クロフィブラート

3.3

3.39

OIL

COLORLESS TO PALE YELLOW LIQ

Insoluble

INSOL IN WATER; SOL IN ALC, CHLOROFORM

MISCIBLE WITH ACETONE, ETHER

2.90e-02 g/L

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

118-119

< 25 °C

Danger

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P354+P338, P317, P319, P321, P330, P332+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 42 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

COHEN AJ, GRASSO P; REVIEW OF THE HEPATIC RESPONSE TO HYPOLIPIDEMIC DRUGS IN RODENTS AND ASSESSMENT OF ITS TOXICOLOGICAL SIGNIFICANCE TO MAN; FOOD COSMET TOXICOL 19 (5): 585 (1981). A REVIEW OF THE HEPATIC RESPONSE TO HYPOLIPIDEMIC DRUGS, INCLUDING CLOFIBRATE, IN RODENTS & ASSESSMENT OF THEIR TOXICOLOGICAL SIGNIFICANCE TO MAN.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

ONE CASE REPORT HAS APPEARED DESCRIBING A PATIENT WITH TYPE-IV HYPERLIPOPROTEINEMIA CONTROLLED ON CLOFIBRATE THERAPY WHO DEVELOPED A RETURN OF ELEVATED SERUM CHOLESTEROL AND TRIGLYCERIDE AFTER TAKING AN ORAL CONTRACEPTIVE.

IT IS PROPOSED THAT FUROSEMIDE AND CLOFIBRATE MAY COMPETE FOR PLASMA ALBUMIN BINDING SITES.

Clofibrate also has been reported to increase the release of antidiuretic hormone from the posterior pituitary, block arginine-induced insulin and glucagon secretion by the pancreas, and lower fasting blood glucose concn and serum insulin concn in patients with diabetes mellitus. Clofibrate has variable effects on serum uric acid.

Clofibrate stimulates peroxisomal fatty acid oxidation, increases peroxide levels and thereby enhances ethanol oxidation by catalase. However, it would only be under such unusual circumstances that catalase would be expected to play a significant role in ethanol metabolism.

For more Interactions (Complete) data for CLOFIBRATE (15 total), please visit the HSDB record page.

Mild, transient serum aminotransferase elevations develop in a small proportion of patients receiving clofibrate, but values above 3 times normal occur in 2% or less. These abnormalities are usually asymptomatic and transient, resolving even with continuation of clofibrate. There have been rare reports of clinically apparent liver injury in patients on clofibrate. Onset of injury is usually after 2 to 3 months of treatment and the pattern of serum enzyme elevations can be either cholestatic or hepatocellular. Symptoms of immunoallergic hepatitis are rare as are autoantibodies. Chronic therapy with clofibrate has also been linked to an increased rate of gallstones, particularly among patients with chronic cholestatic liver disease (primary biliary cirrhosis).

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-‘± 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.

The clinical evidence for the efficacy of clofibrate in preventing deaths from coronary artery disease is not encouraging. A number of clinical trials have been completed, and none has shown a clear-cut beneficial effect. A double blind study ... compared clofibrate with placebo in 10,000 men in the upper third of the distribution of plasma cholesterol concentrations. Patients treated with clofibrate had a decrease in nonfatal myocardial infarctions. ... Clofibrate treated patients had a higher noncardiac mortality rate than did control subjects, owing mainly to an increased incidence of malignant neoplasms and complications of cholecystectomy.

The fibric acids are generally well tolerated. Mild gastrointestinal distress (abdominal pain, diarrhea, nausea) is the most frequent side effect and occurs in 2 to 5% of patients. Skin rash, alopecia, blurred vision, weight gain, impotence, leukopenia, and anemia have been reported occasionally. Atrial and ventricular arrhythmias have been noted only for clofibrate.

