Fenofibrate metabolism

Tsimihodimos V, Miltiadous G, Daskalopoulou SS, et al. Fenofibrate metabolic and pleiotropic effects. Curr Vase Pharmacol. 2005 3 87-98. 

Comu-Chagnon, M. C., Dupont, H., and Edgar, A. (1995). Fenofibrate metabolism and species differences for peroxisome proliferation in cultured hepatocytes. Fundam Appl Toxicol 26, 63-74. 

Gariot, R, Barrat, E., Drouin, R, Genton, R, Pointel, J. R, Foliguet, B., Kolopp, M., and Debry, G. (1987). Morphometric study of human hepatic cell modifications induced by fenofibrate. Metabolism... 

Caslake MJ, Packard CJ, Gaw A, Murray E, Griffin BA, Vallance BD, et al. Fenofibrate and LDL metabolic heterogeneity in hypercholesterolemia. Arterios-cler Thromb 1993 13 702-711. 

Another therapeutic class to be briefly discussed is that of the lipid-lowering agents known as fibrates, e.g., clofibrate and fenofibrate (8.5). Here also, the acidic metabolite is the active form clofibrate (an ethyl ester) is rapidly hydrolyzed to clofibric acid by liver carboxylesterases and blood esterases [11], Human metabolic studies of fenofibrate (8.5), the isopropyl ester of fenofibric acid, showed incomplete absorption after oral administration, while hydrolysis of the absorbed fraction was quantitative [12], This was followed by other reactions of biotransformation, mainly glucuronidation of the carboxylic acid group. 

Metabolism - Fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid no unchanged fenofibrate is detected in plasma. Fenofibric acid is primarily conjugated with glucuronic acid. 

Fenofibrate appears to be complementary with certain statins in the treatment of familial combined hyperlipoproteinemia and other conditions involving elevations of both LDL and VLDL. The combination of fenofibrate with rosuvastatin is particularly effective. Some other statins may interact unfavorably owing to effects on cytochrome P450 metabolism. 

The fibrates are another class of antihyperlipidemic drug and are frequently coadministered with a statin. Fibrates act as agonists of the peroxisome proliferator-activated receptors (PPAR), particularly PPAR-a. PPARs are nuclear receptors that influence gene expression and lipid metabolism. Examples of fibrates include gemfibrozil (Lopid, A.110) and fenofibrate (Tricor, A.lll) (Figure A.30). Fenofibrate is hydrolyzed in the body to its active form, fenofibric acid (A.112). Fibrates do not decrease LDL levels as effectively as statins, but fibrates do elevate HDL cholesterol levels. 

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

Fibrates activate peroxisome proliferator-activated receptors, which are intracellular receptors that cause the transcription of a number of genes on the DNA that facilitate lipid metabolism. They are well absorbed from the gastrointestinal tract (with the exception of medium-acting fenofibrate), display a high degree of binding to albumin, are metabolized by CYP3A4 and are primarily excreted via kidneys there is thus some increase in half-life in patients with severe renal impairment. 

FIBRATES SULPHONYLUREAS- TOLBUTAMIDE Fibrates may t the efficacy of sulphonylureas Uncertain postulated that fibrates displace sulphonylureas from plasma proteins and 1 their hepatic metabolism. In addition, fenofibrate may inhibit CYP2C9-mediated metabolism of tolbutamide Monitor blood glucose levels closely... 

REPAGLINIDE FIBRATES-GEMFIBROZIL Nearly eightfold t in repaglinide levels. Risk of severe and prolonged hypoglycaemia Hepatic metabolism inhibited The European Agency for the Evaluation of Medicinal products contraindicated concurrent use in 2003. Bezafibrate and fenofibrate are suitable alternatives if a fibric acid derivative is required... 

Fibric adds Clofibrate Gemfibrozil Fenofibrate Increase VLtt-catabolism PPAR , agonist LDLi 5-20% HDL t 10%-20% TG i 20%-S0% Gl upset, dyspepsia, gallstones, T LFTs, myopathy Nonmetabolism Warfarin Cyclosporine Statins Liver or severe renal disease primary biliary cirrhosis preexisting gallbladder disease... 

Amongst fatty acids, C20 5n-3 is considered as being a potent activator of PPARa in hepatocytes and in vivo, in the liver of animals fed n-3 PUFA diets. C20 5n-3 seem to have both the metabolic (Pawar and Jump, 2003) and structural (Jump, 2002) characteristics for being a PPARa activator. C20 5n-3 is a weak PPARa activator when compared to synthetic agonist such as fenofibrate. However, unlike fenofibrate, PUFAs also display other hypolipidemic effects on other transcription factors. For example, C20 5n-3 is known to suppress the activity of SREBP-lc (Sekiya et al., 2003). 

A. Mechanism and Effects Fibric acid derivatives (eg, gemfibrozil, fenofibrate, clofibrate) are ligands for the peroxisome proliferator-activated receptor-alpha (PPAR-a) protein, a receptor that regulates transcription of genes involved in lipid metabolism. Tbis interaction with PPAR-a results in increased activity of lipoprotein lipase and enhanced clearance of triglyceride-rich lipoproteins (Figure 35-2). Cholesterol biosynthesis in the liver is seeondarily reduced. The fibrates reduce serum triglyceride concentrations (Table 35-3). There may be a small reduction in LDL cholesterol and a small increase in HDL levels. 

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