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Identification
Name Clofibrate
Accession Number DB00636 (APRD00879)
Type small molecule
Groups approved
Description

A fibric acid derivative used in the treatment of hyperlipoproteinemia type III and severe hypertriglyceridemia. (From Martindale, The Extra Pharmacopoeia, 30th ed, p986)
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Chlorfenisate
  • Chlorphenisate
  • Clofibate
  • Clofibrato
  • Clofibratum
  • CPIB
  • EPIB
  • Ethyl chlorophenoxyisobutyrate
  • Ethyl clofibrate
  • Ethyl p-chlorophenoxyisobutyrate
  • Ethyl para-chlorophenoxyisobutyrate
Brand names
  • Amotril
  • Amotril S
  • Angiokapsul
  • Anparton
  • Antilipid
  • Antilipide
  • Apolan
  • Arterioflexin
  • Arterosol
  • Artes
  • Artevil
  • Ateculon
  • Ateriosan
  • Athebrate
  • Atheromide
  • Atheropront
  • Athranid-Wirkstoff
  • Atrolen
  • Atromid
  • Atromid S
  • Atromid-S
  • Atromida
  • Atromidin
  • Atrovis
  • Azionyl
  • Bioscleran
  • Bresit
  • Cartagyl
  • Citiflus
  • Claripex
  • Claripex CPIB
  • Cloberat
  • Clobrat
  • Clobren-5F
  • Clobren-SF
  • Clofar
  • Clofibram
  • Clofibrat
  • Clofinit
  • Clofipront
  • Delipid
  • Deliva
  • Dura clofibrat
  • ELPI
  • Fibralem
  • Gerastop
  • Hyclorate
  • Klofibrat
  • Klofiran
  • Levatrom
  • Lipamid
  • Lipavil
  • Lipavlon
  • Lipide 500
  • Lipidsenker
  • Lipofacton
  • Lipomid
  • Liponorm
  • Liporeduct
  • Liporil
  • Liposid
  • Liprin
  • Liprinal
  • Lobetrin
  • Miscleron
  • Negalip
  • neo-Atomid
  • Neo-Atromid
  • Normalip
  • Normat
  • Normolipol
  • Novofibrate
  • Oxan 600
  • Persantinat
  • Regardin
  • Regelan
  • Regelan N
  • Robigram
  • Scrobin
  • Serofinex
  • Serotinex
  • Skerolip
  • Sklerepmexe
  • Sklero
  • Sklero-Tablinen
  • Sklero-tablinene
  • Sklero-tabuls
  • Sklerolip
  • Skleromex
  • Skleromexe
  • Tetrasipton
  • Thillate
  • Thiosan
  • Ticlobran
  • Vincamin compositum
  • Xyduril
  • Yoclo
Brand name mixtures Not Available
Categories
  • Anticholesteremic Agents
  • Antilipemic Agents
CAS number 637-07-0
Weight Average: 242.699
Monoisotopic: 242.070972053
Chemical Formula C12H15ClO3
InChI Key InChIKey=KNHUKKLJHYUCFP-UHFFFAOYSA-N
InChI
InChI=1S/C12H15ClO3/c1-4-15-11(14)12(2,3)16-10-7-5-9(13)6-8-10/h5-8H,4H2,1-3H3
Plain Text
IUPAC Name
ethyl 2-(4-chlorophenoxy)-2-methylpropanoate
SMILES
CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1
Plain Text
Mass Spec show (7.8 KB)
Taxonomy
Kingdom Organic
Classes
  • Phenoxyacetates
Substructures
  • Carboxylic Acids and Derivatives
  • Acetates
  • Phenols and Derivatives
  • Phenoxyacetates
  • Short-chain Hydroxy Acids
  • Ethers
  • Benzene and Derivatives
  • Aryl Halides
  • Halobenzenes
  • Aromatic compounds
  • Anisoles
  • Phenyl Esters
Pharmacology
Indication For Primary Dysbetalipoproteinemia (Type III hyperlipidemia) that does not respond adequately to diet. This helps control high cholesterol and high triglyceride levels.
Pharmacodynamics Clofibrate is an antilipidemic agent similar to gemfibrozil. It acts to lower elevated serum lipids by reducing the very low-density lipoprotein fraction (Sf 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.
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.
Volume of distribution Not Available
Protein binding Highly protein-bound (95% to 97%).
Metabolism

