Fenofibrate drug

While the fibric acid derivatives have antihyperlipidemic effects, their use varies depending on the drug. For example, Clofibrate (Atromid-S) and gemfibrozil (Lopid) are used to treat individuals with very high serum triglyceride levels who present a risk of abdominal pain and pancreatitis and who do not experience a response to diet modifications. Clofibrate is not used for the treatment of other types of hyperlipidemia and is not thought to be effective for prevention of coronary heart disease. Fenofibrate (Tricor) is used as adjunctive treatment for the reduction of LDL, total cholesterol, and triglycerides in patients with hyperlipidemia. 

The lipid regulator drugs bezafibrate and fenofibrate at initial concentrations of 4.5 and 4.2 ng g-1 in sterile sludge were completely removed after the fungal treatment. The fate of fenofibrate, also present in non-sterile sludge, was the same. Meanwhile, the most abundant atorvastatin, a cholesterol lowering statin, decreased its concentration in 80% and 65% in sterile and non-sterile conditions, respectively. 

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

Gemfibrozil, fenofibrate, and lovastatin are available as generic products. This table does not include all drugs used for treating dyslipidemia. 

Granero GE, Ramachandran C, Amidon GL (2005) Dissolution and solubility behavior of fenofibrate in sodium lauryl sulfate solutions. Drug Dev. Ind. Pharm. 31 917-922. 

Elderly Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, take care in dose selection. 

Skeletal muscle effects The use of fibrates alone, including fenofibrate, may occasionally be associated with myopathy. Treatment with drugs of the fibrate class has been associated on rare occasions with rhabdomyolysis, usually in patients with impaired renal function. Consider myopathy in any patient with diffuse myalgias, muscle tenderness or weakness, or marked elevations of creatine phosphokinase levels. 

Drugs that may affect fenofibrate include bile acid sequestrants. 

Drugs that may be affected by fenofibrate include anticoagulants, cyclosporine, and HMG-CoA reductase inhibitors. 

Drug/Food interactions The absorption of micronized fenofibrate is increased when administered with food. 

The antihyperlipidemic drugs, such as clofibrate, fenofibrate, bezafibrate, ciprofi-brate and gemfibrozil are associated with liver toxicity and hepatomegaly in some patients. Fenofibrate inhibits complex I and to lesser extent complex V, whereas clofibrate inhibits predominantly complex V. Gemfibrozil also inhibits complex I, even more potently than fenofibrate [52, 53]. 

Gemfibrozil is absorbed quantitatively from the intestine and is tightly bound to plasma proteins. It undergoes enterohepatic circulation and readily passes the placenta. The plasma half-life is 1.5 hours. Seventy percent is eliminated through the kidneys, mostly unmodified. The liver modifies some of the drug to hydroxymethyl, carboxyl, or quinol derivatives. Fenofibrate is an isopropyl ester that is hydrolyzed completely in the intestine. Its plasma half-life is 20 hours. Sixty percent is excreted in the urine as the glucuronide, and about 25% in feces. 

It is possible that the combination of rosiglitazone with fenofibrate was responsible for the severe myopathy, although the possibility of a single drug cannot be excluded. Raised creatine kinase activity has been reported with troglitazone, and there has been a report of rhabdomyolysis in a patient with type 2 diabetes taking pioglitazone when fenofibrate was added. 

Possible mechanisms of fenofibrate-induced liver injury include activation of peroxisome proliferation-activator receptors, a hypersensitivity reaction, and immune -mediated injury from cross-reactivity of the drug with autoantigens. The authors referred to six reported cases of hepatic fibrosis attributed to fenofibrate. Raised transaminase activities occur commonly with fenofibrate but are generally transient, reverse on withdrawal, and do not result in long-term injury. Fenofibrate should be withdrawn if higher than normal enzyme activities persist, and a liver biopsy should be considered if liver enzymes do not normalize after withdrawal. 

Photosensitivity due to fenofibrate (38) was confirmed by systemic photochallenge (39). Photodermatitis has been associated with cross-reactivity between ketoprofen and fenofibrate this was thought to be due to chemical similarities between these two drugs (40). 

Hypothyroidism predisposes to rhabdomyolysis (53,54) and screening of thyroid function has been advocated before starting hypolipidemic drugs (SEDA-21, 458). This notion has been supported by observations in a 69-year-old man taking fenofibrate 200 mg daily (55). The muscular syndrome appears to be a special risk in patients with nephrotic syndrome (SEDA-13,1325 56). 

Adkins JC, Faulds D. Micronised fenofibrate a review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia. Drugs 1997 54(4) 615-33. 

Dierkes J, Westphal S, Luley C. Fenofibrate-induced hyper-homocysteinemia clinical implications and management. Drug Saf 2003 26 81-91. 

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-... 

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