Fomepizole

Fomepizole
IUPAC name 4-Methyl-1H-pyrazole
Other names 4-Methylpyrazole
Identifiers
CAS number	7554-65-6 Y
PubChem	3406
ChemSpider	3289 Y
UNII	83LCM6L2BY Y
DrugBank	DB01213
KEGG	D00707 Y
ChEBI	CHEBI:5141 Y
ChEMBL	CHEMBL1308 Y
Jmol-3D images	Image 1
SMILES n1cc(cn1)C
InChI InChI=1S/C4H6N2/c1-4-2-5-6-3-4/h2-3H,1H3,(H,5,6) Y Key: RIKMMFOAQPJVMX-UHFFFAOYSA-N Y 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	204-207 °C (97,3 kPa)
Hazards
Flash point	96.0 °C
Y (verify) (what is: Y/N?) 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 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.

Medical use

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 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.

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.

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.

External links

• Antizol
• Antizol Product Monograph
• Advanced Consumer Drug Information