What is the mechanism of action of fenofibrate (Fibric acid derivative)?

Mechanism of Action of Fenofibrate

Fenofibrate works primarily by activating peroxisome proliferator-activated receptor alpha (PPARα), which modifies lipid metabolism by increasing lipolysis and elimination of triglyceride-rich particles from plasma. 1

Primary Mechanisms

Fenofibrate is a pro-drug that is rapidly hydrolyzed by esterases to its active metabolite, fenofibric acid, after oral administration. The active metabolite exerts its effects through several key mechanisms:

1. PPARα Activation:

   • Increases lipoprotein lipase activity, enhancing triglyceride clearance
   • Reduces production of apoprotein C-III (an inhibitor of lipoprotein lipase)
   • Induces increased synthesis of apolipoproteins A-I, A-II, and HDL-cholesterol 1

2. LDL Particle Modification:

   • Alters the size and composition of LDL particles from small, dense atherogenic particles to larger, more buoyant particles
   • These larger particles have greater affinity for cholesterol receptors and are catabolized more rapidly 1

3. Triglyceride Reduction:

   • Decreases hepatic production of triglyceride-rich lipoproteins
   • Enhances clearance of triglyceride-rich particles from circulation 2

4. HDL-C Elevation:

   • Increases production of HDL components (apo A-I and apo A-II)
   • Promotes reverse cholesterol transport 2, 3

Additional Pharmacological Effects

Beyond its primary lipid-modifying actions, fenofibrate has several other effects:

• Uric Acid Reduction: Increases urinary excretion of uric acid, reducing serum levels in both hyperuricemic and normal individuals 1

• Pleiotropic Effects:

  • Reduces fibrinogen levels
  • Lowers C-reactive protein and other pro-inflammatory markers
  • Improves flow-mediated dilation 2, 3

• Microvascular Benefits:

  • Reduces albuminuria progression
  • Decreases need for laser treatment in diabetic retinopathy 4, 5

Pharmacokinetics

• Absorption: Well absorbed from GI tract, with approximately 60% of a dose appearing in urine
• Distribution: Extensively protein-bound (99%)
• Metabolism: Rapidly hydrolyzed to fenofibric acid; no unchanged fenofibrate detected in plasma
• Elimination: Primarily conjugated with glucuronic acid and excreted in urine
• Peak plasma levels: Reached within 6-8 hours after administration
• Steady state: Achieved within 5 days of multiple dosing 1

Clinical Applications

Fenofibrate is particularly effective in patients with:

• Hypertriglyceridemia
• Mixed dyslipidemia
• Atherogenic dyslipidemia (high triglycerides, low HDL-C, and small dense LDL particles)
• Diabetic dyslipidemia 4

Important Considerations

• Fenofibrate can cause a temporary rise in serum creatinine (approximately 15%), which is reversible upon discontinuation 4
• When combined with statins, there is a risk of myopathy, though fenofibrate appears to have lower risk compared to other fibrates 4
• Renal function monitoring is recommended, particularly in elderly patients and those with renal impairment 1

Fenofibrate's multifaceted mechanism of action makes it particularly valuable for managing complex dyslipidemic states, especially those characterized by elevated triglycerides and low HDL-C levels.