Comparative study of four hypolipidaemic agents on the activity of drug-metabolizing enzymes in rat liver microsomes.

In order to understand the secondary effects of hypolipidaemic agents in human therapy, the authors have studied the inductive properties of four of these drugs, clofibrate, F1379, fenofibrate and probucol, on hepatic drug metabolizing enzymes in the rat. Each hypolipidaemic molecule was administered once a day for five days at doses ranging from 100 to 450 mg/kg/day. All the drugs tested caused hepatomegaly, the effect being particularly marked in the case of F1379 and fenofibrate; on the other hand they decreased the microsomal protein content, especially after F1379 or probucol treatment. Cytochrome P-450 concentration was not greatly affected, with only a 40% increase by clofibrate (dose 200 mg/kg/day) and by F1379 at the lower dose. It is of interest that all the hypolipidaemic agents tested enhanced the activity of epoxide hydrolase with 4, 5 benzo(a)pyrene oxide as the substrate. Except for fenofibrate and probucol at the lower dose, they all strongly increased the activity. The greatest change was effected by F1379 which led to a three to eight-fold increase over the control values. We also measured UDP-glucuronosyltransferase activities using two substrates belonging to group I (4-nitrophenol) and group II (4-hydroxybiphenyl). It appears that the changes in enzyme activity found depended both on the type and the dose of the drug administered and on the chemical structure of the substrate. This study showed that hypolipidaemic drugs which are chemically related to clofibrate could greatly modify the activity of drug metabolizing enzymes and therefore alter the transformation of drugs administered concomitantly.(ABSTRACT TRUNCATED AT 250 WORDS)