Basic information Safety Supplier Related
ChemicalBook >  Product Catalog >  API >  Circulatory system drugs >  Lipid regulating drugs >  Clofibrate


Basic information Safety Supplier Related

Clofibrate Basic information

Product Name:
  • Androtor
  • 2-(4-Chlorophenoxy)isobutyric Acid Ethyl Ester Ethyl 2-(4-Chlorophenoxy)isobutyrate
  • 2-(4-Chlorophenoxy)-2-methylpropionic acid ethyl ester, Ethyl 2-(4-chlorophenoxy)-2-methylpropionate, Ethyl 2-(4-chlorophenoxy)isobutyrate
  • 2-(P-chlorophenoxy)-2-methylpropionic*acid ethyl
  • Phenoxyisobutyricacidethylester
  • Fibrate
  • Clofibrate 0.1
  • Anti-PPFIA1 (N-terminal) antibody produced in rabbit
Product Categories:
  • Intracellular receptor
  • Aromatics Compounds
  • Aromatics
  • Intermediates & Fine Chemicals
  • Pharmaceuticals
Mol File:

Clofibrate Chemical Properties

Melting point:
<25 °C
Boiling point:
154 °C
1.14 g/mL at 25 °C(lit.)
refractive index 
n20/D 1.503
Flash point:
113 °C
storage temp. 
Soluble to 100 mM in DMSO.
clear, colorless
Water Solubility 
97.08mg/L(room temperature)
CAS DataBase Reference
637-07-0(CAS DataBase Reference)
3 (Vol. Sup 7, 66) 1996
NIST Chemistry Reference
EPA Substance Registry System
Clofibrate (637-07-0)

Safety Information

Hazard Codes 
Risk Statements 
Safety Statements 
UN 3082 9/PG 3
WGK Germany 
HS Code 
Hazardous Substances Data
637-07-0(Hazardous Substances Data)
LD50 in mice, rats (g/kg): 1.28, 1.65 orally (Metz)



Clofibrate Usage And Synthesis


Researchers in France observed in 1953 that structures derived from dehydrocholic acid, phenylethyl acetic acid, and certain other disubstituted acetic acids exhibited hypocholesterolemic properties in rats and humans. Several years later, Thorp and Waring discovered clof ibrate as an effective compound for lowering lipids in animal models, with minimal toxicity. Its mode of action was initially attributed to seasonal variations in adrenal and thyroid function, and the administration of androsterone was found to potentiate the hypocholesterolemic effect of this compound. Subsequently, several clinical trials were performed which showed that clofibrate decreases lipid levels in hypercholesterolemic patients, mainly as the result of a reduction in the very-low-density lipoprotein (VLDL), and less in the low-density lipoprotein (LDL) fraction, and that the coadministration of androsterone was not necessary for its hypolipidemic effect. Despite reported hepatomegaly in rats following long-term treatment with clofibrate, this drug was approved in the United States in 1967 for the treatment of hyperlipidemias.
Clofibrate can be chemically synthesized by the condensation of phenol with ethyl 2-chloro-2-methylpropionate in the presence of a dehydrochlorinating agent, followed by chlorination and purification. It can also be synthesized by the condensation of p-chlorophenol with acetone and chloroform followed by esterifying the resultant acid to give clofibrate.


Clofibrate is a selective agonist of peroxisome proliferator-activated receptor α (PPARα). In a transactivation assay, clofibrate exhibits EC50 values of 50 and 55 μM for murine and human PPARα, respectively. It also binds to PPARγ but with 10-fold less affinity and is inactive at PPARδ at concentrations up to 100 μM. Formulations containing clofibrate have been used to treat dyslipidemia and cardiovascular disease.

Chemical Properties

Clear Colorless Oil








inhibits cholesterol biosynthesis


Clofibrate is a lipid-lowering agent (antilipidemic) used for controlling high cholesterol (anticholesteremic) and triacylglyceride levels in the blood. It increases lipoprotein lipase activity to promote the conversion of VLDL to LDL, thereby reducing VLDL levels. It is indicated only in subjects with increased concentrations of VLDL and intermediate-density lipoproteins (IDL) who have failed to respond adequately to gemfibrozil or nicotinic acid. Clofibrate is of limited utility for patients with either familial hypercholesterolemia or polygenic hypercholesterolemia, as comparatively more effective drugs are available for lowering the concentration of LDL in these patients.
Clofibrate has no effect on hyperchylomicronemia, nor does it affect concentrations of high-density lipoproteins (HDL). Thus, clofibrate appears to have specific efficacy only in patients with familial type-III hyperlipoproteinemia. There is no substantial evidence proving efficacy of clofibrate in preventing deaths from coronary artery disease. Clofibrate has been used to prevent or control polydipsia, polyuria, and dehydration in a limited number of patients with mild to moderate neurohypophyseal diabetes insipidus. A 5-year multicenter study reported failure of clofibrate in reducing or preventing mortality in cardiovascular disorders, which has provided a setback for the prophylactic use of this drug.


