Gemfibrozil

Gemfibrozil is a fibric acid agent, similar to clofibrate, used to treat Type IIb, IV, and V hyperlipidemias. Gemfibrozil is not a first line treatment and is prescribed to patients who have not responded adequately to weight loss, diet, exercise, and other medications.

Gemfibrozil is a lipid regulator that is used in the reduction of serum triglyceride levels in high-risk patients with hyperlipidemia.

Gemfibrozil is indicated to treat patients with Types IV and V hyperlipidemia who have elevated serum triglycerides (usually above 2000mg/dL), elevated VLDL cholesterol, fasting chylomicrons, are at risk of developing pancreatitis, and do not adequately respond to dietary restrictions. Gemfibrozil is also indicated to reduce the risk of developing coronary heart disease in patients with Type IIb hyperlipidemia without history or symptoms of coronary heart disease; who do not adequately respond to weight loss, diet, exercise, and other medications; and have low HDL, raised LDL, and raised triglycerides.

• Coronary Heart Disease (CHD)
• Fredrickson classification type IV Hyperlipidemia
• Fredrickson classification type V Hyperlipidemia

Gemfibrozil alters lipid metabolism to treat patients with hyperlipidemia. The duration of action requires twice daily dosing as the mean residence time of gemfibrozil is up to 9.6h in patients with chronic renal failure. Gemfibrozil has a wide therapeutic index as trials with twice the standard dose were not associated with severe side effects. Patients taking gemfibrozil may be at an increased risk of developing cholelithiasis and cholecystitis, as seen in patients taking clofibrate.

Gemfibrozil activates peroxisome proliferator-activated receptor-α (PPARα), which alters lipid metabolism. This activation leads to increased HDL, apo AI, apo AII, lipoprotein lipase (LPL), inhibition of apo B synthesis, peripheral lipolysis, decreased removal of free fatty acids by the liver, and increased clearance of apoB.

Upregulated LPL reduces plasma triglyceride levels. Decreased hepatic removal of fatty acids decreases the production of triglycerides. The effects on apoB synthesis and clearance decrease VLDL production which also reduce plasma triglyceride levels.

Gemfibrozil's glucuronide metabolite is also an inhibitor of CYP2C8.

Gemfibrozil is absorbed from the gastrointestinal tract.

In healthy volunteers, a 900mg oral dose of gemfibrozil has a C_max of 46±16µg/mL with a T_max of 2.2±1.1h. In patients with chronic renal failure, gemfibrozil has a C_max of 13.8±11.1µg/mL with a T_max of 2.3±1.0h. In patients with liver disease, gemfibrozil has a C_max of 23.0±10.3µg/mL with a T_max of 2.6±1.7h.

The volume of distribution of gemfibrozil is estimated to be 0.8L/kg.

Gemfibrozil is 99% protein bound. It is 98.6% bound to serum albumin, 0.8% bound to erythrocytes, and 0.8% unbound. There is negligible binding to alpha-1-acid glycoprotein.

Approximately 70% of a dose of gemfibrozil is eliminated in the urine. The majority of a dose is eliminated as a glucuronide conjugate and 11 6% of a dose is eliminated in the feces.

In healthy volunteers, 0.02-0.15% of a dose was detected in the urine as unmetabolized gemfibrozil, with 7-14% detected as conjugated metabolites. In patients with renal failure, trace amounts of unmetabolized gemfibrozil is present in the urine, with 0.5-9.8% detected as conjugated metabolites. In patients with liver disease, 0.1-0.2% of a dose was detected in the urine as unmetabolized gemfibrozil, with 25-50% detected as conjugated metabolites.

Gemfibrozil has a plasma half-life of 1.5 hours. In patients with renal failure the half life is 2.4h and in patients with liver disease the half life is 2.1h.

The clearance of gemfibrozil is estimated to be 6.0L/h.

The oral TDLO of gemfibrozil in humans is 18gm/kg/3Y. The oral LD₅₀ in mice is 2218mg/kg and in rats is 1414mg/kg. The intraperitoneal LD₅₀ in rats is 445mg/kg.

Patients experiencing an overdose may present with abdominal cramps, adnormal liver function tests, diarrhea, increased CPK, joint and muscle pain, nausea, and vomiting. Patients should be treated with symptomatic and supportive measures.

• Take before a meal. Take 30 minutes before meals.