Fibrate
Encyclopedia
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
, the fibrates are a class of amphipathic carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
s. They are used for a range of metabolic
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
disorders, mainly hypercholesterolemia
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
(high cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
), and are therefore hypolipidemic agent
Hypolipidemic agent
Hypolipidemic agents, or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of hyperlipidemias. They are called lipid-lowering drugs or agents.- Classes of hypolipidemic drugs :...
s.
Members
Fibrates prescribed commonly are:- BezafibrateBezafibrateBezafibrate is a fibrate drug used for the treatment of hyperlipidaemia. It helps to lower LDL cholesterol and triglyceride in the blood, and increase HDL.-Mode of action:...
(e.g. Bezalip) - CiprofibrateCiprofibrateCiprofibrate is a fibrate.Crystalline powder white or almost white.Melting point about 115 to 120°C....
(e.g. Modalim) - ClofibrateClofibrateClofibrate is a fibrate. It is a lipid lowering agent used for controlling the high cholesterol and triacylglyceride level in the blood. It increases lipoprotein lipase activity to promote the conversion of VLDL to LDL, and hence reduce the level of VLDL...
(largely obsolete due to side-effect profile, e.g. gallstoneGallstoneA gallstone is a crystalline concretion formed within the gallbladder by accretion of bile components. These calculi are formed in the gallbladder, but may pass distally into other parts of the biliary tract such as the cystic duct, common bile duct, pancreatic duct, or the ampulla of...
s) - GemfibrozilGemfibrozilGemfibrozil is the generic name for an oral drug used to lower lipid levels. It belongs to a group of drugs known as fibrates. It is most commonly sold as the brand name, Lopid...
(e.g. Lopid) - FenofibrateFenofibrateFenofibrate is a drug of the fibrate class. Fenofibrate was developed by Groupe Fournier SA, before it was acquired in 2005 by Solvay Pharmaceutical, a business unit owned by the Belgian corporation, Solvay S.A. In 2009 Solvay Pharmaceutical was acquired by Abbott Laboratories. It is mainly used to...
(e.g. TriCor)
Indications
Fibrates are used in accessory therapy in many forms of hypercholesterolemiaHypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
, usually in combination with statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s. Clinical trials do support their use as monotherapy agents. Fibrates reduce the number of non-fatal heart attacks, but do not improve all-cause mortality and are therefore indicated only in those not tolerant to statins.
Although less effective in lowering LDL, fibrates improve HDL and triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
levels by increasing HDL levels and decreasing triglyceride levels, and seem to improve insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
when the dyslipidemia
Dyslipidemia
Dyslipidemia or dyslipidaemia is an abnormal amount of lipids in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood, often due to diet and lifestyle. The prolonged elevation of insulin levels can lead to dyslipidemia...
is associated with other features of the metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
(hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
type 2). They are therefore used in many hyperlipidemias.
Mechanism of Action
Evidence from studies in rodents and in humans is available to implicate 5 major mechanisms underlying the above-mentioned modulation of lipoprotein phenotypes by fibrates:1. Induction of lipoprotein lipolysis. Increased TRL lipolysis could be a reflection of changes in intrinsic lipoprotein lipase (LPL) activity17 or increased accessibility of TRLs for lipolysis by LPL owing to a reduction of TRL apoC-III content.18
2. Induction of hepatic fatty acid (FA) uptake and reduction of hepatic triglyceride production. In rodents, fibrates increase FA uptake and conversion to acyl-CoA by the liver owing to the induction of FA transporter protein (FATP)19 and acyl-CoA synthetase (ACS) activity.20 Induction of the ß-oxidation pathway with a concomitant decrease in FA synthesis by fibrates results in a lower availability of FAs for triglyceride synthesis, a process that is amplified by the inhibition of hormone-sensitive lipase in adipose tissue by fibrates.21
3. Increased removal of LDL particles. Fibrate treatment results in the formation of LDL with a higher affinity for the LDL receptor, which are thus catabolized more rapidly.11
4. Reduction in neutral lipid (cholesteryl ester and triglyceride) exchange between VLDL and HDL may result from decreased plasma levels of TRL.22
5. Increase in HDL production and stimulation of reverse cholesterol transport. Fibrates increase the production of apoA-I and apoA-II in liver,23 24 which may contribute to the increase of plasma HDL concentrations and a more efficient reverse cholesterol transport.
Side effects
Most fibrates can cause mild stomach upset and myopathyMyopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
(muscle pain with CPK
Creatine kinase
Creatine kinase , also known as creatine phosphokinase or phospho-creatine kinase , is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate...
elevations). Since fibrates increase the cholesterol content of bile, they increase the risk for gallstone
Gallstone
A gallstone is a crystalline concretion formed within the gallbladder by accretion of bile components. These calculi are formed in the gallbladder, but may pass distally into other parts of the biliary tract such as the cystic duct, common bile duct, pancreatic duct, or the ampulla of...
s.
In combination with statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
drugs, fibrates cause an increased risk of rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
, idiosyncratic destruction of muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
tissue, leading to renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
. A powerful statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
drug, cerivastatin
Cerivastatin
Cerivastatin is a synthetic member of the class of statins used to lower cholesterol and prevent cardiovascular disease. It was marketed by the pharmaceutical company Bayer A.G. in the late 1990s, competing with Pfizer's highly successful atorvastatin...
(Lipobay), was withdrawn because of this complication. The less lipophilic
Lipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...
statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s are less prone to cause this reaction, and are probably safer when combined with fibrates.
Pharmacology
Peroxisome proliferator-activated receptor
In the field of molecular biology, the peroxisome proliferator-activated receptors are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes...
(peroxisome proliferator-activated receptors), especially PPARα. The PPARs are a class of intracellular receptors that modulate carbohydrate
Carbohydrate metabolism
Carbohydrate metabolism denotes the various biochemical processes responsible for the formation, breakdown and interconversion of carbohydrates in living organisms....
and fat metabolism
Lipid metabolism
Lipid metabolism refers to the processes that involve the intercourse and degradation of lipids.The types of lipids involved include:* Bile salts* Cholesterols* Eicosanoids* Glycolipids* Ketone bodies* Fatty acids - see also fatty acid metabolism...
and adipose tissue differentiation
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
.
Activating PPARs induces the transcription of a number of gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s that facilitate lipid metabolism
Lipid metabolism
Lipid metabolism refers to the processes that involve the intercourse and degradation of lipids.The types of lipids involved include:* Bile salts* Cholesterols* Eicosanoids* Glycolipids* Ketone bodies* Fatty acids - see also fatty acid metabolism...
.
Fibrates are structurally and pharmacologically related to the thiazolidinedione
Thiazolidinedione
The thiazolidinediones , also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s.- Mechanism of action :...
s, a novel class of anti-diabetic drug
Anti-diabetic drug
Anti-diabetic medications treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents...
s that also act on PPARs
Peroxisome proliferator-activated receptor
In the field of molecular biology, the peroxisome proliferator-activated receptors are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes...
(more specifically PPARγ)
Fibrates are a substrate of (metabolized by) CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
.