- Fomepizole
-
Fomepizole 
4-Methyl-1H-pyrazoleOther names4-MethylpyrazoleIdentifiers CAS number 7554-65-6 
PubChem 3406 ChemSpider 3289 UNII 83LCM6L2BY DrugBank DB01213 KEGG D00707 ChEBI CHEBI:5141 ChEMBL CHEMBL1308 Jmol-3D images Image 1 - n1cc(cn1)C
- InChI=1S/C4H6N2/c1-4-2-5-6-3-4/h2-3H,1H3,(H,5,6)
Key: RIKMMFOAQPJVMX-UHFFFAOYSA-N
InChI=1/C4H6N2/c1-4-2-5-6-3-4/h2-3H,1H3,(H,5,6)
Key: RIKMMFOAQPJVMX-UHFFFAOYAT
Properties Molecular formula C4H6N2 Molar mass 82.1 g mol−1 Density 0.99 g/cm3 Boiling point 99-100 °C
Hazards Flash point 96.0 °C 
(verify) (what is: 
/
?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)Infobox references Fomepizole or 4-methylpyrazole is indicated for use as an antidote in confirmed or suspected methanol[1] or ethylene glycol[2] poisoning. It may be used alone or in combination with hemodialysis. Apart from medical uses, the role of 4-methylpyrazole in coordination chemistry has been studied.[3]
Contents
Medical use
Fomepizole is a competitive inhibitor of alcohol dehydrogenase,[4] 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 glycolaldehyde 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.
- Methanol is first metabolized to formaldehyde and then undergoes subsequent oxidation via formaldehyde dehydrogenase to become formic acid.[5] It is formic acid that is primarily responsible for the metabolic acidosis and visual disturbances that are associated with methanol poisoning.
- Concurrent use with ethanol is contraindicated because fomepizole is known to prolong the half-life of ethanol.
When used as an antidote in cases of methanol or ethylene glycol poisoning, fomepizole is administered by injection. Fomepizole is supplied as brand name Antizol in 1.5 mL vials containing 1500 mg of fomepizole. The cost per vial is around $1000 when purchased as a brand name product as of 2010, and therefore is not widely stocked in some hospital pharmacy stocks.
Raptor Pharmaceuticals is investigating 4-methylpyrazole as possible solution to curing "Asian Glow" or "Asian Flush" due to ALDH2 deficiency. The drug is currently named Convivia and has completed Phase 2a of FDA clinical trails showing that it did have success in reducing acetaldehyde levels in subjects with ALDH2 deficiency.[6]
Kinetics
Absorption and distribution
Fomepizole distributes rapidly into total body water. The volume of distribution is between 0.6 and 1.02 L/kg. The therapeutic concentration is from 8.2 to 24.6 mg (100 to 300 micromoles) per liter. Peak concentration following single oral doses of 7 to 50 mg/kg of body weight occurred in 1 to 2 hours. The half-life varies with dose and therefore has not been calculated.
Metabolism and elimination
Hepatic; the primary metabolite is 4-carboxypyrazole (approximately 80 to 85% of an administered dose). Other metabolites include the pyrazoles 4-hydroxymethylpyrazole and the N -glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole.
Following multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system.
In healthy volunteers, 1 to 3.5% of an administered dose was excreted unchanged in the urine. The metabolites also are excreted unchanged in the urine.
Fomepizole is dialyzable.
References
- ^ International Programme on Chemical Safety (IPCS): Methanol (PIM 335), [1], retrieved on March 1, 2008
- ^ Velez LI, Shepherd G, Lee YC, Keyes DC (September 2007). "Ethylene glycol ingestion treated only with fomepizole". J Med Toxicol 3 (3): 125–8. doi:10.1007/BF03160922. PMID 18072148. http://jmt.pennpress.org/strands/jmt/pdfHandler.pdf?issue=20070303&file=20070303_125_128.pdf.
- ^ Vos, Johannes G.; Groeneveld, Willem L. (1979). "Pyrazolato and related anions. Part V. Transition metal salts of 4-methylpyrazole". Transition Metal Chemistry 4 (3): 137. doi:10.1007/BF00619054.
- ^ Casavant MJ (January 2001). "Fomepizole in the treatment of poisoning". Pediatrics 107 (1): 170. doi:10.1542/peds.107.1.170. PMID 11134450.
- ^ "Forensic Pathology". http://library.med.utah.edu/WebPath/FORHTML/FOR011.html.
- ^ http://www.raptorpharma.com/convivia.html
External links
Antidotes (V03AB) Nervous system Barbiturate overdoseBemegride • EthamivanBenzodiazepine overdoseGHB overdoseReversal of neuromuscular blockadeCardiovascular Other Ethanol • FomepizoleParacetamol toxicity (Acetaminophen)OtherPrednisolone/promethazine • oxidizing agent (potassium permanganate) • iodine-131 (Potassium iodide) • Methylthioninium chloride#Emetic Ipecacuanha (Syrup of ipecac) • Copper sulfate#WHO-EM. ‡Withdrawn from market. Clinical trials: †Phase III. §Never to phase III Categories:- Antidotes
- Pyrazoles
Wikimedia Foundation. 2010.
