indication

For Primary Dysbetalipoproteinemia (Type III hyperlipidemia) that does not respond adequately to diet. This helps control high cholesterol and high triglyceride levels.

pharmacology

Clofibrate is an antilipidemic agent similar to gemfibrozil. It acts to lower elevated serum lipids by reducing the very low-density lipoprotein fraction (S_f 20-400) rich in triglycerides. Serum cholesterol may be decreased, particularly in those patients whose cholesterol elevation is due to the presence of IDL as a result of Type III hyperlipoproteinemia. Several investigators have observed in their studies that clofibrate may produce a decrease in cholesterol linoleate but an increase in palmitoleate and oleate, the latter being considered atherogenic in experimental animals. The significance of this finding is unknown at this time. Reduction of triglycerides in some patients treated with clofibrate or certain of its chemically and clinically similar analogs may be associated with an increase in LDL cholesterol. Increase in LDL cholesterol has been observed in patients whose cholesterol is initially normal. Animal studies suggest that clofibrate interrupts cholesterol biosynthesis prior to mevalonate formation.

mechanism of action

Clofibrate increases the activity of extrahepatic lipoprotein lipase (LL), thereby increasing lipoprotein triglyceride lipolysis. 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. Clofibrate also inhibits the synthesis and increases the clearance of apolipoprotein B, a carrier molecule for VLDL. Also, as a fibrate, Clofibrate is an agonist of the PPAR-α receptor[4] in muscle, liver, and other tissues. This agonism ultimately leads to modification in gene expression resulting in increased beta-oxidation, decreased triglyceride secretion, increased HDL, increased lipoprotein lipase activity.

toxicity

Oral, mouse: LD₅₀ = 1220 mg/kg; Oral, rabbit: LD₅₀ = 1370 mg/kg; Oral, rat: LD₅₀ = 940 mg/kg. No reported case of overdosage in humans.

biotransformation

Hepatic and gastrointestinal: rapid de-esterification occurs in the gastrointestinal tract and/or on first-pass metabolism to produce the active form, clofibric acid (chlorophenoxy isobutyric acid [CPIB]).

absorption

Completely but slowly absorbed from the intestine. Between 95% and 99% of an oral dose of clofibrate is excreted in the urine as free and conjugated clofibric acid; thus, the absorption of clofibrate is virtually complete.

half life

Half-life in normal volunteers averages 18 to 22 hours (range 14 to 35 hours) but can vary by up to 7 hours in the same subject at different times.

drug interactions

Acenocoumarol: The fibrate increases the anticoagulant effect

Acetohexamide: Clofibrate may increase the effect of sulfonylurea, acetohexamide.

Anisindione: The fibrate increases the anticoagulant effect

Chlorpropamide: Clofibrate may increase the effect of sulfonylurea, chlorpropamide.

Dicumarol: The fibrate increases the anticoagulant effect

Gliclazide: Clofibrate may increase the effect of sulfonylurea, gliclazide.

Glipizide: Clofibrate may increase the effect of sulfonylurea, glipizide.

Glisoxepide: Clofibrate may increase the effect of sulfonylurea, glisoxepide.

Glyburide: Clofibrate may increase the effect of sulfonylurea, glibenclamide.

Glycodiazine: Clofibrate may increase the effect of sulfonylurea, glycodiazine.

Insulin Aspart: Increases the effect of insulin

Insulin Detemir: Increases the effect of insulin

Insulin Glulisine: Increases the effect of insulin

Tolazamide: Clofibrate may increase the effect of sulfonylurea, tolazamide.

Tolbutamide: Clofibrate may increase the effect of sulfonylurea, tolbutamide.

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

Warfarin: The fibrate increases the anticoagulant effect