|Jmol-3D images||Image 1|
|Molar mass||82.10 g mol−1|
204-207 °C (97,3 kPa)
|Flash point||96.0 °C|
| (what is: / ?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Fomepizole or 4-methylpyrazole is indicated for use as an antidote in confirmed or suspected methanol or ethylene glycol 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.
- 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. 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. Extending the half-life of ethanol may increase and extend the intoxicating effects of ethanol, allowing for greater (potentially dangerous) levels of intoxication at lower doses. Fomepizole will slow the production of acetaldehyde by inhibiting alcohol dehydrogenase which in turn will allow more time to further convert acetaldehyde into acetic acid (vinegar) by acetaldehyde dehydrogenase. The result will be a patient with a prolonged and deeper level of intoxication for any given dosage of ethanol, and reduced "hangover" symptoms (since these adverse symptoms are largely mediated by acetaldehyde build up). In a chronic alcoholic who has built up a tolerance to ethanol, this will remove some of the disincentives to ethanol consumption ("positive punishment") while allowing them to become intoxicated with a lower dose of ethanol. The danger is that the alcoholic will then overdose on ethanol (possibly fatally). If the alcoholic instead very carefully reduces their dose to reflect the now slower metabolism, they may get the "rewarding" stimulus of intoxication at lower dosages with less adverse "hangover" effects - leading potentially to increased psychological dependency. However, these lower dosages may therefore produce less chronic toxicity and may therefore provide a harm minimization approach to chronic alcoholism. It is, in essence, the antithesis of a disulfram approach which tries to increase the buildup of acetaldehyde resulting in positive punishment for the patient (needless to say compliance / adherence is a substantial problem in disulfram-based approaches).
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.
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.
- International Programme on Chemical Safety (IPCS): Methanol (PIM 335), , 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.
- 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".