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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 KeyRIKMMFOAQPJVMX-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
Not Available
4-carboxypyrazoleDetails
Fomepizole
Not Available
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

Targets

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

Enzymes

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

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