Clinical pharmacokinetics of fibric acid derivatives (fibrates).
Beginning with the description of clofibrate in 1962, derivatives of fibric acid (fibrates) have been used clinically to treat dyslipidaemias. Subsequently, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate and long-acting forms of gemfibrozil, fenofibrate and bezafibrate have been developed. Clinically, this class of drugs appears to be most useful in lipoprotein disorders characterised by elevations of very low density lipoprotein and plasma triglycerides, which are often accompanied by reductions in high density lipoprotein (HDL) levels. The principal effects are a reduction in triglyceride and increase in HDL levels, with increases in the activity of hepatic lipase and lipoprotein lipase. There is some reduction of low density lipoprotein (LDL), lipoprotein (a), fibrinogen and uric acid. As a class, these drugs are generally well absorbed from the gastrointestinal tract (immediate-acting fenofibrate being the exception) and display a high degree of binding to albumin. Fibrates are metabolised by the hepatic cytochrome P450 (CYP) 3A4. All members of this class are primarily excreted via the kidneys and display some increase in plasma half-life in individuals with severe renal impairment. The long-acting forms of gemfibrozil and bezafibrate have pharmacokinetic properties similar to those of their immediate-acting parent compounds. The long-acting form of fenofibrate, produced by the process of micronisation, has increased oral bioavailability with less variability in absorption compared with the immediate-acting form of fenofibrate. Drug interactions are seen with other drugs that share a high degree of binding to albumin or are metabolised by CYP3A4. Clinically the most important and most commonly reported drug interactions are with HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin and fluvastatin), warfarin, cyclosporin and oral hypoglycaemic agents [including metformin, tolbutamide and glibenclamide (glyburide)]. The main potential for drug interactions is with drugs or compounds that are metabolised by or affect CYP3A4, including imidazoles, grapefruit juice, erythromycin, mibefradil and others.
Miller
D B
DB
Robarts Research Institute, London, Ontario, Canada.
Spence
J D
JD
D000924:Anticholesteremic Agents / Q000493:pharmacokinetics*; D002994:Clofibrate / Q000493:pharmacokinetics; D016572:Cyclosporine / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D011345:Fenofibrate / Q000493:pharmacokinetics; D015248:Gemfibrozil / Q000493:pharmacokinetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D014859:Warfarin / Q000378:metabolism
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D014859:Warfarin; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D002994:Clofibrate; D015248:Gemfibrozil; D011345:Fenofibrate