ChEBI: The ethyl ester of clofibric acid.

Manufacturing Process

The ethyl p-chlorophenoxyisobutyrate may be obtained by heating a mixture of 206 parts of dry p-chlorophenoxyisobutyric acid, 1,000 parts of ethanol and 40 parts of concentrated sulfuric acid under reflux during 5 hours. The alcohol is then distilled off and the residue is diluted with water and extracted with chloroform. The chloroform extract is washed with sodium hydrogen carbonate solution, dried over sodium sulfate and the chloroform removed by distillation. The residue is distilled under reduced pressure and there is obtained ethyl pchlorophenoxyisobutyrate, BP 148° to 150°C/20 mm.
The p-chlorophenoxyisobutyric acid used as starting material may be obtained as follows. A mixture of 200 parts of p-chlorophenol, 1,000 parts of acetone and 360 parts of sodium hydroxide pellets is heated under reflux and 240 parts of chloroform are gradually added at such a rate that the mixture continues to reflux without further application of heat.
When addition is complete the mixture is heated under reflux during 5 hours and then the acetone is removed by distillation. The residue is dissolved in water, acidified with hydrochloric acid and the mixture extracted with chloroform. The chloroform extract is stirred with sodium hydrogen carbonate solution and the aqueous layer is separated. The alkaline extract is acidified with hydrochloric acid and filtered. The solid product is drained free from oil on a filter pump, then washed with petroleum ether (BP 40° to 60°C), and dried at 50°C. The solid residue, MP 114° to 116°C, may be crystallized from methanol (with the addition of charcoal) to give p-chlorophenoxyisobutyric acid, MP 118° to 119°C.

brand name

Atromid (Wyeth);Aatroayerst;Aitiflus;Angiocapsul;Arterioflexion;Artriosan;Asa/cpib;Aterioplexin;Ateroayrest;Ateroclar;Aterofront;Ateronlen;Aterosol;Atevil;Atheroayerst;Atrofort;Atrolan;Atromid-s;Atrom-s;Ay 61;Biocleran;Clareden;Cloberab;Clobrate;Clobren-5 f;Clofenit;Clofibral;Clofibrate ayerst;Clofibrate compose;Clofibrato ayerst;Clofibrato procaps;Clofibrem;Clofimide;Clofin-icn;Clofipront 5000;Clofirem;Clofirin;Clofi-t;Clopin;Col 180;Contra-lipide;Corafen;Cr/085;Dabical;Dilectus;Doctus;Duplinal;Duraclofibrate;Ellemger;Eramid;Fibramid;Fibrolynt;Geri-70;Geromid;Healthclass;Ici 28257nt;Ipolipid;Kontalipide;Levatram;Liapten;Liparil;Lipaten;Lipavlon 500;Lipicidon;Lipidicon;Liporan;Liptrinal;Lostat;Neoatromid;Nibratal;Nibratol;Nnormet;Nobret;Norinolipol;Normet richter;Nosterolin;Novofibrate;Omelip;Provasa;Recade;Regelan n 500;Sclerovasal;Serolipid;Sinteroid;Sklerocip;Sklerolip;Sklerovasal;Supraoxid;Tepincal;Tepingal;Vimedel;Vocaline.

Therapeutic Function


World Health Organization (WHO)

Clofibrate, an antihyperlipidaemic agent, was introduced in 1967 and was subsequently extensively studied in the primary and secondary prevention of ischaemic heart disease. Following reports, published in 1978, of increased mortality among patients receiving clofibrate in a WHO-sponsored cooperative trial concerned with the primary prevention of ischaemic heart disease, the drug was withdrawn in some countries and its approved indications were severely restricted in many others. These restrictions have become the norm for more recently developed analogues of clofibrate. (Reference: (WHODI) WHO Drug Information, 2, 6, 1979)

