepatocytes in co-culture with epithelial cells, hepatocytes in suspension and in primary culture and subcellular hepatic microsomal fractions. Because they can be easily prepared from both animals (pharmacological and toxicological species) and humans (whole livers as well as biopsies obtained during surgery) hepatocytes in primary culture provide the most powerful model to better elucidate drug behavior at an early stage of preclinical development such as: the characterization of main biotransformation reactions, the identification of phase I and phase II isozymes involved in such reactions, the evaluation of inter-species differences allowing the selection of a second toxicological animal species more closely related to man on the basis of metabolic profiles, the detection of the inducing and/or inhibitory effects of a drug on metabolic enzymes, the prediction of drug interactions, the estimation of inter-individual variability in biotransformation reactions. The use of hepatocytes, and in particular those obtained from humans, at an early stage of drug development allows the obtention of more predictive preclinical data and a better knowledge of drug behavior in humans before the first administration of the drug in healthy volunteers.
Fabre
G
G
Sanofi Recherche Service de Métabolisme et de Pharmacocinétique, Montpellier, France.
Combalbert
J
J
Berger
Y
Y
Cano
J P
JP
D000818:Animals; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological