Indications
Fenofibrate is prescribed as an adjunct to dietary measures for the management of lipid disorders. It is specifically indicated for the treatment of primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. The therapeutic goal is to support reductions in cholesterol levels and improve lipid profiles in conjunction with lifestyle and dietary modifications.
Pharmacodynamics
Fenofibrate functions as a fibrate, acting primarily through the activation of peroxisome proliferator-activated receptor alpha (PPARα). This action facilitates alterations in lipid metabolism, thereby addressing lipid disorders like hypercholesterolemia and dyslipidemia. The drug is typically administered once daily, benefiting from a relatively long half-life of 19 to 27 hours, which contributes to its prolonged duration of action. Recommended doses for fenofibrate capsules range between 50 mg to 150 mg daily, indicative of a broad therapeutic index. It is important to counsel patients regarding potential adverse effects such as rhabdomyolysis, myopathy, and cholelithiasis associated with fibrate use.
Absorption
Following the administration of a single 300 mg oral dose in healthy fasting individuals, fenofibrate achieves peak plasma concentrations (Cmax) ranging from 6 to 9.5 mg/L. The time to reach maximum concentration (Tmax) occurs within 4 to 6 hours post-dose. These pharmacokinetic parameters should be considered to optimize the timing and efficiency of therapeutic effects.
Metabolism
Fenofibrate undergoes complete hydrolysis to fenofibric acid, primarily facilitated by liver carboxylesterase 1. Further metabolic processes involve the glucuronidation of fenofibric acid or the reduction of its carbonyl group to a benzhydrol, followed by glucuronidation. The glucuronidation of fenofibrate metabolites is primarily mediated by UGT1A9. Additionally, the reduction of the carbonyl group is largely driven by carbonyl reductase 1 (CBR1), with minor contributions from enzymes such as AKR1C1, AKR1C2, AKR1C3, and AKR1B1. These pathways underscore the extent of liver involvement in fenofibrate metabolism.
Mechanism of Action
Fenofibrate functions by activating peroxisome proliferator-activated receptor alpha (PPARα), which plays a crucial role in lipid metabolism. This activation promotes lipolysis, stimulates lipoprotein lipase activity, and decreases apoprotein C-III levels. PPARα, a nuclear receptor, when activated, induces changes in the regulation of lipid, glucose, and amino acid metabolism. Through gene transcription and translation, PPARα activation leads to the formation of peroxisomes, which contain hydrogen peroxide, reactive oxygen species, and hydroxyl radicals, all contributing to enhanced lipolysis. This process of increased lipid metabolism is linked to elevated oxidative stress in the liver, which, in rare circumstances, may progress to cirrhosis or chronic active hepatitis.
