Mechanism of Action at Molecular and Tissue Levels
The action of fibrates is based on the stimulation of peroxisome proliferator-activated receptors, specifically PPARα. This triggers a cascade of reactions in the body:
- Upregulation of endothelial lipoprotein lipase expression located on vascular endothelium.
- Accelerated breakdown of triglyceride-rich particles — chylomicrons and VLDL.
- Upregulation of Apo A protein synthesis, leading to elevated levels of protective high-density lipoproteins (HDL).
- Increased density of lipoprotein receptors on the surface of hepatocytes, alongside the suppression of hepatic cholesterol and VLDL synthesis.
Clinical Application and Drug Representatives
In modern clinical practice, physicians use several main fibric acid derivatives: gemfibrozil, fenofibrate, bezafibrate, and ciprofibrate.
The primary indications for their use are type II, IV, and V dyslipidemias. The main advantage of these drugs is their exceptional ability to lower blood concentrations of triglycerides. For instance, fenofibrate can reduce TG levels by 30–60% and total cholesterol by 16–35%. Additionally, it possesses a useful uricosuric property, helping to excrete uric acid.
Pharmacokinetic Properties and Safety
The drugs in this group differ in elimination rate and metabolism:
- Gemfibrozil is well absorbed from the gastrointestinal tract, reaching peak concentration in 1–2 hours ($t_{1/2}$ is approximately 1.5 hours). It is excreted primarily by the kidneys.
- Fenofibrate acts as a prodrug, converting in tissues into active fenofibric acid. Its micronized formulation allows for once-daily administration.
- Ciprofibrate features a notably long half-life ($t_{1/2}$ ranging from 48 to 120 hours) and is taken once daily.
Safety: Adverse effects include dyspepsia, headaches, cholestasis, and hazardous toxic effects on muscle tissue (myalgia, myopathy, and rarely, rhabdomyolysis). For this reason, it is strictly contraindicated to combine fibrates with statins to avoid cumulative toxic effects.