CLOFIBRATE IS USUALLY WELL TOLERATED, BUT OCCASIONALLY PATIENTS EXPERIENCE NAUSEA, DIARRHEA, OR WEIGHT GAIN (APPARENTLY RELATED TO INCREASED APPETITE). SKIN RASH, ALOPECIA, WEAKNESS, IMPOTENCE, BREAST TENDERNESS, AND DECREASED LIBIDO ALSO HAVE BEEN REPORTED ... A MORE DISTURBING EFFECT IS A NOW-WELL CHARACTERIZED FLULIKE SYNDROME, ASSOCIATED WITH SEVERE MUSCLE CRAMPS AND TENDERNESS, STIFFNESS, AND WEAKNESS. THE SYNDROME RECURS WHENEVER THE DRUG IS TAKEN AND IS ASSOCIATED WITH ELEVATED ACTIVITIES OF CREATINE PHOSPHOKINASE AND GLUTAMIC-OXALACETIC TRANSAMINASE IN THE PLASMA. ADMIN OF CLOFIBRATE ALSO INCREASES THE LITHOGENICITY OF BILE AND HAS THUS BEEN ASSOCIATED WITH A HIGH INCIDENCE OF CHOLELITHIASIS AND CHOLECYSTITIS.

CLOFIBRATE...HAS BEEN GIVEN TO A NUMBER OF GLAUCOMATOUS PATIENTS & HAS SHOWN NO TENDENCY TO RAISE OCULAR PRESSURE. NO SIGNIFICANT OCULAR TOXIC EFFECTS... OBSERVED...IN INSTANCE OF OVERDOSAGE IN ATTEMPTED SUICIDE.

For more Human Toxicity Excerpts (Complete) data for CLOFIBRATE (15 total), please visit the HSDB record page.

Clofibrate

Group 3: Not classifiable as to its carcinogenicity to humans

Volume Sup 7: Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42, 1987; 440 pages; ISBN 92-832-1411-0 (out of print)

1996

1996

3, not classifiable as to its carcinogenicity to humans. (L135)

Drug Induced Liver Injury Rank (DILIrank 2.0)

Clofibrate

vLess-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

RATS GIVEN FOOD CONTAINING 1% CLOFIBRATE OR SC INJECTIONS OF 0.3-0.9 G/KG DAILY FOR 2 DAYS SHOWED SPONTANEOUS ELECTROMYOGRAPHIC RESPONSES IN HIND LIMBS.

...15 MALE FISCHER 344 RATS, WEIGHING 84-100 G, WERE FED CLOFIBRATE...AT DIETARY CONCN OF...[ABOUT 250 MG/KG BODY WEIGHT/DAY] IN GROUND RAT CHOW FOR UP TO 28 MONTHS. ... ONE OR MORE HEPATOCELLULAR CARCINOMAS DEVELOPED IN 10/11 RATS, COMPARED WITH 0/14 CONTROLS...5 OF THE ANIMALS...SHOWED METASTASIS. IN ADDITION, PANCREATIC EXOCRINE ACINAR CARCINOMAS WERE FOUND IN 2/11 RATS, A DERMATOFIBROSARCOMA IN 1 RAT AND A LEIOMYOMA OF THE INTESTINE IN 1 RAT IN THE CLOFIBRATE-FED GROUP. NO SUCH TUMORS WERE SEEN IN CONTROLS.

CLOFIBRATE...WAS FED...TO 25 MALE FISCHER 344 RATS, WEIGHING APPROX 100 G, FOR 97 WEEKS, TO GIVE A TOTAL INTAKE OF 25-33 G CLOFIBRATE/RAT. THE STUDY WAS TERMINATED AT 129 WEEKS... AMONG THE TREATED RATS, 10 DEVELOPED MALIGNANT TUMORS AT VARIOUS SITES.../INCLUDING/ AN ADENOCARCINOMA OF THE STOMACH IN 1 RAT; A RENAL-CELL CARCINOMA IN 1 RAT; A PAPILLARY CARCINOMA OF URINARY BLADDER IN 1 RAT; A SARCOMA OF THE URINARY BLADDER IN 1 RAT; A SARCOMA OF THE PAROTID IN 1 RAT; SARCOMAS OF THE LUNG IN 2 RATS; AND A LYMPHOSARCOMA INVOLVING THE PANCREAS IN 1 RAT. NONE OF THE TUMORS WERE ENCOUNTERED IN THE 25 CONTROL RATS.

