Dulofibrate

Various hypolipidaemic agents differentially induced microsomal drug-metabolizing enzymes. Clofibrate, clofibric acid, fenofibric acid and dulofibrate, which are mainly hypotriglyceridaemic, increased the content in cytochromes P-450 (77-185% over control), and especially cytochrome P-452-dependent lauric acid 12-hydroxylation (5.6- to 8.4-fold increase). Bilirubin glucuronidation was 2.1- to 2.8-fold stimulated; epoxide hydrolase activity (benzo(a)pyrene-oxide) was only slightly increased by the drugs. By contrast, F1379, which lowers plasma cholesterol only, did not change cytochromes P-450 content and slightly affected the 12-hydroxylation of lauric acid. It dramatically enhanced the epoxide hydrolase activity (7.6-fold), and increased (200%) the glucuronidation of planar group I substrates (4-nitrophenol, 4-methylumbelliferone, 1-naphthol). These effects were accompanied by a highly positive staining of gamma-glutamyltransferase in the liver characterized by a great number of intensively coloured foci in the periportal and perilobular area of the tissue. Treatment of rats for three weeks with F1379 did not modify this typical profile in enzyme induction. Such continuous effect could reveal some biochemical changes of hepatocytes with important toxicological relevance. Compared to the parent compound, treatment of rats with two metabolites of F1379 led to a decrease in the induction potency on epoxide hydrolase and on the forms I of UDP-glucuronosyltransferase; by contrast, the content in cytochromes P-450 was increased.