FOMEPIZOLE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C4H6N2
Molecular Weight	82.1038
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=CNN=C1

InChI

InChIKey=RIKMMFOAQPJVMX-UHFFFAOYSA-N

InChI=1S/C4H6N2/c1-4-2-5-6-3-4/h2-3H,1H3,(H,5,6)

HIDE SMILES / InChI

Description
Sources: https://www.rxlist.com/antizol-drug.htm | https://www.tga.gov.au/sites/default/files/auspar-fomepizole-170817-pi.pdf | doi: 10.1016/B978-0-323-08500-7.00095-3

Fomepizole (4-methylpyrazole) is a competitive ADH inhibitor. Fomepizole has been shown in vitro to block alcohol dehydrogenase enzyme activity in dog, monkey and human liver. Fomepizole 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. It should be given when a known or suspected toxic ethylene glycol or methanol ingestion has occurred and the patient has metabolic acidosis and elevated osmolar gap. The most frequent adverse events reported as drug-related or unknown relationship were headache (14%), nausea (11%), and dizziness, increased drowsiness, and bad taste/metallic taste. Reciprocal interactions may occur with concomitant use of fomepizole and drugs that increase or inhibit the cytochrome P450 system (e.g. phenytoin, carbamazepine, cimetidine, ketoconazole). Fomepizole has been shown to induce the expression of CYP2E1 and to inhibit its activity. These effects were enhanced in rats that had been exposed to ethanol. Fomepizole may also inhibit other CYP enzymes and therefore may alter the exposure to other drugs that are metabolised by CYP enzymes.

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Alcohol dehydrogenase 6 Target ID: CHEMBL2096668 Sources: https://www.tga.gov.au/sites/default/files/auspar-fomepizole-170817-pi.pdf \| doi: 10.1016/B978-0-323-08500-7.00095-3	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Ethylene glycol Poisoning 2 Sources: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020696	Primary		Approved 8429	ANTIZOL Approved Use Fomepizole injection 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. Launch Date 8.8119358E11

C_max

Value	Dose	Co-administered	Analyte	Population
18.5 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/15167624	10 mg/kg 2 times / day steady-state, oral dose: 10 mg/kg route of administration: Oral experiment type: STEADY-STATE co-administered:		FOMEPIZOLE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
14.5 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/15167624	10 mg/kg 2 times / day steady-state, oral dose: 10 mg/kg route of administration: Oral experiment type: STEADY-STATE co-administered:		FOMEPIZOLE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
100 mg/kg single, oral Highest studied dose Dose: 100 mg/kg Route: oral Route: single Dose: 100 mg/kg Sources: https://pubmed.ncbi.nlm.nih.gov/3056073 Page: p.519	healthy, 25+/-3 n = 4 Health Status: healthy Age Group: 25+/-3 Sex: M Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/3056073 Page: p.519	DLT: Nausea, Dizziness... Dose limiting toxicities: Nausea (grade 1-2, 33%) Dizziness (grade 1-2, 33%) Appetite lost (grade 1-2, 33%) Vertigo (mild, 33%) Sources: https://pubmed.ncbi.nlm.nih.gov/3056073 Page: p.519
15 mg/kg 2 times / day multiple, intravenous Recommended Dose: 15 mg/kg, 2 times / day Route: intravenous Route: multiple Dose: 15 mg/kg, 2 times / day Sources: https://www.aafp.org/afp/1999/0701/p294.html	unhealthy n = 23 Health Status: unhealthy Condition: Ethylene glycol poisoning Sex: M+F Population Size: 23 Sources: https://www.aafp.org/afp/1999/0701/p294.html	Sources: https://www.aafp.org/afp/1999/0701/p294.html

