Identification

Name
Fomepizole
Accession Number
DB01213  (APRD00985)
Type
Small Molecule
Groups
Approved, Vet Approved
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
  • 4-Methylpyrazol
  • 4-methylpyrazole
  • Fomepizol
  • Fomepizole
  • Fomepizolum
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AntizolInjection1 g/mLIntravenousPaladin Labs Inc2009-07-31Not applicableUs
AntizolLiquid1 gIntravenousPaladin Labs Inc2001-03-30Not applicableCanada
Fomepizole for InjectionSolution1 gIntravenousSterimax Inc2015-09-22Not applicableCanada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FomepizoleInjection, solution1 g/mLIntravenousMylan Institutional2012-10-09Not applicableUs
FomepizoleInjection, solution1 g/mLIntravenousX Gen Pharmaceuticals2007-12-14Not applicableUs
FomepizoleInjection, solution1 g/mLIntravenousSandoz2008-03-06Not applicableUs
International/Other Brands
Antizol
Categories
UNII
83LCM6L2BY
CAS number
7554-65-6
Weight
Average: 82.1038
Monoisotopic: 82.053098202
Chemical Formula
C4H6N2
InChI Key
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

Pharmacology

Indication

Antizol 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

Structured Indications
Pharmacodynamics

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. 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 action

Antizol (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.

TargetActionsOrganism
AAlcohol dehydrogenase 1A
inhibitor
Human
AAlcohol dehydrogenase 1B
inhibitor
Human
AAlcohol dehydrogenase 1C
inhibitor
Human
ACatalase
inhibitor
Human
Absorption

Rapid and complete

Volume of distribution
  • 0.6 to 1.02 L/kg
Protein binding
Not 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.

Route of elimination

In 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 life

The plasma half-life of Antizol varies with dose, even in patients with normal renal function, and has not been calculated.

Clearance
Not Available
Toxicity

Headache, nausea, dizziness

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
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.Approved, Investigational
Food Interactions
Not Available

References

General References
Not Available
External Links
Human Metabolome Database
HMDB15344
KEGG Drug
D00707
KEGG Compound
C07837
PubChem Compound
3406
PubChem Substance
46508566
ChemSpider
3289
ChEBI
5141
ChEMBL
CHEMBL1308
Therapeutic Targets Database
DAP000568
PharmGKB
PA449697
HET
4PZ
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Fomepizole
ATC Codes
V03AB34 — Fomepizole
AHFS Codes
  • 92:12.00 — Antidotes
PDB Entries
3e4e
MSDS
Download (64.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentMacular Dystrophy, Corneal1
1, 2CompletedTreatmentAcetaldehyde Toxicity / ALDH2 Deficiency / Altered Ethanol Metabolism1
Not AvailableRecruitingNot AvailableEthylene Glycol Poisoning, Methanol Poisoning1

Pharmacoeconomics

Manufacturers
Not 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)
US7553863No2007-06-302027-06-30Us

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)25 °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 FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Download (8.42 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-001i-9000000000-a316743b875614673db9
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-001i-9000000000-42791f260f9285d6f780
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-001i-9000000000-569b1673c9ab233c4013
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-015c-9000000000-5ae86e9abf74bac03fba
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-014l-9000000000-41e338b06d239025c0e7

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azoles
Sub Class
Pyrazoles
Direct Parent
Pyrazoles
Alternative Parents
Heteroaromatic compounds / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Hydrocarbon derivatives
Substituents
Heteroaromatic compound / Pyrazole / Azacycle / Organic nitrogen compound / Organopnictogen compound / Hydrocarbon derivative / Organonitrogen compound / Aromatic heteromonocyclic compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
pyrazoles (CHEBI:5141) / a small molecule (CPD0-1652)

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
Uniprot Name
Alcohol dehydrogenase 1A
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
Uniprot Name
Alcohol dehydrogenase 1B
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
Uniprot Name
Alcohol dehydrogenase 1C
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 c...
Gene Name
CAT
Uniprot ID
P04040
Uniprot Name
Catalase
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 ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
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. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
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]

Drug created on June 13, 2005 07:24 / Updated on November 19, 2017 20:34