Fenofibrate

Absorption

A single 300mg oral dose of fenofibrate reaches a Cmax of 6-9.5mg/L with a Tmax of 4-6h in healthy, fasting volunteers.

Toxicity

The oral LD50 in rats is >2g/kg and in mice is 1600mg/kg. The oral TDLO in rats is 9mg/kg.
Treat patients with supportive care including monitoring of vital signs and observing clinical status. Recent overdose may be treated with inducing vomiting or gastric lavage. Due to fenofibrate's extensive protein binding, hemodialysis is not expected to be useful.

Chemical properties

Crystalline Solid

Originator

Lipantyl,Fournier,France,1975

The Uses of Fenofibrate

Fenofibrate has been used:

• to study its effect on plasma lipids, liver phenotype and gene expression
• to study its impact on endothelium-dependent vasodilatation of thoracic aorta
• to administer to NASH knock-in mice along with a high fat diet (HFD) to study its effect

The Uses of Fenofibrate

Antilipemic. It is a lipid regulating drug. Increases high density lipoprotein levels by reducing cholesteryl ester transfer protein expresion.

The Uses of Fenofibrate

antihyperlipidemic

The Uses of Fenofibrate

Cardiovascular disease

Indications

Fenofibrate is indicated as adjunctive therapy to diet to reduce elevated LDL-C, Total-C, Triglycerides, and Apo B, and to increase HDL-C adults with primary hypercholesterolemia or mixed dyslipidemia. Fenofibrate is also indicated to treat adults with severe hypertriglyceridemia.

What are the applications of Application

Fenofibrate is a hypolipidemic PPARα agonist

Background

Fenofibrate is a fibric acid derivative like clofibrate and gemfibrozil. Fenofibrate is used to treat primary hypercholesterolemia, mixed dyslipidemia, severe hypertriglyceridemia.
Fenofibrate was granted FDA approval on 31 December 1993.

Definition

ChEBI: A chlorobenzophenone that is (4-chlorophenyl)(phenyl)methanone substituted by a [2-methyl-1-oxo-1-(propan-2-yloxy)propan-2-yl]oxy group at position 1 on the phenyl ring.

Manufacturing Process

(a) Preparation of p-(4-chlorobenzoyl)-phenoxyisobutyric acid: 1 mol of 4- hydroxy-4'-chlorobenzophenone is dissolved in anhydrous acetone and then 5 mols of powdered sodium hydroxide is added. The corresponding sodium phenoxide precipitates. Refluxing is effected, and then, 1.5 mols of CHCl3 diluted with anhydrous acetone is added and the resulting mixture is refluxed for 10 hours. After cooling, water is added, the acetone is evaporated, the aqueous phase is washed with ether and acidified and the organic phase is redissolved in ether and extracted into a solution of bicarbonate. The bicarbonate solution is than acidified to obtain the desired acid, having a melting point of 185°C, with a yield of 75%.
(b) Preparation of fenofibrate: 1 mol of the acid obtained is converted into its acid chloride using thionyl chloride (2.5 mols). 1 mol of the acid chloride is then condensed with 1.05 mol of isopropyl alcohol in the presence of 0.98 mol of pyridine in an inert solvent such as benzene.
Since traces of SO2 (which has a bad smell) may be obtained from the thionyl chloride, it is preferable to avoid this disadvantage by carrying out the esterification directly.

Therapeutic Function

Antihyperlipoproteinemic

General Description

Fenofibrate, 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid 1-methylethyl ester (Tricor),has structural features represented in clofibrate. The primarydifference involves the second aromatic ring. This imparts agreater lipophilic character than exists in clofibrate, resultingin a much more potent hypocholesterolemic and triglycerideloweringagent. Also, this structural modification results in alower dose requirement than with clofibrate or gemfibrozil.

Biochem/physiol Actions

Fenofibrate increases high density lipoprotein levels by reducing cholesteryl ester transfer protein expression. It is used in treating the condition of increased cholesterol levels in the blood, abnormal lipid levels in the body and also hypertriglyceridaemia. Fenofibrate is a lipid regulating drug and proliferator-activated receptor-α (PPARα) mediates its action. It decreases the plasma levels of fibrinogen and C-reactive protein. By this fenofibrate allows better flow-mediated dilatation and reduces the risk of atherosclerosis. Fenofibrate is also known to reduce uric acid levels.

Pharmacokinetics

Fenofibrate is a fibrate that activates peroxisome proliferator activated receptor alpha (PPARα) to alter lipid metabolism and treat primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Fenofibrate requires once daily dosing and has a half life of 19-27 hours so its duration of action is long. Fenofibrate capsules are given at a dose of 50-150mg daily so the therapeutic index is wide. Patients should be counselled about the risk of rhabdomyolysis, myopathy, and cholelithiasis when taking fibrates.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: increased risk of myopathy with daptomycin - try to avoid concomitant use.
Anticoagulants: enhances effect of coumarins and phenindione; dose of anticoagulant should be reduced by up to 50% and readjusted by monitoring INR.
Antidiabetics: may improve glucose tolerance and have an additive effect with insulin or sulphonylureas.
Ciclosporin: ciclosporin levels appear to be unaffected; however, it is recommended that concomitant therapy should be avoided because of the possibility of elevated serum creatinine levels.
Colchicine: possible increased risk of myopathy.
Lipid-regulating drugs: increased risk of myopathy in combination with statins and ezetimibe (maximum 20 mg of rosuvastatin); increased risk of cholelithiasis and gallbladder disease with ezetimibe - avoid with ezetimibe.

Metabolism

Fenofibrate is completely hydrolyzed by liver carboxylesterase 1 to fenofibric acid. Fenofibric acid is either glucuronidated or has its carbonyl group reduced to a benzhydrol that is then glucuronidated. Glucuronidation of fenofibrate metabolites is mediated by UGT1A9. Reduction of the carbonyl group is primarily mediated by CBR1 and minorly by AKR1C1, AKR1C2, AKR1C3, and AKR1B1.

Metabolism

After oral administration, fenofibrate is rapidly hydrolysed by esterases to the active metabolite fenofibric acid.
No unchanged fenofibrate can be detected in the plasma. Fenofibric acid is excreted mainly in the urine, mainly as the glucuronide conjugate, but also as a reduced form of fenofibric acid and its glucuronide; practically all the drug is eliminated from the body within 6 days

storage

Store at RT