AEs

AE	Significance	Dose	Population
Appetite lost	grade 1-2, 33% DLT	100 mg/kg single, oral Highest studied dose Dose: 100 mg/kg Route: oral Route: single Dose: 100 mg/kg Sources: https://pubmed.ncbi.nlm.nih.gov/3056073 Page: p.519	healthy, 25+/-3 n = 4 Health Status: healthy Age Group: 25+/-3 Sex: M Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/3056073 Page: p.519
Dizziness	grade 1-2, 33% DLT	100 mg/kg single, oral Highest studied dose Dose: 100 mg/kg Route: oral Route: single Dose: 100 mg/kg Sources: https://pubmed.ncbi.nlm.nih.gov/3056073 Page: p.519	healthy, 25+/-3 n = 4 Health Status: healthy Age Group: 25+/-3 Sex: M Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/3056073 Page: p.519
Nausea	grade 1-2, 33% DLT	100 mg/kg single, oral Highest studied dose Dose: 100 mg/kg Route: oral Route: single Dose: 100 mg/kg Sources: https://pubmed.ncbi.nlm.nih.gov/3056073 Page: p.519	healthy, 25+/-3 n = 4 Health Status: healthy Age Group: 25+/-3 Sex: M Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/3056073 Page: p.519
Vertigo	mild, 33% DLT	100 mg/kg single, oral Highest studied dose Dose: 100 mg/kg Route: oral Route: single Dose: 100 mg/kg Sources: https://pubmed.ncbi.nlm.nih.gov/3056073 Page: p.519	healthy, 25+/-3 n = 4 Health Status: healthy Age Group: 25+/-3 Sex: M Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/3056073 Page: p.519

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:5141	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:5141
ChemicalBook	CB8233079	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB8233079
MolPort	MolPort-016-633-159	https://www.molport.com/shop/molecule-link/MolPort-016-633-159
ZINC	ZINC000000897288	http://zinc15.docking.org/substances/ZINC000000897288
eMolecules	489528	https://www.emolecules.com/cgi-bin/more?vid=489528

PubMed

Title	Date	PubMed
Mechanism of aerobic transformation of carbon tetrachloride by poplar cells.	2002	12688582
Fomepizole therapy for pediatric butoxyethanol intoxication.	2002	12507064
American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning.	2002	12216995
Rat ventral prostate microsomal biotransformation of ethanol to acetaldehyde and 1-hydroxyethyl radicals: its potential contribution to prostate tumor promotion.	2002	12210496
Formate kinetics in methanol poisoning.	2002	12126185
Extracorporeal therapies for acute intoxications.	2002 Apr	12053840
Side-chain metabolism of propranolol: involvement of monoamine oxidase and mitochondrial aldehyde dehydrogenase in the metabolism of N-desisopropylpropranolol to naphthoxylactic acid in rat liver.	2002 Apr 19	12269395
Central effects of 1,4-butanediol are mediated by GABA(B) receptors via its conversion into gamma-hydroxybutyric acid.	2002 Apr 26	12063087
Differential role of CYP2E1 binders and isoniazid on CYP2E1 protein modification in NADPH-dependent microsomal oxidative reactions: free radical scavenging ability of isoniazid.	2002 Aug	12420748
Mechanism of superoxide anion production by hepatic sinusoidal endothelial cells and Kupffer cells during short-term ethanol perfusion in the rat.	2002 Aug	12296966
Role of endotoxin in NF-kappaB activation by ethanol in rat hepatocytes.	2002 Aug	12198367
Oxidative bioactivation of crotyl alcohol to the toxic endogenous aldehyde crotonaldehyde: association of protein carbonylation with toxicity in mouse hepatocytes.	2002 Aug	12184789
Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP).	2002 Aug 9	12036955
Fomepizole therapy for reversal of visual impairment after methanol poisoning: a case documented by visual evoked potentials investigation.	2002 Dec	12470767
New developments in the therapy of intoxications.	2002 Feb 28	12052670
Spectroscopic study on charge transfer molecular complexes of pyrazole derivatives with some pi-electron acceptors.	2002 Jul	12164488
Increased proteolysis after single-dose exposure with hepatotoxins in HepG2 cells.	2002 Jul 15	12106824
Pretreatment of CD-1 mice with 4-methylpyrazole blocks toxicity from the gamma-hydroxybutyrate precursor, 1,4-butanediol.	2002 Jul 5	12074936
Enzyme and receptor antagonists for preventing toxicity from the gamma-hydroxybutyric acid precursor 1,4-butanediol in CD-1 mice.	2002 Jun	12105121
Temporal activation of p42/44 mitogen-activated protein kinase and c-Jun N-terminal kinase by acetaldehyde in rat hepatocytes and its loss after chronic ethanol exposure.	2002 Jun	12023518
Fomepizole as an antidote for ethylene glycol poisoning.	2002 Jun	12022913
