Fomepizole, also known as 4-methylpyrazole, is a medication used to treat methanol and ethylene glycol poisoning.
Common side effects include headache, nausea, sleepiness, and unsteadiness.
Fomepizole was approved for medical use in the United States in 1997.
Medical uses
Fomepizole is used to treat ethylene glycol and methanol poisoning. It acts to inhibit the conversion of these alcohols into their respective aldehydes by alcohol dehydrogenase. The prevents further conversion to the more active toxic metabolites oxalic acid and formic acid, respectively.
Fomepizole is most effective when given soon after ingestion of ethylene glycol or methanol. Delaying its administration allows for the generation of harmful metabolites.
Adverse effects
Common side effects associated with fomepizole use include
headache and
nausea.
Interactions
Interaction with ethanol
Concurrent use with ethanol is contraindicated because fomepizole is known to prolong the half-life of ethanol via inhibiting its metabolism to acetaldehyde by alcohol dehydrogenase.
Pharmacology
Mechanism of action
Fomepizole is a competitive inhibitor of the enzyme alcohol dehydrogenase,
found in the liver. This enzyme plays a key role in the metabolism of ethylene glycol, and of methanol.
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Ethylene glycol is first metabolized to glycolaldehyde by alcohol dehydrogenase. Glycolaldehyde then undergoes further oxidation to glycolate, glyoxylate, and oxalate. Glycolate and oxalate are the primary toxins responsible for the metabolic acidosis, and for the renal damage, seen in ethylene glycol poisoning.
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Methanol is first metabolized to formaldehyde by alcohol dehydrogenase. Formaldehyde then undergoes further oxidation, via formaldehyde dehydrogenase, to become formic acid.
By competitively inhibiting the first enzyme, alcohol dehydrogenase, in the metabolism of ethylene glycol and methanol, fomepizole slows the production of the toxic metabolites. The slower rate of metabolite production allows the liver to process and excrete the metabolites as they are produced, limiting the accumulation in tissues such as the kidney and eye. As a result, much of the organ damage is avoided.
Pharmacokinetics
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, so has not been calculated.
Metabolism and elimination
Hepatic – the primary metabolite is 4-carboxypyrazole (about 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, 1.0 to 3.5% of an administered dose was excreted unchanged in the urine. The metabolites also are excreted unchanged in the urine.
Fomepizole is Kidney dialysis.
Research
Apart from medical uses, the role of 4-methylpyrazole in coordination chemistry has been studied.
