Fibrates metabolism

Once the LDL cholesterol goal is achieved, assess non-HDL cholesterol in those with metabolic syndrome and intensify LDL-lowering therapy further or consider adding niacin or fibrate. 

Staels s. Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fru-chart J. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998 98 2088-2093. 

Fruchard (FI 6) found two distinct classes of particles that contain apo(a), having different structural and metabolic character and behaving differently on fibrate and mucine treatment. Cholestyramin does not influence Lp(a) levels (V8). 

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. 

Auwerx, J., Schoonjans, K., Fruchart, J. C., and Staels, B. (1996). Transcriptional control of triglyceride metabolism Fibrates and fatty acids change the expression of the LPL and apo C-111 genes by activating the nuclear receptor PPAR. Atherosclerosis 124(Suppl.), S29-S37. 

Peroxisome proliferator-activated receptors (PPARs) PPREs Regulate multiple aspects of lipid metabolism Activated by fibrates and thiazolidinediones Zinc finger... 

Interactions Antacids ciclosporin colestipol druas metabolized bv cytochrome P450 3A4 fibrates oral-contraceptiyes warfarin niacin erythromycin diaoxin azole-antifunaals... 

The exact mechanism of these drugs is unclear, but they probably work by binding to a specific nuclear receptor known as the peroxisome proliferator activated receptor.52,141 This receptor, found primarily in the liver and adipose tissues, affects the transcription of genes that affect lipid metabolism.89 Fibrates activate this receptor, thereby mediating several changes at the nuclear level that ultimately cause a decrease in triglycerides and other beneficial changes in plasma lipid metabolism.30,52 In a manner similar to the statins, fibrates may also exert anti-inflammatory, antioxidant, and other beneficial effects in addition to their positive effects on plasma lipids.42,49... 

Although it is not exactly clear how much these agents can reduce the risk of a major cardiac event (e.g., infarction, stroke), these drugs will probably remain the first choice for people with certain hyper-lipidemias (e.g., increased triglycerides). These drugs are likewise advocated for mixed hyperlipidemias that are common in metabolic disorders such as type 2 diabetes mellitus (see Chapter 32).32,141 Certain fibrates can be used with other drugs, such as statins, to provide more comprehensive pharmacologic control of certain lipid disorders.30,147... 

Elisaf M. Effects of fibrates on serum metabolic parameters. Curr Med Res Opin. 2002 18 269-276. 

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. 

Prueksaritanont T, Tang C, Qiu Y, et al. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab. Dispos., 2002, 30, 1280-1287. 

Fibrate absorption may be reduced in the presence of cholestasis. Metabolism will be reduced in liver dysfunction. Renal failure increases the risk of myopathy with fibrate use. During an episode of HRS, anti-hyperlipidaemic medication should be withheld. 

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... 

Figure 7.12 show the results of a validation study. The task was to identify bioisosteric replacements for fragments in known PPAR (peroxisome pro-liferator-activated receptor) ligands. Fibrates are therapeutic agents for the treatment of metabolic disorders and activate PPARoc, a member of the PPAR family.It has been demonstrated that the 2-methyl-propionic acid moiety 7.6 is responsible for the selectivity of fibrates toward PPARa. SQUIRRELnovo suggests bioisosteric replacement for this group. These groups have been patented for action on PPARoc. ... 

Statins are well absorbed after administration orally, and are metabolised in the liver. They are well tolerated, the commonest adverse effect being transient, and usually minor abnormality of liver function tests in some 1% of patients. Asymptomatic elevation of muscle enzymes (creatine phos-phokinase, CPK) and myositis (with a generalised muscle discomfort) occur more rarely, but is more frequent when statins are combined with other anti-hyperlidaemic drugs such as fibrates and nicotinic acid patients should be counseled about myositis when these drugs are co-administered. Myositis is also more likely with co-administered anti-HIV protease inhibitors, and with drugs that interfere with metabolism of some statins, e.g. ciclosporin. 

In conclusion, fibrates exert their lipid-lowering effects through activation of a broad range of lipid metabolism pathways. Some of these could be selectively targeted by future drugs. 

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