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Identification
NameFomepizole
Accession NumberDB01213  (APRD00985)
Typesmall molecule
Groupsapproved
Description

Fomepizole is used as an antidote in confirmed or suspected methanol or ethylene glycol poisoning. Fomepizole is a competitive inhibitor of alcohol dehydrogenase, the enzyme that catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites.

Structure
Thumb
Synonyms
SynonymLanguageCode
4-methylpyrazoleNot AvailableNot Available
FomepizolSpanishINN
FomepizoleNot AvailableINN, USAN
FomepizolumLatinINN
SaltsNot Available
Brand names
NameCompany
AntizolNot Available
Brand mixturesNot Available
Categories
CAS number7554-65-6
WeightAverage: 82.1038
Monoisotopic: 82.053098202
Chemical FormulaC4H6N2
InChI KeyInChIKey=RIKMMFOAQPJVMX-UHFFFAOYSA-N
InChI
InChI=1S/C4H6N2/c1-4-2-5-6-3-4/h2-3H,1H3,(H,5,6)
IUPAC Name
4-methyl-1H-pyrazole
SMILES
CC1=CNN=C1
Mass Specshow(8.42 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassAzoles
SubclassPyrazoles
Direct parentPyrazoles
Alternative parentsPolyamines
Substituentspolyamine; organonitrogen compound
Classification descriptionThis compound belongs to the pyrazoles. These are compounds containing a pyrazole ring, which is a five-member aromatic ring with two nitrogen atoms (at positions 1 and 2) and three carbon atoms.
Pharmacology
IndicationAntizol is indicated as an antidote for ethylene glycol (such as antifreeze) or methanol poisoning, or for use in suspected ethylene glycol or methanol ingestion, either alone or in combination with hemodialysis
PharmacodynamicsFomepizole is a competitive inhibitor of alcohol dehydrogenase, the enzyme that catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites. Ethylene glycol is first metabolized to glycoaldehyde which then undergoes further oxidation to glycolate, glyoxylate, and oxalate. It is glycolate and oxalate that are primarily responsible for the metabolic acidosis and renal damage that are seen in ethylene glycol poisoning. {01}{03} Methanol is first metabolized to formaldehyde and then undergoes subsequent oxidation via formaldehyde dehydrogenase to become formic acid. It is formic acid that is primarily responsible for the metabolic acidosis and visual disturbances that are associated with methanol poisoning.
Mechanism of actionAntizol (fomepizole) is a competitive inhibitor of alcohol dehydrogenase. Alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde. Alcohol dehydrogenase also catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites.
AbsorptionRapid and complete
Volume of distribution
  • 0.6 to 1.02 L/kg
Protein bindingNot Available
Metabolism

Primarily hepaticm the primary metabolite is 4-carboxypyrazole (approximately 80 to 85% of an administered dose). Other metabolites include 4-hydroxymethylpyrazole and the N -glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole.

