Fomepizole
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| Identifiers | |
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3D model (JSmol)
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| ECHA InfoCard | 100.028.587 |
CompTox Dashboard (EPA)
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| Properties | |
| C4H6N2 | |
| Molar mass | 82.10 g/mol |
| Density | 0.99 g/cm3 |
| Boiling point | 99-100 °C |
| Hazards | |
| Flash point | 96.0 °C< |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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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]
Uses
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.
Medical Use
When used as an antidote in cases of methanol or ethylene glycol poisoning, fomepizole is administered by injection. For a 70kg patient, a loading dose of 1050 milligrams is given followed by a 700 mg dose every 12 hours for 4 doses. Afterwards doses of 1050 milligrams are given every 12 hours until methanol or the ethylene glycol concentrations is below 20 mg/dL and the patient has no symptoms and a normal blood pH. Fomepizole is supplied as brand name Antizol® in 1.5 mL vials containing 1500 mg of fomepizole. Unfortunately some emergency rooms do not stock the drug because the cost per vial is around $1000 when purchased as a brand name product.
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 (2007). "Ethylene glycol ingestion treated only with fomepizole" (PDF). J Med Toxicol. 3 (3): 125–8. PMID 18072148.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Vos, Johannes G. (1979). "Pyrazolato and related anions. Part V. Transition metal salts of 4-methylpyrazole". Transition Metal Chemistry. 4: 137. doi:10.1007/BF00619054.
- ^ Casavant MJ (2001). "Fomepizole in the treatment of poisoning". Pediatrics. 107 (1): 170. doi:10.1542/peds.107.1.170. PMID 11134450.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ "Forensic Pathology".