Mechanism of Action

The three structurally related fibrates available in the United States are gemfibrozil (Lopid), fenofibrate (Tricor) and clofibrate (Atromid-S). They share common uses and toxicities. The fibrates typically lower VLDL triglyceride by 40% or more and elevate plasma HDL cholesterol by 10 to 15%. The reduction of plasma triglycerides in humans appears due to increased lipopro-tein lipase (LPL) activity. The fibrates activate a nuclear receptor (transcription factor) termed peroxisomal proliferation activated receptor (PPAR) that is a member of the steroid hormone receptor superfamily. PPAR increases transcription of the LPL gene and decreases transcription of the apolipoprotein CIII gene (apo CIII). Since LPL is responsible for catabolism of VLDL triglyceride and apo CIII is an inhibitor of LPL activity, the combined consequences of these changes are increased LPL activity and enhanced removal of triglyceride from the circulation (mechanism II in Fig. 23.2).

The elevation of HDL levels by fibrates may be due to two drug actions: induced synthesis of apo-A1, the principal apoprotein of HDL, and increased assembly of new HDL particles in the circulation. Surface components of VLDL contribute to formation of HDL, as the VLDL particles are reduced in size through the action of LPL. The increased rate of catabolism of VLDL caused by the fibrates would provide more components for assembly of HDL particles.

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