MAINTENANCE OF THE BIOTRANSFORMATION CAPACITY BY CULTURED HUMAN HEPATOCYTES AFTER SEVERAL DAILY EXPOSURES TO DRUGS

Adult human hepatocytes were obtained from four different donors and exposed to three new drugs (DPI 201-106, CK 204-933 and SDZ 203-150) for 4 or 5 days with daily renewal of both medium and drug. Both the rates and the routes of metabolism were analysed every day by HPLC and thin-layer chromatography. Metabolism of the three drugs resulted in the formation of several metabolites, which involved various phase I and phase II reactions. For the three drugs, both qualitative and quantitative metabolic capacity was roughly maintained during the period studied. However, some minor metabolites were identified only after two or three incubations, probably because of their low rate of formation and/or multistep synthesis. Individual variations, which were maintained during the whole incubation period, were observed. The maintenance of the same metabolic pathways even after several daily treatments indicates that adult human hepatocytes in primary culture represent a suitable in vitro model system for studies on drug inhibition or induction, drug interactions and long-term drug cytotoxicity.