General Description

Clofibrate, ethyl 2-(p-chlorophenoxy)-2-methylpropionate (Atromid-S), is a stable, colorless topale yellow liquid with a faint odor and a characteristictaste. It is soluble in organic solvents but insoluble in water.
Clofibrate is prepared by a Williamson synthesis, condensingp-chlorophenol with ethyl -bromoisobutyrate, or bythe interaction of a mixture of acetone, p-chlorophenol, andchloroform in the presence of excess potassium hydroxide.The acid obtained by either of these methods is esterified togive clofibrate. Both acid and ester are active; the latter, however,is preferred for medicinal use. Clofibrate is hydrolyzedrapidly to 2-p-chlorophenoxy-2-methylpropionic acid by esterasesin vivo and, bound to serum albumin, circulates inblood. The acid has been investigated as a hypolipidemicagent. It is absorbed more slowly and to a smaller extent thanis the ester. The aluminum salt of the acid gives even lowerblood levels than p-chlorophenoxy-2-methylpropionic acid.


Questionable carcinogen; toxic; causes nausea, vomiting, diarrhea, weakness, stiffness, cramps, and muscle tenderness.

Biological Activity

PPAR agonist (EC 50 values are 50, 500 and > 100 μ M at PPAR α , PPAR γ and PPAR δ respectively). Antihyperlipoproteinemic.

Mechanism of action

The three structurally related fibrates available in the United States are gemfibrozil (Lopid), fenofibrate (Tricor) and clofibrate (Atromid-S).They share common uses and toxicities. The fibrates typically lower VLDL triglyceride by 40% or more and elevate plasma HDL cholesterol by 10 to 15%. The reduction of plasma triglycerides in humans appears due to increased lipoprotein lipase (LPL) activity. The fibrates activate a nuclear receptor (transcription factor) termed peroxisomal proliferation activated receptor (PPAR) that is a member of the steroid hormone receptor superfamily. PPAR increases transcription of the LPL gene and decreases transcription of the apolipoprotein CIII gene (apo CIII). Since LPL is responsible for catabolism of VLDL triglyceride and apo CIII is an inhibitor of LPL activity, the combined consequences of these changes are increased LPL activity and enhanced removal of triglyceride from the circulation.
The elevation of HDL levels by fibrates may be due to two drug actions: induced synthesis of apo-A1, the principal apoprotein of HDL, and increased assembly of new HDL particles in the circulation. Surface components of VLDL contribute to formation of HDL, as the VLDL particles are reduced in size through the action of LPL.The increased rate of catabolism of VLDL caused by the fibrates would provide more components for assembly of HDL particles.


The pro-drug, fenofibrate, requires a longer time to reach peak concentrations compared with gemfibrozil. Because of differences in aromatic substitution, fenofibrate also has a much longer half-life than gemfibrozil. As previously mentioned, the 2,5-dimethyl substitution in gemfibrozil is much more susceptible to oxidative metabolism than the para-chloro group present in fenofibrate. Similar to HMGRIs, changes in lipid levels are not seen immediately, and up to 2 months may be required to reach maximal clinical effects and to determine the overall clinical efficacy.
Fibrates have excellent bioavailability and are extensively bound to plasma proteins. Because food can significantly enhance their oral absorption, these compounds should be taken either with or just before meals. Fenofibrate was available in Europe and elsewhere as standard tablet and capsule formulations for many years before its approval and marketing in the United States, where it was introduced only after the development of a micronized formulation that allowed better oral absorption, a lower daily dose, and once-daily administration. A 67-mg dose of micronized fenofibrate is bioequivalent to a 100-mg dose of nonmicronized drug. Since that time, two additional tablet formulations have been developed. Abbott Laboratories currently markets TriCor as 48- and 145-mg tablets. The 48-mg formulation is equivalent to previous 54- and 67-mg formulations, and the 145-mg tablet is equivalent to previous 160- and 200-mg formulations. As noted in Table 30.10, fenofibrate is currently available in all of these strengths.
Renal elimination is the primary route through which these compounds are excreted from the body. Patients with mild renal dysfunction often can be managed with minor dosage adjustments, whereas those with severe impairment or renal failure may have to discontinue its use.