SubstrateEnzymesProduct
Fomepizole
    4-carboxypyrazoleDetails
    Fomepizole
      4-hydroxymethylpyrazoleDetails
      Route of eliminationIn healthy volunteers, only 1-3.5% of the administered dose of Antizol® (7-20 mg/kg oral and IV) was excreted unchanged in the urine, indicating that metabolism is the major route of elimination. In humans, the primary metabolite of Antizol® is 4-carboxypyrazole (approximately 80-85% of administered dose), which is excreted in the urine. The metabolites of Antizol® are excreted renally.
      Half lifeThe plasma half-life of Antizol varies with dose, even in patients with normal renal function, and has not been calculated.
      ClearanceNot Available
      ToxicityHeadache, nausea, dizziness
      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 + 0.9902
      Caco-2 permeable + 0.526
      P-glycoprotein substrate Non-substrate 0.8392
      P-glycoprotein inhibitor I Non-inhibitor 0.9617
      P-glycoprotein inhibitor II Non-inhibitor 0.9872
      Renal organic cation transporter Non-inhibitor 0.8355
      CYP450 2C9 substrate Non-substrate 0.8533
      CYP450 2D6 substrate Non-substrate 0.8888
      CYP450 3A4 substrate Non-substrate 0.7657
      CYP450 1A2 substrate Non-inhibitor 0.9046
      CYP450 2C9 substrate Non-inhibitor 0.9085
      CYP450 2D6 substrate Non-inhibitor 0.9231
      CYP450 2C19 substrate Non-inhibitor 0.9026
      CYP450 3A4 substrate Non-inhibitor 0.8505
      CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7534
      Ames test Non AMES toxic 0.6456
      Carcinogenicity Non-carcinogens 0.7102
      Biodegradation Not ready biodegradable 0.9152
      Rat acute toxicity 2.1558 LD50, mol/kg Not applicable
      hERG inhibition (predictor I) Weak inhibitor 0.9162
      hERG inhibition (predictor II) Non-inhibitor 0.9683
      Pharmacoeconomics
      Manufacturers
      • Paladin labs usa inc
      • Bioniche pharma usa llc
      • Navinta llc
      • Pharmaforce inc
      • Synerx pharma llc
      Packagers
      Dosage forms
      FormRouteStrength
      LiquidIntravenous
      Prices
      Unit descriptionCostUnit
      Antizol 1.5 gm/1.5 ml vial1849.8USDml
      Antizol 1 gm/ml vial1516.5USDml
      Fomepizole 1.5 gm/1.5 ml vial1364.85USDml
      DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
      Patents
      CountryPatent NumberApprovedExpires (estimated)
      United States75538632007-06-302027-06-30
      Properties
      Stateliquid
      Experimental Properties
      PropertyValueSource
      melting point25 °CNot Available
      logP0.9Not Available
      Predicted Properties
      PropertyValueSource
      water solubility5.59e+02 g/lALOGPS
      logP0.41ALOGPS
      logP0.79ChemAxon
      logS0.83ALOGPS
      pKa (strongest acidic)15.82ChemAxon
      pKa (strongest basic)2.13ChemAxon
      physiological charge0ChemAxon
      hydrogen acceptor count1ChemAxon
      hydrogen donor count1ChemAxon
      polar surface area28.68ChemAxon
      rotatable bond count0ChemAxon
      refractivity24.79ChemAxon
      polarizability8.58ChemAxon
      number of rings1ChemAxon
      bioavailability1ChemAxon
      rule of fiveYesChemAxon
      Ghose filterNoChemAxon
      Veber's ruleYesChemAxon
      MDDR-like ruleNoChemAxon
      Spectra
      SpectraNot Available
      References
      Synthesis ReferenceNot Available
      General ReferenceNot Available
      External Links
      ResourceLink
      KEGG DrugD00707
      KEGG CompoundC07837
      PubChem Compound3406
      PubChem Substance46508566
      ChemSpider3289
      ChEBI5141
      ChEMBLCHEMBL1308
      Therapeutic Targets DatabaseDAP000568
      PharmGKBPA449697
      Drug Product Database2242980
      RxListhttp://www.rxlist.com/cgi/generic/antizol.htm
      Drugs.comhttp://www.drugs.com/mtm/fomepizole.html
      WikipediaFomepizole
      ATC CodesV03AB34
      AHFS Codes
      • 92:00.00
      PDB EntriesNot Available
      FDA labelNot Available
      MSDSshow(64.1 KB)
      Interactions
      Drug InteractionsSearched, but no interactions found.
      Food InteractionsNot Available

      1. Alcohol dehydrogenase 1A

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Actions: inhibitor

      Components

      Name UniProt ID Details
      Alcohol dehydrogenase 1A P07327 Details

      References:

      1. Nagata H, Sekizuka E, Morishita T, Tatemichi M, Kurokawa T, Mizuki A, Ishii H: Adenosine A2-receptor mediates ethanol-induced arteriolar dilation in rat stomach. Am J Physiol. 1996 Dec;271(6 Pt 1):G1028-33. Pubmed
      2. Mukherjee PK, Mohamed S, Chandra J, Kuhn D, Liu S, Antar OS, Munyon R, Mitchell AP, Andes D, Chance MR, Rouabhia M, Ghannoum MA: Alcohol dehydrogenase restricts the ability of the pathogen Candida albicans to form a biofilm on catheter surfaces through an ethanol-based mechanism. Infect Immun. 2006 Jul;74(7):3804-16. Pubmed
      3. Nussrallah BA, Dam R, Wagner FW: Characterization of Coturnix quail liver alcohol dehydrogenase enzymes. Biochemistry. 1989 Jul 25;28(15):6245-51. Pubmed
      4. Brent J: Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 2009 May 21;360(21):2216-23. Pubmed
      5. Calello DP, Osterhoudt KC, Henretig FM: New and novel antidotes in pediatrics. Pediatr Emerg Care. 2006 Jul;22(7):523-30. Pubmed
      6. Betten DP, Vohra RB, Cook MD, Matteucci MJ, Clark RF: Antidote use in the critically ill poisoned patient. J Intensive Care Med. 2006 Sep-Oct;21(5):255-77. Pubmed

