Clofibric acid is a biologically active metabolite of the lipid-lowering drugs clofibrate, etofibrate and theofibrate with the molecular formula C₁₀H₁₁ClO₃. It is chemically 2-(4-chlorophenoxy)-2-methylpropionic acid, a weak organic acid with a pKa near 3.8 and a log P around 2.1, making it moderately lipophilic and persistent under aerobic conditions. Analytical characterization is routinely performed by reversed-phase HPLC with UV detection and by LC-MS/MS for environmental monitoring; melting point is typically reported in the 160 to 165 degrees C range for the crystalline form. The compound undergoes phase II conjugation in mammals to give glucuronide and sulfate conjugates and exhibits low volatility and limited biodegradation in some aquatic systems, which explains detections in surface waters. Industrial and analytical handling notes include recommended storage in a cool, dry place protected from light, use of anhydrous solvents for formulation work, and attention to nominal particle size and polymorphic form when used as a reference standard.
Parent: Clofibric Acid
Parent: Clofibric Acid
Material supplied for analytical or research use is commonly specified with an assay of 98.0 percent or greater by HPLC. Typical specification limits are total related substances not more than 2.0 percent and each individual unspecified impurity not more than 0.5 percent. Common related compounds and impurities include residual ester forms such as clofibrate (isopropyl ester) and ethyl ester analogs, mono- and di-glucuronide conjugates, small amounts of 4-chlorophenol or 4-chlorophenoxyacetic fragments from hydrolysis or side reactions, and trace oxidative byproducts. Typical amounts observed in a quality certificate are: clofibrate and other ester residues combined 0.1 to 0.5 percent, 4-chlorophenol less than 0.05 percent, individual oxidative or dealkylated impurities below 0.2 percent, residual solvents below ICH Q3C limits (for example ethanol or isopropanol not more than 0.5 percent by weight), water below 0.5 percent, and heavy metals typically below 20 parts per million. Identification and quantification of these related substances are normally performed by HPLC with diode array detection and confirmed by LC-MS.
Clofibric acid itself is primarily used as a reference standard and as an analytical target in environmental monitoring because it is the major active metabolite of several fibrate drugs; it is not typically administered as a therapeutic agent.
Clofibrate was used as a lipid-lowering agent to reduce elevated triglycerides and to a lesser extent to lower low-density lipoprotein cholesterol; it was administered as the isopropyl ester prodrug which is metabolized to clofibric acid, the active moiety.
Clofibrate and related fibrates act mainly through activation of the peroxisome proliferator-activated receptor alpha, PPAR alpha, which modulates transcription of genes involved in fatty acid beta-oxidation, increases lipoprotein lipase activity, and decreases hepatic very low density lipoprotein production, leading to reduced plasma triglycerides and altered lipoprotein profiles.
Clofibrate use declined or was withdrawn in many markets because clinical outcome studies did not demonstrate clear cardiovascular benefit and because concerns emerged about adverse effects including gallstones, potential hepatic toxicity, and an increased incidence of certain cancers in long-term animal studies; risk benefit assessments favored newer agents with improved safety and efficacy profiles.