Accreditation of skin from a methanol-poisoned victim for banking and grafting.	2002 Jun 27	12131687
Suppression of the contact hypersensitivity response following topical exposure to 2-butoxyethanol in female BALB/c mice.	2002 Mar-Apr	12022630
Comparative metabolism of N-tert-butyl-N-[1-(1-oxy-pyridin-4-yl)-ethyl]- and N-tert-butyl-N-(1-phenyl-ethyl)-nitroxide by the cytochrome P450 monooxygenase system.	2002 May	12018998
Mediation by nitric oxide of the stimulatory effects of ethanol on blood flow.	2002 May 10	12138012
Pathways of carbamazepine bioactivation in vitro I. Characterization of human cytochromes P450 responsible for the formation of 2- and 3-hydroxylated metabolites.	2002 Nov	12386121
The metabolic activation of abacavir by human liver cytosol and expressed human alcohol dehydrogenase isozymes.	2002 Nov 10	12399160
Alcohol-induced increases in insulin-like growth factor binding protein-1 are partially mediated by TNF.	2002 Oct	12394292
[Severe ethylene glycol poisoning treated wtih fomepizole (4-methylpyrazole)].	2002 Oct 20	12448112
Treatment of ethylene glycol poisoning.	2002 Sep 1	12322772
Rethinking the toxic methanol level.	2003	14677789
Testosterone increases in men after a low dose of alcohol.	2003 Apr	12711931
In vivo study of salsolinol produced by a high concentration of acetaldehyde in the striatum and nucleus accumbens of free-moving rats.	2003 Aug	12960514
Ethylene glycol intoxication: case report and pharmacokinetic perspectives.	2003 Dec	14695045
Are there teratogenic risks associated with antidotes used in the acute management of poisoned pregnant women?	2003 Feb	12769509
Cinnamic compound metabolism in human skin and the role metabolism may play in determining relative sensitisation potency.	2003 Feb	12615359
Inhalational methanol toxicity in pregnancy treated twice with fomepizole.	2003 Feb	12583693
Agitation by sedation.	2003 Jan 25	12559866
Antidote review: fomepizole for methanol poisoning.	2003 Jan-Feb	12522524
Alcohol potentiates hepatitis C virus replicon expression.	2003 Jul	12829987
Pyrazolato-bridged polynuclear palladium and platinum complexes. Synthesis, structure, and reactivity.	2003 Jun 16	12793829
Acetylation of histone H3 at lysine 9 by ethanol in rat hepatocytes.	2003 Jun 27	12804592
Metabolism of chloroform in the human liver and identification of the competent P450s.	2003 Mar	12584152
Species variations in cutaneous alcohol dehydrogenases and aldehyde dehydrogenases may impact on toxicological assessments of alcohols and aldehydes.	2003 Mar 3	12499113
Allyl alcohol activation of protein kinase C delta leads to cytotoxicity of rat hepatocytes.	2003 May	12755590
Methanol ingestion: prevention of toxic sequelae after massive ingestion.	2003 May	12745047
In vivo formation of salsolinol induced by high acetaldehyde concentration in rat striatum employing microdialysis.	2003 May-Jun	12711651
Cytochrome P450-dependent metabolism of l-deprenyl in monkey (Cercopithecus aethiops) and C57BL/6 mouse brain microsomal preparations.	2003 Sep	12911625
Interferon gamma enhances proteasome activity in recombinant Hep G2 cells that express cytochrome P4502E1: modulation by ethanol.	2003 Sep 1	12948850
Increased prooxidant production and enhanced susceptibility to glutathione depletion in HepG2 cells co-expressing HCV core protein and CYP2E1.	2004 Feb	14695664

Patents

Sample Use Guides

In Vivo Use Guide

A loading dose of 15 mg/kg should be administered, followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until ethylene glycol or methanol concentrations are undetectable or have been reduced below 20 mg/dL (ethylene glycol 3.22 mmol/L, methanol 6.24 mmol/L), and the patient is asymptomatic with normal pH. All doses should be administered as a slow intravenous infusion over 30 minutes

Route of Administration: Intravenous

Name

Type

Language

FOMEPIZOLE

Official Name

English

FOMEPIZOLE [ORANGE BOOK]

Common Name

English

FOMEPIZOLE [JAN]

Common Name

English

NSC-760365

Code

English

FOMEPIZOLE [GREEN BOOK]

Common Name

English

FOMEPIZOLE [MART.]

Common Name

English

1H-PYRAZOLE, 4-METHYL-

Systematic Name

English

FOMEPIZOLE [VANDF]

Common Name

English

FOMEPIZOLE [USAN]

Common Name

English

4-Methylpyrazole

Systematic Name

English

4-MP

Code

English

fomepizole [INN]

Common Name

English

FOMEPIZOLE [MI]

Common Name

English

Fomepizole [WHO-DD]

Common Name

English

ANTIZOL

Brand Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

33388