CLOFIBRATE.../HAS INDUCED/ RELATIVE ENLARGEMENT OF THE LIVER IN PROPORTION TO THE BODY OF NEWBORN RATS...AS WELL AS AN ABNORMAL POSTNATAL FETAL THROMBOSIS SYNDROME. THE POSTNATAL THROMBOSIS CONSISTED OF AN EXTENSION OF THE NORMAL THROMBOSIS IN THE UMBILICAL ARTERIES, AND THIS CAUSED NECROSIS OF THE TAIL OR PARTS OF THE HINDLIMBS.

For more Non-Human Toxicity Excerpts (Complete) data for CLOFIBRATE (11 total), please visit the HSDB record page.

There is inadequate evidence in humans for the carcinogenicity of clofibrate. There is limited evidence in experimental animals for the carcinogenicity of clofibrate. OVERALL EVALUATION: Clofibrate is not classifiable as to its carcinogenicity in humans (Group 3).

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

C - Cardiovascular system

QC - Cardiovascular system

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.

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.

Clofibrate decreases serum very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) concn in healthy individuals and abnormal lipoproteins in patients with type III hyperlipoproteinemia. Serum triglyceride concn are usually reduced more than cholesterol concn.

The exact mechanism by which clofibrate lowers serum concn of triglycerides and cholesterol is unknown. Apparently, the drug has several antilipemic actions, including increasing triglyceride and VLDL clearance, inhibition of the biosynthesis of cholesterol before mevalonate formation, mobilization of cholesterol from tissues, increasing fecal excretion of neutral sterols, decreasing hepatic lipoprotein synthesis and/or secretion (particularly VLDL), decreasing free fatty acid release, and decreasing triglyceride synthesis.

Clofibrate induces changes in blood coagulation which are independent of the lipid-lowering action of the drug. The drug decreases platelet adhesiveness. Plasma fibrinogen concn decrease during the first 6 wk to 4 mo of therapy after which the concn return toward normal. Plasma fibrinolysis is usually increased.

Their primary effect is to increase the activity of lipoprotein lipase, which in turn promotes the catabolism of the triglyceride rich lipoproteins, VLDL and IDL. The drugs may also decrease the hepatic synthesis and secretion of VLDL. Fibric acids are believed to raise HDL cholesterol indirectly as a result of the decrease in the concentration of VLDL triglyceride. VLDL normally exchanges lipids with HDL, the triglycerides of VLDL moving to HDL and the cholesteryl esters of HDL moving to VLDL. When VLDL concentrations are reduced, this exchange is slowed. Cholesteryl esters remain in HDL and thus the concentration of HDL cholesterol increases. /Fibric Acids/

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.

THE PLASMA ELIMINATION HALF-LIFE OF CLOFIBRIC ACID RANGES BETWEEN 12-25 HOURS.

Clofibric acid has an elimination half-life of 12-35 hr (mean 12-22 hr) in healthy adults and 29-88 hr in patients with renal failure. /Clofibric acid/

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]).

IN MAN, CLOFIBRATE ... APPEARS IN PLASMA AS DEESTERIFIED PARA-CHLOROPHENOXYISOBUTYRIC ACID ... ESSENTIALLY ALL ACID ... EXCRETED IN URINE, ABOUT 60% AS GLUCURONIDE.

AN ACYL-LINKED ACID METABOLITE OF CLOFIBRATE HAS BEEN IDENTIFIED IN HUMAN URINE. THIS REPRESENTS THE FIRST ACYL-LINKED MERCAPTURATE FOUND IN MAN. AUTHORS PROPOSE THAT CLOFIBRATE ACYL GLUCURONIDE IS AN ELECTROPHILIC METABOLITE WHICH REACTS WITH SULFHYDRYL GROUPS & THEREFORE MAY BE RESPONSIBLE FOR THE HUMAN HEPATOTOXICITY OF CLOFIBRATE.

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]). 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.

Substances used to lower plasma CHOLESTEROL levels.

Substances that lower the levels of certain LIPIDS in the BLOOD. They are used to treat HYPERLIPIDEMIAS.

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.