      2. Alcohol dehydrogenase 1B

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Actions: inhibitor

      Components

      Name UniProt ID Details
      Alcohol dehydrogenase 1B P00325 Details

      References:

      1. Yin SJ, Liao CS, Chen CM, Fan FT, Lee SC: Genetic polymorphism and activities of human lung alcohol and aldehyde dehydrogenases: implications for ethanol metabolism and cytotoxicity. Biochem Genet. 1992 Apr;30(3-4):203-15. Pubmed
      2. Eriksson CJ, Fukunaga T, Sarkola T, Chen WJ, Chen CC, Ju JM, Cheng AT, Yamamoto H, Kohlenberg-Muller K, Kimura M, Murayama M, Matsushita S, Kashima H, Higuchi S, Carr L, Viljoen D, Brooke L, Stewart T, Foroud T, Su J, Li TK, Whitfield JB: Functional relevance of human adh polymorphism. Alcohol Clin Exp Res. 2001 May;25(5 Suppl ISBRA):157S-163S. Pubmed
      3. Kassam JP, Tang BK, Kadar D, Kalow W: In vitro studies of human liver alcohol dehydrogenase variants using a variety of substrates. Drug Metab Dispos. 1989 Sep-Oct;17(5):567-72. Pubmed
      4. Brent J: Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 2009 May 21;360(21):2216-23. Pubmed
      5. Calello DP, Osterhoudt KC, Henretig FM: New and novel antidotes in pediatrics. Pediatr Emerg Care. 2006 Jul;22(7):523-30. Pubmed
      6. Betten DP, Vohra RB, Cook MD, Matteucci MJ, Clark RF: Antidote use in the critically ill poisoned patient. J Intensive Care Med. 2006 Sep-Oct;21(5):255-77. Pubmed

      3. Alcohol dehydrogenase 1C

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Actions: inhibitor

      Components

      Name UniProt ID Details
      Alcohol dehydrogenase 1C P00326 Details

      References:

      1. Eriksson CJ, Fukunaga T, Sarkola T, Chen WJ, Chen CC, Ju JM, Cheng AT, Yamamoto H, Kohlenberg-Muller K, Kimura M, Murayama M, Matsushita S, Kashima H, Higuchi S, Carr L, Viljoen D, Brooke L, Stewart T, Foroud T, Su J, Li TK, Whitfield JB: Functional relevance of human adh polymorphism. Alcohol Clin Exp Res. 2001 May;25(5 Suppl ISBRA):157S-163S. Pubmed
      2. Brent J: Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 2009 May 21;360(21):2216-23. Pubmed
      3. Calello DP, Osterhoudt KC, Henretig FM: New and novel antidotes in pediatrics. Pediatr Emerg Care. 2006 Jul;22(7):523-30. Pubmed
      4. Betten DP, Vohra RB, Cook MD, Matteucci MJ, Clark RF: Antidote use in the critically ill poisoned patient. J Intensive Care Med. 2006 Sep-Oct;21(5):255-77. Pubmed

      4. Catalase

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Actions: inhibitor

      Components

      Name UniProt ID Details
      Catalase P04040 Details

      References:

      1. Thurman RG, McKenna WR, Brentzel HJ Jr, Hesse S: Significant pathways of hepatic ethanol metabolism. Fed Proc. 1975 Oct;34(11):2075-81. Pubmed
      2. Handler JA, Thurman RG: Catalase-dependent ethanol oxidation in perfused rat liver. Requirement for fatty-acid-stimulated H2O2 production by peroxisomes. Eur J Biochem. 1988 Sep 15;176(2):477-84. Pubmed
      3. Bradford BU, Forman DT, Thurman RG: 4-Methylpyrazole inhibits fatty acyl coenzyme synthetase and diminishes catalase-dependent alcohol metabolism: has the contribution of alcohol dehydrogenase to alcohol metabolism been previously overestimated? Mol Pharmacol. 1993 Jan;43(1):115-9. Pubmed

      1. Cytochrome P450 2E1

      Kind: protein

      Organism: Human

      Pharmacological action: unknown

      Actions: inhibitor

      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. 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

      Comments
      Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13