Bezafibrate (marketed as Bezalip and various other brand names) is a

fibrate In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid (phenoxyisobutyric acid). They are used for a range of metabolic disorders, mainly hypercholesterolemia (high choles ...

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

used as a

lipid-lowering agent Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins, such as choleste ...

to treat

hyperlipidaemia Hyperlipidemia is abnormally high levels of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also use ...

. It helps to lower

LDL cholesterol Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall dens ...

and

triglyceride A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates ...

in the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood is com ...

, and increase HDL. It was patented in 1971 and approved for medical use in 1978.

Medical uses

Bezafibrate improves markers of

combined hyperlipidemia Combined hyperlipidemia (or -aemia) is a commonly occurring form of hypercholesterolemia (elevated cholesterol levels) characterised by increased LDL and triglyceride concentrations, often accompanied by decreased HDL. On lipoprotein electrophor ...

, effectively reducing LDL and triglycerides and improving HDL levels. The main effect on cardiovascular morbidity is in patients with the

metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndro ...

, the features of which are attenuated by bezafibrate. Studies show that in patients with impaired glucose tolerance, bezafibrate may delay progress to diabetes, and in those with

insulin resistance Insulin resistance (IR) is a pathological response in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia. Insulin is a horm ...

it slowed progress in the HOMA severity marker. In addition, a prospective observational study of dyslipidemic patients with diabetes or hyperglycemia showed that bezafibrate significantly reduces haemoglobin A1c (HbA1c) concentration as a function of baseline HbA1c levels, regardless of concurrent use of antidiabetic drugs.

Side-effects

The main toxicity is

hepatic The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

(abnormal liver enzymes);

myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...

and on rare occasions

rhabdomyolysis Rhabdomyolysis (shortened as rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some o ...

have been reported.

Other uses

The Australian biotech company Giaconda combines bezafibrate with

chenodeoxycholic acid Chenodeoxycholic acid (CDCA; also known as chenodesoxycholic acid, chenocholic acid and 3α,7α-dihydroxy-5β-cholan-24-oic acid) is a bile acid. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the ...

in an anti-

hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include ...

drug combination called Hepaconda. Bezafibrate has been shown to reduce

tau protein The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintainin ...

hyperphosphorylation Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural ...

and other signs of

tauopathy Tauopathies are a class of neurodegenerative diseases characterized by the aggregation of abnormal tau protein. Hyperphosphorylation of tau proteins causes them to dissociate from microtubules and form insoluble aggregates called neurofibrillary ...

transgenic mice A genetically modified mouse, genetically engineered mouse model (GEMM) or transgenic mouse is a mouse (''Mus musculus'') that has had its genome altered through the use of genetic engineering techniques. Genetically modified mice are commonly use ...

having human tau

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

. The combination of a cholesterol-lowering drug, bezafibrate, and a contraceptive steroid, medroxyprogesterone acetate, could be an effective, non-toxic treatment for a range of cancers, researchers at the University of Birmingham have found.

Mode of action

Like the other fibrates, bezafibrate is an agonist of

PPARα Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the ''PPARA'' gen ...

; some studies suggest it may have some activity on PPARγ and PPARδ as well.

Synthesis

Further evidence that substantial bulk tolerance is available in the para position is given by the lipid lowering agent bezafibrate. Bezafibrate synthesis

The ''p''-chlorobenzamide of

tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the bl ...

undergoes a

Williamson ether synthesis The Williamson ether synthesis is an organic reaction, forming an ether from an organohalide and a deprotonated alcohol (alkoxide). This reaction was developed by Alexander Williamson in 1850. Typically it involves the reaction of an alkoxide ...

with ethyl 2-bromo-2-methylpropionate to complete the synthesis. The ester group is hydrolyzed in the alkaline reaction medium.

History

Bezafibrate was first introduced by

Boehringer Mannheim F. Hoffmann-La Roche AG, commonly known as Roche (), is a Swiss multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on ...

in 1977.

References

{{PPAR modulators 2-Methyl-2-phenoxypropanoic acid derivatives 4-Chlorophenyl compounds Benzamides