IN MAN, CLOFIBRATE IS COMPLETELY ABSORBED FROM INTESTINE & APPEARS IN PLASMA AS DEESTERIFIED P-CHLOROPHENOXYISOBUTYRIC ACID (CPIB); PEAK PLASMA CONCN OF THE ACID OCCUR WITHIN 4 HR AFTER ORAL ADMIN ... MAJOR FRACTION OF CPIB ... BOUND TO PLASMA ALBUMIN. ELIMINATION OF CPIB PROCEEDS IN 2 KINETIC PHASES, WITH SLOWER EXPONENTIAL PHASE HAVING MEAN HALF-LIFE OF NEARLY 15 HR. ESSENTIALLY ALL ACID ... EXCRETED IN URINE, ABOUT 60% AS GLUCURONIDE.

TRANSFER ACROSS THE PLACENTA AND INTO THE MILK AND A POSTNATAL INCREASE IN LIVER ALPHA-GLYCEROPHOSPHATE DEHYDROGENASE HAS BEEN REPORTED IN NEWBORN RATS WHOSE MOTHERS WERE FED CLOFIBRATE.

CLOFIBRATE IS RAPIDLY AND COMPLETELY ABSORBED AFTER ORAL ADMINISTRATION. IN MAN, CLOFIBRIC ACID, A MAJOR METABOLITE OF CLOFIBRATE, IS EXCRETED IN THE URINE IN THE FORM OF THE GLUCURONIDE CONJUGATE; THE PLASMA ELIMINATION HALF-LIFE OF CLOFIBRIC ACID RANGES BETWEEN 12-25 HOURS.

Clofibrate is readily and reportedly almost completely absorbed from the GI tract; approx 95-99% of an orally admin dose ... is excreted in urine as free and conjugated clofibric acid. The drug is rapidly hydrolyzed by serum enzymes to the free acid, clofibric acid ... . Peak plasma clofibric acid concn 4-6 hr after oral admin of a single 500-mg, 1-g, or 2-g doses of clofibrate in healthy individuals average 49-53, 89, or 151 ug/ml, respectively.

For more Absorption, Distribution and Excretion (Complete) data for CLOFIBRATE (7 total), please visit the HSDB record page.

AGENT TO LOWER PLASMA VERY-LOW-DENSITY-LIPOPROTEIN CONCN; AGENT TO LOWER CONCN OF PLASMA TRIGLYCERIDES

MEDICATION

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

(1972) PROBABLY LESS THAN 4.54X10+5 GRAMS

(1975) PROBABLY LESS THAN 4.54X10+5 GRAMS

CONDENSATION OF PHENOL WITH ETHYL 2-CHLORO-2-METHYLPROPIONATE IN PRESENCE OF A DEHYDROCHLORINATING AGENT, FOLLOWED BY CHLORINATION AND PURIFICATION

Synthesized by the condensation of p-chlorophenol with acetone and chloroform and the resultant acid is esterified to give clofibrate.

CLOFIBRATE IS AVAILABLE IN THE US AS A USP GRADE CONTAINING 97.0-103.0% ACTIVE INGREDIENT CALCULATED ON THE ANHYDROUS BASIS; IT SHOULD NOT CONTAIN MORE THAN 0.2% WATER OR MORE THAN 0.003% PARA-CHLOROPHENOL.

DOSAGE FORM- CAPSULES: 500 MG.

THERE ARE ABOUT 10 PRODUCERS OF CLOFIBRATE IN WESTERN EUROPE, WITH AN ANNUAL PRODUCTION OF 50,000-100,000 KG.

FOLLOWING THE REPORT OF A WHO-SPONSORED COOPERATIVE STUDY OF THE USE OF CLOFIBRATE IN THE PRIMARY PREVENTION OF ISCHEMIC HEART DISEASE, IT WAS WITHDRAWN IN THE FEDERAL REPUBLIC OF GERMANY AND IN NORWAY... IN...OTHER COUNTRIES, INCLUDING FRANCE, ITALY, SWEDEN, SWITZERLAND, THE UK AND THE US (WHERE THE DRUG IS AVAILABLE ONLY ON PRESCRIPTION), PRACTITIONERS HAVE BEEN ADVISED TO RESERVE ITS USE FOR PATIENTS WITH HIGH PLASMA LIPID CONCENTRATIONS THAT ARE REFRACTORY TO DIETARY MEASURES AND TO CONSIDER CAREFULLY THE RISKS AND BENEFITS OF THE TREATMENT.