indication

For treatment of adult patients with very high elevations of serum triglyceride levels (types IV and V hyperlipidemia) who are at risk of developing pancreatitis (inflammation of the pancreas) and who do not respond adequately to a strict diet.

pharmacology

Gemfibrozil, a fibric acid antilipemic agent similar to clofibrate, is used to treat hyperlipoproteinemia and as a second-line therapy for type IIb hypercholesterolemia. It acts to reduce triglyceride levels, reduce VLDL levels, reduce LDL levels (moderately), and increase HDL levels (moderately).

mechanism of action

Gemfibrozil increases the activity of extrahepatic lipoprotein lipase (LL), thereby increasing lipoprotein triglyceride lipolysis. It does so by activating Peroxisome proliferator-activated receptor-alpha (PPARα) 'transcription factor ligand', a receptor that is involved in metabolism of carbohydrates and fats, as well as adipose tissue differentiation. This increase in the synthesis of lipoprotein lipase thereby increases the clearance of triglycerides. Chylomicrons are degraded, VLDLs are converted to LDLs, and LDLs are converted to HDL. This is accompanied by a slight increase in secretion of lipids into the bile and ultimately the intestine. Gemfibrozil also inhibits the synthesis and increases the clearance of apolipoprotein B, a carrier molecule for VLDL.

toxicity

Oral, mouse: LD₅₀ = 3162 mg/kg. Symptoms of overdose include abdominal cramps, diarrhea, joint and muscle pain, nausea, and vomiting.

biotransformation

Hepatic. Gemfibrozil mainly undergoes oxidation of a ring methyl group to successively form a hydroxymethyl and a carboxyl metabolite.

absorption

Well absorbed from gastrointestinal tract (within 1-2 hours).

half life

1.5 hours

route of elimination

Approximately seventy percent of the administered human dose is excreted in the urine, mostly as the glucuronide conjugate, with less than 2% excreted as unchanged gemfibrozil.

drug interactions

Acenocoumarol: Gemfibrozil may increase the anticoagulant effect of acenocoumarol.

Anisindione: Gemfibrozil may increase the anticoagulant effect of anisindione.

Atorvastatin: Increased risk of myopathy/rhabdomyolysis

Bexarotene: Gemfibrozil may increase the serum concentration of bexarotene. This combination should be avoided.

Carisoprodol: Strong CYP2C19 inhibitors such as gemfibrozil may decrease the metabolism of CYP2C19 substrates such as carisoprodol. Consider an alternative for one of the interacting drugs in order to avoid toxicity of the substrate. Some combinations are specifically contraindicated by manufacturers. Suggested dosage adjustments are also offered by some manufacturers. Please review applicable package inserts. Monitor for increased effects of the CYP substrate if a CYP inhibitor is initiated/dose increased, and decreased effects if a CYP inhibitor is discontinued/dose decreased.

Cerivastatin: Increased risk of myopathy/rhabdomyolysis

Dicumarol: Gemfibrozil may increase the anticoagulant effect of dicumarol.

Fluvastatin: Increased risk of myopathy/rhabdomyolysis

Glimepiride: Gemfibrozil increases the effect and toxicity of rosiglitazone/pioglitazone

Lovastatin: Increased risk of myopathy/rhabdomyolysis

Pioglitazone: Gemfibrozil may increase the effect and toxicity of pioglitazone.

Pravastatin: Increased risk of myopathy/rhabdomyolysis

Repaglinide: Gemfibrozil may increase the effect and toxicity of repaglinide.

Rosiglitazone: Increases the effect and toxicity of rosiglitazone/pioglitazone

Rosuvastatin: Gemfibrozil may increase the therapeutic and toxic effects of rosuvastatin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of rosuvastatin if gemfibrozil is initiated, discontinued or dose changed.

Simvastatin: Increased risk of myopathy/rhabdomyolysis

Tacrine: The metabolism of Tacrine, a CYP1A2 substrate, may be reduced by Gemfibrozil, a CYP1A2 inhibitors. Monitor the efficacy and toxicity of Tacrine if Gemfibrozil is initiated, discontinued or if the dose is changed.

Tamoxifen: Gemfibrozil may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Gemfibrozil is initiated, discontinued or dose changed.

Tizanidine: Gemfibrozil may decrease the metabolism and clearance of Tizanidine. Consider alternate therapy or use caution during co-administration.

Tolbutamide: Gemfibrozil, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Gemfibrozil is initiated, discontinued or dose changed.

Torasemide: Gemfibrozil, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Gemfibrozil is initiated, discontinued or dose changed.

Tretinoin: The strong CYP2C8 inhibitor, Gemfibrozil, may decrease the metabolism and clearance of oral Tretinoin. Consider alternate therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Gemfibrozil is initiated, discontinued to dose changed.

Trimethoprim: The strong CYP2C9 inhibitor, Gemfibrozil, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Gemfibrozil is initiated, discontinued or dose changed.

Trimipramine: The strong CYP2C19 inhibitor, Gemfibrozil, may decrease the metabolism and clearance of Trimipramine, a CYP2C19 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Gemfibrozil is initiated, discontinued or dose changed.

Ursodeoxycholic acid: The fibric acid derivative decreases the effect of ursodiol

Voriconazole: Gemfibrozil, a strong CYP2C9 inhibitor, may increase the serum concentration of voriconazole by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of voriconazole if gemfibrozil is initiated, discontinued or dose changed.

Warfarin: Gemfibrozil, a strong CYP2C9 inhibitor, may decrease the metabolism of warfarin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of warfarin if gemfibrozil is initiated, discontinued or dose changed.

Zafirlukast: Gemfibrozil, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of zafirlukast. Consider alternate therapy or monitor for changes in zafirlukast therapeutic and adverse effects if gemfibrozil is initiated, discontinued or dose changed.