What is the mechanism of action of Gemfibrozil (Gemfibrizol)?

Mechanism of Action of Gemfibrozil

Gemfibrozil primarily works by activating peroxisome proliferator-activated receptor alpha (PPAR-α), which leads to decreased triglyceride production and increased HDL cholesterol levels through multiple metabolic pathways. 1

Primary Mechanisms

Gemfibrozil affects lipid metabolism through several key mechanisms:

1. Inhibition of Peripheral Lipolysis

   • Decreases hepatic extraction of free fatty acids
   • Reduces hepatic triglyceride production 2

2. Effects on VLDL Metabolism

   • Inhibits synthesis of VLDL carrier apolipoprotein B
   • Increases clearance of VLDL apolipoprotein B
   • Decreases overall VLDL production 2

3. HDL Metabolism Enhancement

   • Stimulates synthesis of apolipoprotein AI and AII (key HDL components)
   • Increases production of smaller, denser HDL particles that may be more effective in cholesterol transport 1

4. Lipoprotein Lipase Activity

   • Increases extrahepatic lipoprotein lipase activity by approximately 25%
   • Leads to appearance of smaller VLDL particles with decreased apolipoprotein CIII:CII ratio 1

Pharmacokinetic Properties

• Nearly 100% bioavailability after oral administration
• Peak plasma concentrations reached within 1-2 hours
• Plasma half-life of approximately 1.5 hours after multiple doses
• Highly protein-bound in plasma 2
• Primarily metabolized through oxidation of a ring methyl group to form hydroxymethyl and carboxyl metabolites
• Approximately 70% excreted in urine (mostly as glucuronide conjugates)
• Less than 2% excreted as unchanged gemfibrozil 2

Drug Interactions and Metabolism

Gemfibrozil has important drug interaction properties that explain its contraindication with statins:

• Gemfibrozil and its glucuronide metabolite are potent irreversible inhibitors of CYP2C8 3
• Potent inhibition of OATP1B1/3-mediated hepatic uptake of statin acids
• Inhibition of OATP2B1, Na+-taurocholate cotransporting polypeptide, and renal transporter OAT3
• Inhibition of statin glucuronidation and lactonization 3

These interactions explain why gemfibrozil significantly increases plasma concentrations of various statins:

• Increases lovastatin acid AUC by 280% 4
• Increases simvastatin acid by 2-3 fold
• Increases pravastatin concentrations by 202% and reduces its renal clearance
• Increases rosuvastatin by 1.56-1.88 fold 3

Clinical Implications

• Gemfibrozil is primarily indicated for severe hypertriglyceridemia (>500 mg/dL) to reduce pancreatitis risk 5
• Can reduce triglycerides by approximately 50-54% 5
• Increases HDL cholesterol by 23-36% 5
• Important caution: Combination therapy with any statin and gemfibrozil should be avoided due to increased risk of muscle-related toxicity 3
• Fenofibrate has a significantly lower risk of rhabdomyolysis when combined with statins compared to gemfibrozil (0.58 vs 8.6 per million prescriptions) 3

Understanding gemfibrozil's mechanism of action helps explain both its therapeutic effects on lipid profiles and its potentially dangerous drug interactions, particularly with statins.