Structure and biochemical effects of fenofibrate.

The structures of various fibric acid derivatives are compared. Fenofibrate inhibits de novo hepatic fatty acid synthesis and seems to inhibit hepatic very low-density lipoprotein synthesis, but it enhances mitochondrial and peroxisomal fatty acid oxidation and lipoprotein lipase activity. It produces a very significant reduction in the plasma triglyceride concentration. Fenofibrate also inhibits cholesterol synthesis prior to processing mevalonate, indirectly causing significant reduction of hydroxymethylglutaryl coenzyme A reductase activity. The drug may inhibit acyl-coenzyme A-cholesterol transferase activity, reducing cholesterol ester accumulation within cells. Fenofibrate significantly increases the fractional rate of lecithin-cholesterol acyltransferase activity in normolipidemic and hypercholesterolemic patients. This may explain the increase in cholesterol ester levels observed in high-density lipoproteins. It may stimulate bile acid synthesis from exogenous cholesterol. It causes a marked reduction of increased spontaneous platelet aggregation. Fenofibrate also markedly diminishes the effect of platelet-derived growth factor upon DNA synthesis in vitro, an effect that might impede a key event in early atherogenesis. Thus, fenofibrate has effects not directly related to its lipid- and lipoprotein-lowering action.