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]).
Route of elimination Not Available
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.
Clearance Not Available
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.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Wyeth ayerst laboratories
  • Banner pharmacaps inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Usl pharma inc
  • Watson laboratories inc
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Prices Not Available
Patents Not Available
Properties
State liquid
Melting point < 25 oC (boiling point 148-150°C at 25 mm Hg)
Experimental Properties
Property Value Source
water solubility Insoluble PhysProp
logP 3.3 PhysProp
Predicted Properties
Property Value Source
water solubility 2.90e-02 g/l ALOGPS
logP 3.99 ALOGPS
logP 3.40 ChemAxon Molconvert
logS -3.92 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 0 ChemAxon Molconvert
polar surface area 35.53 ChemAxon Molconvert
rotatable bond count 5 ChemAxon Molconvert
refractivity 62.14 ChemAxon Molconvert
polarizability 24.70 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00279 Link_out
KEGG Compound C06916 Link_out
PubChem Compound 2796 Link_out
PubChem Substance 46504748 Link_out
ChemSpider 2694 Link_out
ChEBI 3750 Link_out
ChEMBL 3750 Link_out
Therapeutic Targets Database DAP000262 Link_out
PharmGKB PA449045 Link_out
Drug Product Database 2038 Link_out
RxList http://www.rxlist.com/cgi/generic2/clofibrate.htm Link_out
Drugs.com http://www.drugs.com/mtm/clofibrate.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Clofibrate Link_out
ATC Codes
  • C10AB01
  • C10AB03
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS show (62.6 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Take with food, since it may reduce gastric irritation.
Targets

1. Peroxisome proliferator-activated receptor alpha

Pharmacological action: yes
Actions: agonist

Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids

Organism class: human
UniProt ID: Q07869 Link_out
Gene: PPARA Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Barclay TB, Peters JM, Sewer MB, Ferrari L, Gonzalez FJ, Morgan ET: Modulation of cytochrome P-450 gene expression in endotoxemic mice is tissue specific and peroxisome proliferator-activated receptor-alpha dependent. J Pharmacol Exp Ther. 1999 Sep;290(3):1250-7. Pubmed
  2. Murata M, Kaji H, Takahashi Y, Iida K, Mizuno I, Okimura Y, Abe H, Chihara K: Stimulation by eicosapentaenoic acids of leptin mRNA expression and its secretion in mouse 3T3-L1 adipocytes in vitro. Biochem Biophys Res Commun. 2000 Apr 13;270(2):343-8. Pubmed
  3. Hunt MC, Lindquist PJ, Peters JM, Gonzalez FJ, Diczfalusy U, Alexson SE: Involvement of the peroxisome proliferator-activated receptor alpha in regulating long-chain acyl-CoA thioesterases. J Lipid Res. 2000 May;41(5):814-23. Pubmed
  4. Casas F, Domenjoud L, Rochard P, Hatier R, Rodier A, Daury L, Bianchi A, Kremarik-Bouillaud P, Becuwe P, Keller J, Schohn H, Wrutniak-Cabello C, Cabello G, Dauca M: A 45 kDa protein related to PPARgamma2, induced by peroxisome proliferators, is located in the mitochondrial matrix. FEBS Lett. 2000 Jul 28;478(1-2):4-8. Pubmed
  5. Komuves LG, Hanley K, Lefebvre AM, Man MQ, Ng DC, Bikle DD, Williams ML, Elias PM, Auwerx J, Feingold KR: Stimulation of PPARalpha promotes epidermal keratinocyte differentiation in vivo. J Invest Dermatol. 2000 Sep;115(3):353-60. Pubmed
  6. Gelosa P, Banfi C, Gianella A, Brioschi M, Pignieri A, Nobili E, Castiglioni L, Cimino M, Tremoli E, Sironi L: PPAR-alpha agonism prevents the oxidative stress and inflammatory processes involved in brain and renal damage in stroke-prone rats. J Pharmacol Exp Ther. 2010 Jul 29. Pubmed
  7. Palkar PS, Anderson CR, Ferry CH, Gonzalez FJ, Peters JM: Effect of prenatal peroxisome proliferator-activated receptor alpha (PPARalpha) agonism on postnatal development. Toxicology. 2010 Jul 15. Pubmed
Enzymes

1. Cytochrome P450 2E1

Actions: inducer

Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms

UniProt ID: P05181 Link_out
Gene: CYP2E1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Glutathione S-transferase A2

Actions: inhibitor

Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles

UniProt ID: P09210 Link_out
Gene: GSTA2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Foliot A, Touchard D, Mallet L: Inhibition of liver glutathione S-transferase activity in rats by hypolipidemic drugs related or unrelated to clofibrate. Biochem Pharmacol. 1986 May 15;35(10):1685-90. Pubmed
  2. Foliot A, Touchard D, Celier C: Impairment of hepatic glutathione S-transferase activity as a cause of reduced biliary sulfobromophthalein excretion in clofibrate-treated rats. Biochem Pharmacol. 1984 Sep 15;33(18):2829-34. Pubmed

3. Cytochrome P450 3A4

Actions: substrate, inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 1A1

Actions: inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P04798 Link_out
Gene: CYP1A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 2A6

Actions: inhibitor

Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase

UniProt ID: P11509 Link_out
Gene: CYP2A6
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

6. Cytochrome P450 2B6

Actions: inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20813 Link_out
Gene: CYP2B6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

7. Cytochrome P450 4A11

Actions: substrate, inducer

Catalyzes the omega- and (omega-1)-hydroxylation of various fatty acids such as laurate, myristate and palmitate. Has little activity towards prostaglandins A1 and E1

UniProt ID: Q02928 Link_out
Gene: CYP4A11 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on August 10, 2011 15:44

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.