Bezafibrate

Absorption

Bezafibrate is almost completely absorbed after oral administration. The relative bioavailability of bezafibrate retard compared to the standard form is about 70%.

Description

Bezafibrate is a non-selective agonist of peroxisome proliferator-activated receptors (PPARs; EC₅₀s = 50, 60, and 20 μM for human PPARα, PPARγ, and PPARδ, respectively). It reduces triglyceride levels and the size of lipid droplets in an oleic acid-induced HepaRG hepatocyte model of steatosis when used at a concentration of 25 μM. Bezafibrate (10 mg/kg per day) reduces plasma VLDL and LDL mass and triglyceride and free fatty acid levels in a high-fructose plus lard diet-induced rat model of insulin resistance.

Chemical properties

Off-White Solid

Originator

Bezafibrate,Eipico Co.

The Uses of Bezafibrate

Bezafibrate has been used:

• a supplement in the standard diet (SD)?for mice to study its effect on diabetes
• to evaluate its effect on hepatitis C virus (HCV) assembly and secretion
• to evaluate its effect on gonadal steroidogenesis and?spermatogenesis?of zebrafish and also used as standard for HPLC

The Uses of Bezafibrate

Antilipemic

The Uses of Bezafibrate

antihyperlipidemic

The Uses of Bezafibrate

anti-hyperlipoproteinemic

Indications

For the treatment of primary hyperlipidaemia types IIa, IIb, III, IV and V (Fredrickson classification) corresponding to groups I, II and III of the European Atherosclerosis Society guidelines - when diet alone or improvements in lifestyle such as increased exercise or weight reduction do not lead to an adequate response. Also for the treatment of secondary hyperlipidaemias, e.g. severe hypertriglyceridemias, when sufficient improvement does not occur after correction of the underlying disorder (e.g. diabetes mellitus).

Background

Antilipemic agent that lowers cholesterol and triglycerides. It decreases low density lipoproteins and increases high density lipoproteins.

What are the applications of Application

Bezafibrate is a peroxisome proliferator and hypolipidaemic agent

definition

ChEBI: Bezafibrate is a monocarboxylic acid amide obtained by the formal condensation of the carboxy group of 4-chlorobenzoic acid with the amino group of 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoic acid. Benafibrate is used for the treatment of hyperlipidaemia. It has a role as a xenobiotic, an environmental contaminant, a geroprotector and an antilipemic drug. It is a monocarboxylic acid, an aromatic ether, a member of monochlorobenzenes and a monocarboxylic acid amide. It is functionally related to a propionic acid.

Manufacturing Process

0.292 moles p-chlorobenzoyl chloride and 50 ml dry pyridine were added dropwise to 0.146 moles tyramine in 60 ml dry pyridine for 10 minutes. Then the mixture was poured in about 500 g of ice with water. The fallen-out crystals was filtered off, washed with diluted HCl, water and NaHCO3 solution and dried. It was recrystallized from acetone to give di(4-chlorobenzoyl) tyramine; yield 98 %; MP: 203°-205°C.
0.11 moles above product in 400 ml methanol was mixed with 130 ml 2 N KOH and heated at 40°-45°C for 1 hour. On cooling 130 ml 2 N HCl was added. The fallen-out precipitate was filtered off, filtrate was distilled off to dryness. The residue was washed with water, NaHCO3 solution and recrystallized from ethanol to give N-(4-chlorobenzoyl)tyramine; yield 91%; MP: 174°-176°C.
2.14 g sodium was dissolved in 50 ml of absolute methanol and mixed with 0.93 mole N-(4-chlorobenzoyl)tyramine. Methanol was removed in vacuum to dryness. The residue was slurried in 100 ml absolute toluene and 0.137 moles 2-bromo-2-methylpropionic acid ethyl ester was added. The suspension was heated for 25 hours at 80°C. Then it was distilled in vacuum to dryness and the residue was dissolved in CH2Cl2, washed with diluted HCl, NaOH and water, and dried over CaCl2. On removing of the solvent, the crude 2-{4-[2- (4-chlorobenzoylamino)ethyl]phenoxy}-2-methylpropionic acid ethyl ester was obtained. After recrystallization from ether/ ligroin and acetone it had MP: 96°-97°C; yield 67 %.
0.1 mole above ester in 1.5 L of dioxane was slowly mixed with 200 ml 1 N KOH at ambient temperature and stood for 2 hours, then it was heated at 40°C for 1 hour. The substance was dissolved completely. On cooling the mixture was neutralized with 200 ml 1 N HCl. The solvents were removed in vacuum. The residue was washed with water and recrystallized from acetone to give 2-{4-[2-(4-chlorobenzoylamino)ethyl]phenoxy}-2-methylpropionic acid; yield 84%; MP: 186°C.

Therapeutic Function

Antihyperlipidemic

Biochem/physiol Actions

The peroxisome proliferator-activated receptor (PPAR) is a member of the steroid nuclear receptor superfamily. Bezafibrate is a peroxisome proliferator-activated receptor agonist for PPARα, PPARδ, and PPARγ. Lipoprotein lipase (LPL) activator.PPARgamma agonists, including Bezafibrate, have beneficial effects in the suppression of the inflammatory response during RSV infection and therefore might have clinical efficacy in the course of severe RSV-infection.

Pharmacokinetics

Bezafibrate is an antilipemic agent that lowers cholesterol and triglycerides. It decreases low density lipoproteins and increases high density lipoproteins. Bezafibrate lowers elevated blood lipids (triglycerides and cholesterol). Elevated VLDL and LDL are reduced by treatment with bezafibrate, whilst HDL-levels are increased. The activity of triglyceride lipases (lipoprotein lipase and hepatic lipoproteinlipase) involved in the catabolism of triglyceride-rich lipoproteins is increased by bezafibrate. In the course of the intensified degradation of triglyceride-rich lipoproteins (chylomicrons, VLDL) precursors for the formation of HDL are formed which explains an increase in HDL. Furthermore, cholesterol biosynthesis is reduced by bezafibrate, which is accompanied by a stimulation of the LDL-receptor-mediated lipoprotein catabolism. Elevated fibrinogen appears to be an important risk-factor, alongside the lipids, smoking and hypertension, in the development of atheroma. Fibrinogen plays an important role in viscosity, and therefore blood flow, and also appears to play an important role in thrombus development and lysability. Bezafibrate exerts an effect on thrombogenic factors. A significant decrease in elevated plasma fibrinogen levels can be achieved. This may lead, amongst other things, to a reduction in both blood and plasma viscosity. Inhibition of platelet aggregation has also been observed. A reduction in blood glucose concentration due to an increase in glucose tolerance has been reported in diabetic patients. In the same patients, the concentration of fasting and postprandial free fatty acids was reduced by bezafibrate.

Clinical Use

Hyperlipidaemia

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 adjusted by monitoring INR.
Antidiabetics: may improve glucose tolerance and have an additive effect with insulin or sulphonylureas.
Ciclosporin: may increase nephrotoxicity and reduce ciclosporin levels.
Colchicine: possible increased risk of myopathy.
Lipid-regulating drugs: increased risk of myopathy in combination with statins and ezetimibe - avoid with ezetimibe; do not exceed 10 mg of simvastatin and 20 mg of rosuvastatin.

Metabolism

Hepatic.

Metabolism

50% of the administered bezafibrate dose is recovered in the urine as unchanged drug and 20% in the form of glucuronides. Elimination is rapid, with excretion almost exclusively renal. 95% of the activity of the [14C]-labelled drug is recovered in the urine and 3% in the faeces within 48 hours.