Clinical Use

Clofibrate is the drug of choice in the treatment of typeIII hyperlipoproteinemias and may also be useful, to a lesserextent, in types IIb and IV hyperlipoproteinemias. The drugis not effective in types I and IIa.
Clofibrate can lower plasma concentrations of both triglyceridesand cholesterol, but it has a more consistent clinicaleffect on triglycerides. It also affects lipoprotein plasmalevels by enhancing removal of triglycerides from the circulationand causes reduction of VLDL by stimulatinglipoprotein lipase to increase the catabolism of this lipoproteinto LDL. Clofibrate lowers triglyceride levels in theserum much more than cholesterol levels and decreases levelsof FFAs and phospholipids. The lowering of cholesterollevels may result from more than one mechanism. Clofibrateinhibits the incorporation of acetate into the synthesis ofcholesterol, between the acetate and mevalonate step, by inhibitingsn-glyceryl-3-phosphate acyltransferase. Clofibratealso regulates cholesterol synthesis in the liver by inhibitingmicrosomal reduction of 3-hydroxy-3-methylglutaryl-CoA(HMG-CoA), catalyzed by HMG-CoA reductase. Clofibratemay lower plasma lipids by means other than impairment ofcholesterol biosynthesis, such as increasing excretionthrough the biliary tract.

Side effects

The fibrates are generally well tolerated, with GI distress being the most likely complaint. Other adverse effects include myositis and erectile dysfunction, particularly with clofibrate. There is ongoing concern about the fibrates increasing the risk of gallstones, although the extent of risk is unclear. Because clofibrate was associated with increased mortality in early clinical trials, it should be considered as a second-line drug.

Safety Profile

Poison by intravenous route.Moderately toxic by ingestion and other routes. Anexperimental teratogen. Other experimental reproductiveeffects. Reduces plasma lipid levels. Human systemiceffects by ingestion: muscle weakness, muscle spasms, andfever. Q

Chemical Synthesis

Clofibrate, ethyl ether 2-(4-chloropheoxy)-iso-butyric acid (20.2.2), is synthesized by esterifying 2-(4-chlorophenoxy)-iso-butyric acid (20.2.1) with ethyl alcohol. This is synthesized in a single-stage reaction from 4-chlorophenol, acetone, and chloroform in the presence of an alkali, evidently by initial formation of chlorethone-trichloro-tert-butyl alcohol, which under the reaction conditions is converted into (4-chlorophenoxy)trichlorotert- butyl ether, and further hydrolyzed to the desired acid 20.2.1, which is further esterified with ethanol in the presence of inorganic acid.

Drug interactions

The fibrates potentiate the actions of the coumarin anticoagulants, such as warfarin, so care should be taken to reduce the dose of simultaneously administered anticoagulants, and plasma prothrombin should be frequently measured until the level stabilizes. As mentioned earlier, great care should be given to combining a statin with a fibrate, since this combination may increase the risk of myositis and perhaps rhabdomyolysis.

Environmental Fate

Clofibrate characteristically reduces plasma triglycerides by lowering the concentration of VLDL within 2–5 days after initiation of therapy. In a majority of patients, total cholesterol and LDL concentrations in plasma fall slightly. However, some patients who exhibit a large fall in VLDL may show a paradoxical rise in LDL, resulting in minimal net effect on total cholesterol levels.
The drug has several proposed antilipidemic actions, including increased triglyceride and VLDL clearance, mobilization of cholesterol from tissues, increased fecal excretion of neutral sterols, decreased hepatic lipoprotein synthesis and/or secretion, decreased free fatty acid release, and decreased triglyceride synthesis. The precise mechanisms by which clofibrate lowers serum concentrations of triglycerides and cholesterol are not known.


The pro-drug fenofibrate undergoes rapid hydrolysis to produce fenofibric acid. This active metabolite can then be further metabolized by oxidative or conjugative pathways. Gemfibrozil is slightly different in that it does not require initial bioactivation; however, similar to fenofibric acid, it can be oxidized or conjugated. Oxidation of the aromatic methyl groups produces inactive hydroxymethyl and carboxylic acid analogues. As a drug class, fibrates and their oxidized analogues are primarily excreted as glucuronide conjugates in the urine. Oxidization requires the CYP3A4 isozyme; however, because of the ability of these compounds to be conjugated and eliminated either with or without oxidation, drug interactions with other compounds affecting the CYP3A4 system are less important here than with other drug classes.

Toxicity evaluation

Clofibrate is a clear, colorless liquid with a density of 1.14 g ml-1 (at 25°C). The boiling point of clofibrate is 148–150°C at 25mmHg. This drug is a stable, colorless to pale-yellow liquid with a faint odor and characteristic taste. Its melting point is below 25°C, it is soluble in common solvents but not in water, and its solubility or log P (octanol/water) is 3.620.

Clofibrate Preparation Products And Raw materials

Raw materials


010-82848833- ;010-82848833-
Meryer (Shanghai) Chemical Technology Co., Ltd.
3B Pharmachem (Wuhan) International Co.,Ltd.
TCI (Shanghai) Development Co., Ltd.
021-67121386 / 800-988-0390
Energy Chemical