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Identification
NameClofibrate
Accession NumberDB00636  (APRD00879)
TypeSmall Molecule
GroupsApproved
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
Synonyms
SynonymLanguageCode
2-(4-Chlorophenoxy)-2-methylpropanoic acid ethyl esterNot AvailableNot Available
2-(p-Chlorophenoxy)-2-methylpropionic acid ethyl esterNot AvailableNot Available
alpha-(p-Chlorophenoxy)isobutyric acid, ethyl esterNot AvailableNot Available
alpha-p-Chlorophenoxyisobutyryl ethyl esterNot AvailableNot Available
Atromid-SNot AvailableNot Available
ClofibrateNot AvailableNot Available
ClofibratoNot AvailableINN
ClofibratumNot AvailableINN
ELPINot AvailableNot Available
EPIBNot AvailableNot Available
Ethyl 2-(P-chlorophenoxy)isobutyrateNot AvailableNot Available
Ethyl chlorophenoxyisobutyrateNot AvailableNot Available
Ethyl clofibrateNot AvailableNot Available
LipofactonNot AvailableNot Available
LiprinNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AlufibrateThe Central
Atromid-SNot Available
BinogracKotobuki Seiyaku
ClobrateJohnson
ClofibrateBanner
HisunseroNewai Chem
KolivaGolden Horse
MyanlinSinton
Brand mixturesNot Available
Categories
CAS number637-07-0
WeightAverage: 242.699
Monoisotopic: 242.070972053
Chemical FormulaC12H15ClO3
InChI KeyKNHUKKLJHYUCFP-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
IUPAC Name
ethyl 2-(4-chlorophenoxy)-2-methylpropanoate
SMILES
CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1
Mass Specshow(7.78 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenoxyacetic Acid Derivatives
Direct parentPhenoxyacetic Acid Derivatives
Alternative parentsPhenol Ethers; Alkyl Aryl Ethers; Chlorobenzenes; Aryl Chlorides; Carboxylic Acid Esters; Enolates; Polyamines; Organochlorides
Substituentsphenol ether; alkyl aryl ether; chlorobenzene; aryl halide; aryl chloride; carboxylic acid ester; ether; enolate; carboxylic acid derivative; polyamine; organochloride; organohalogen
Classification descriptionThis compound belongs to the phenoxyacetic acid derivatives. These are compounds containing an anisole where the methane group is linked to an acetic acid or a derivative.
Pharmacology
IndicationFor Primary Dysbetalipoproteinemia (Type III hyperlipidemia) that does not respond adequately to diet. This helps control high cholesterol and high triglyceride levels.
PharmacodynamicsClofibrate 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 actionClofibrate 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.
AbsorptionCompletely 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 distributionNot Available
Protein bindingHighly 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 eliminationNot Available
Half lifeHalf-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.
ClearanceNot Available
ToxicityOral, 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9329
Caco-2 permeable + 0.717
P-glycoprotein substrate Non-substrate 0.589
P-glycoprotein inhibitor I Non-inhibitor 0.7133
P-glycoprotein inhibitor II Non-inhibitor 0.8544
Renal organic cation transporter Non-inhibitor 0.8868
CYP450 2C9 substrate Non-substrate 0.8517
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.6692
CYP450 1A2 substrate Inhibitor 0.9107
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Non-inhibitor 0.8861
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5832
Ames test Non AMES toxic 0.9132
Carcinogenicity Non-carcinogens 0.5492
Biodegradation Not ready biodegradable 0.9711
Rat acute toxicity 2.3806 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9891
hERG inhibition (predictor II) Non-inhibitor 0.8735
Pharmacoeconomics
Manufacturers
  • Wyeth ayerst laboratories
  • Banner pharmacaps inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Usl pharma inc
  • Watson laboratories inc
Packagers
Dosage forms
FormRouteStrength
CapsuleOral
PricesNot Available
PatentsNot Available
Properties
Stateliquid
Experimental Properties
PropertyValueSource
melting point118-119Jones, W.G.M.,Thorp, J.M. and Waring, W.S.; U.S. Patent 3,262,850; July 26, 1966; assigned to Imperial Chemical Industries Limited, England.
boiling point149 °C at 2.00E+01 mm HgPhysProp
water solubilityInsolubleNot Available
logP3.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.029ALOGPS
logP3.99ALOGPS
logP3.4ChemAxon
logS-3.9ALOGPS
pKa (Strongest Basic)-4.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area35.53 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity62.14 m3·mol-1ChemAxon
Polarizability24.7 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Spectra
Spectra
References
Synthesis Reference

Jones, W.G.M.,Thorp, J.M. and Waring, W.S.; U.S. Patent 3,262,850; July 26, 1966; assigned to Imperial Chemical Industries Limited, England.

General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00279
KEGG CompoundC06916
PubChem Compound2796
PubChem Substance46504748
ChemSpider2694
ChEBI3750
ChEMBLCHEMBL565
Therapeutic Targets DatabaseDAP000262
PharmGKBPA449045
Drug Product Database2038
RxListhttp://www.rxlist.com/cgi/generic2/clofibrate.htm
Drugs.comhttp://www.drugs.com/mtm/clofibrate.html
WikipediaClofibrate
ATC CodesC10AB01C10AB03
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(62.6 KB)
Interactions
Drug Interactions
Drug
AcenocoumarolThe fibrate increases the anticoagulant effect
AcetohexamideClofibrate may increase the effect of sulfonylurea, acetohexamide.
AnisindioneThe fibrate increases the anticoagulant effect
ChlorpropamideClofibrate may increase the effect of sulfonylurea, chlorpropamide.
DicoumarolThe fibrate increases the anticoagulant effect
GliclazideClofibrate may increase the effect of sulfonylurea, gliclazide.
GlipizideClofibrate may increase the effect of sulfonylurea, glipizide.
GlisoxepideClofibrate may increase the effect of sulfonylurea, glisoxepide.
GlyburideClofibrate may increase the effect of sulfonylurea, glibenclamide.
GlycodiazineClofibrate may increase the effect of sulfonylurea, glycodiazine.
Insulin AspartIncreases the effect of insulin
Insulin DetemirIncreases the effect of insulin
Insulin GlulisineIncreases the effect of insulin
TolazamideClofibrate may increase the effect of sulfonylurea, tolazamide.
TolbutamideClofibrate may increase the effect of sulfonylurea, tolbutamide.
Ursodeoxycholic acidThe fibric acid derivative decreases the effect of ursodiol
WarfarinThe fibrate increases the anticoagulant effect
Food Interactions
  • Take with food, since it may reduce gastric irritation.

Targets

1. Peroxisome proliferator-activated receptor alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Peroxisome proliferator-activated receptor alpha Q07869 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Glutathione S-transferase A2 P09210 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 1A1 P04798 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2A6 P11509 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
Cytochrome P450 4A11 Q02928 Details

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

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Drug created on June 13, 2005 07:24 / Updated on April 07, 2014 15:16