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Identification
NameFomepizole
Accession NumberDB01213  (APRD00985)
TypeSmall Molecule
GroupsApproved, Vet Approved
DescriptionFomepizole 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
4-Methylpyrazol
4-methylpyrazole
Antizol
Fomepizol
Fomepizole
Fomepizolum
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Antizolinjection1 g/mLintravenousPALADIN LABORATORIES (USA) INC2009-07-31Not applicableUs
Antizolliquid1 gintravenousPaladin Labs Inc2001-03-30Not applicableCanada
Fomepizole for Injectionsolution1 gintravenousSterimax Inc2015-09-22Not applicableCanada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Fomepizoleinjection, solution1 g/mLintravenousSandoz Inc.2008-03-06Not applicableUs
Fomepizoleinjection, solution1 g/mLintravenousX Gen Pharmaceuticals, Inc.2007-12-14Not applicableUs
Fomepizoleinjection, solution1 g/mLintravenousMylan Institutional LLC2012-10-09Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII83LCM6L2BY
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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as 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.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassAzoles
Sub ClassPyrazoles
Direct ParentPyrazoles
Alternative Parents
Substituents
  • Heteroaromatic compound
  • Pyrazole
  • Azacycle
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
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.
Related Articles
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
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9902
Caco-2 permeable+0.526
P-glycoprotein substrateNon-substrate0.8392
P-glycoprotein inhibitor INon-inhibitor0.9617
P-glycoprotein inhibitor IINon-inhibitor0.9872
Renal organic cation transporterNon-inhibitor0.8355
CYP450 2C9 substrateNon-substrate0.8533
CYP450 2D6 substrateNon-substrate0.8888
CYP450 3A4 substrateNon-substrate0.7657
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.9085
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8505
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7534
Ames testNon AMES toxic0.6456
CarcinogenicityNon-carcinogens0.7102
BiodegradationNot ready biodegradable0.9152
Rat acute toxicity2.1558 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9162
hERG inhibition (predictor II)Non-inhibitor0.9683
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Injectionintravenous1 g/mL
Liquidintravenous1 g
Injection, solutionintravenous1 g/mL
Solutionintravenous1 g
Prices
Unit descriptionCostUnit
Antizol 1.5 gm/1.5 ml vial1849.8USD ml
Antizol 1 gm/ml vial1516.5USD ml
Fomepizole 1.5 gm/1.5 ml vial1364.85USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7553863 No2007-06-302027-06-30Us
Properties
StateLiquid
Experimental Properties
PropertyValueSource
melting point25 °CNot Available
logP0.9Not Available
Predicted Properties
PropertyValueSource
Water Solubility559.0 mg/mLALOGPS
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 Area28.68 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity24.79 m3·mol-1ChemAxon
Polarizability8.58 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (8.42 KB)
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesV03AB34
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (64.1 KB)
Interactions
Drug Interactions
Drug
ArtesunateThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Fomepizole resulting in a loss in efficacy.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Not Available
Gene Name:
ADH1A
Uniprot ID:
P07327
Molecular Weight:
39858.37 Da
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:8997246 ]
  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:16790752 ]
  3. Nussrallah BA, Dam R, Wagner FW: Characterization of Coturnix quail liver alcohol dehydrogenase enzymes. Biochemistry. 1989 Jul 25;28(15):6245-51. [PubMed:2789998 ]
  4. Brent J: Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 2009 May 21;360(21):2216-23. doi: 10.1056/NEJMct0806112. [PubMed:19458366 ]
  5. Calello DP, Osterhoudt KC, Henretig FM: New and novel antidotes in pediatrics. Pediatr Emerg Care. 2006 Jul;22(7):523-30. [PubMed:16871118 ]
  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:16946442 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Not Available
Gene Name:
ADH1B
Uniprot ID:
P00325
Molecular Weight:
39854.21 Da
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:1590750 ]
  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:11391066 ]
  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:2573502 ]
  4. Brent J: Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 2009 May 21;360(21):2216-23. doi: 10.1056/NEJMct0806112. [PubMed:19458366 ]
  5. Calello DP, Osterhoudt KC, Henretig FM: New and novel antidotes in pediatrics. Pediatr Emerg Care. 2006 Jul;22(7):523-30. [PubMed:16871118 ]
  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:16946442 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Not Available
Gene Name:
ADH1C
Uniprot ID:
P00326
Molecular Weight:
39867.27 Da
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:11391066 ]
  2. Brent J: Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 2009 May 21;360(21):2216-23. doi: 10.1056/NEJMct0806112. [PubMed:19458366 ]
  3. Calello DP, Osterhoudt KC, Henretig FM: New and novel antidotes in pediatrics. Pediatr Emerg Care. 2006 Jul;22(7):523-30. [PubMed:16871118 ]
  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:16946442 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Receptor binding
Specific Function:
Occurs in almost all aerobically respiring organisms and serves to protect cells from the toxic effects of hydrogen peroxide. Promotes growth of cells including T-cells, B-cells, myeloid leukemia cells, melanoma cells, mastocytoma cells and normal and transformed fibroblast cells.
Gene Name:
CAT
Uniprot ID:
P04040
Molecular Weight:
59755.82 Da
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:240743 ]
  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:3416882 ]
  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:8423764 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
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.
Gene Name:
CYP2E1
Uniprot ID:
P05181
Molecular Weight:
56848.42 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
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. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.
Gene Name:
CYP2A6
Uniprot ID:
P11509
Molecular Weight:
56501.005 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
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Drug created on June 13, 2005 07:24 / Updated on September 26, 2016 02:12