The biochemical pharmacology of fenofibrate.
Fenofibrate is metabolized in several stages. First, the carboxyl ester moiety is cleaved by hydrolysis, resulting in fenofibric acid, the main pharmacologically active compound. Fenofibric acid, in turn, undergoes carbonyl reduction, resulting in a pharmacologically active metabolite referred to as reduced fenofibric acid. Both fenofibric acid and reduced fenofibric acid may be conjugated to form glucuronides. There are important species differences in the metabolism and elimination patterns of fenofibrate. In the rat and dog, fenofibric acid and reduced fenofibric acid are the principal metabolites. In humans, the glucuronide of fenofibric acid is predominant. In the rat and dog, approximately 70-80% of fenofibrate and its metabolites are recovered in the feces, whereas in humans approximately 65% of the dose is excreted in the urine. Several mechanisms contribute to fenofibrate's hypolipidemic action, including inhibition of fatty acid synthesis, stimulation of fatty acid beta-oxidation, inhibition of triglyceride synthesis, and enhancement of lipoprotein lipase activity. Fenofibrate's hypocholesterolemic action is a result of both decreased biosynthesis of cholesterol through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and increased low-density lipoprotein (LDL) clearance via modulation of hepatic LDL receptors. Fenofibrate also has three other actions that may result in the prevention or at least slowing of atherogenesis, namely inhibition of cholesterol esterification, platelet aggregation, and platelet-derived growth factor. The native acyl glucuronide of fenofibric acid is very stable, and is unlikely to have any toxic potential. Although the elimination half-life of fenofibrate is prolonged in the elderly and in patients with impaired hepatic function, the area under the curve and its clearance are not altered because of compensatory changes in the volume of distribution.
Caldwell
J
J
Department of Pharmacology and Toxicology, St. Mary's Hospital Medical School, London, UK.
D002784:Cholesterol / Q000096:biosynthesis; D004951:Esterification; D005227:Fatty Acids / Q000096:biosynthesis; D011345:Fenofibrate / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology*; D014280:Triglycerides / Q000096:biosynthesis
D005227:Fatty Acids; D010975:Platelet Aggregation Inhibitors; D011422:Propionates; D014280:Triglycerides; D002784:Cholesterol; D011345:Fenofibrate