In pharmacology, the fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia (high cholesterol), and are therefore hypolipidemic agents.
Contents |
Fibrates prescribed commonly are:
Fibrates are used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins.[1] 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.[2][3]
Although less effective in lowering LDL, fibrates improve HDL and triglyceride levels by increasing HDL levels and decreasing triglyceride levels, and seem to improve insulin resistance when the dyslipidemia is associated with other features of the metabolic syndrome (hypertension and diabetes mellitus type 2). They are therefore used in many hyperlipidemias.
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.
Most fibrates can cause mild stomach upset and myopathy (muscle pain with CPK elevations). Since fibrates increase the cholesterol content of bile, they increase the risk for gallstones.
In combination with statin drugs, fibrates cause an increased risk of rhabdomyolysis, idiosyncratic destruction of muscle tissue, leading to renal failure. A powerful statin drug, cerivastatin (Lipobay), was withdrawn because of this complication. The less lipophilic statins are less prone to cause this reaction, and are probably safer when combined with fibrates.
Although used clinically since the 1930s,[5] if not earlier, the mechanism of action of fibrates remained unelucidated until, in the 1990s, it was discovered that fibrates activate PPAR (peroxisome proliferator-activated receptors), especially PPARα. The PPARs are a class of intracellular receptors that modulate carbohydrate and fat metabolism and adipose tissue differentiation.
Activating PPARs induces the transcription of a number of genes that facilitate lipid metabolism.
Fibrates are structurally and pharmacologically related to the thiazolidinediones, a novel class of anti-diabetic drugs that also act on PPARs (more specifically PPARγ)
Fibrates are a substrate of (metabolized by) CYP3A4.[6]
|
||||||||||||||||||||||||||||||||||||||||