4-methylpyrazole

4-methylpyrazole, also known as fomepizole, is a medication used to treat methanol and ethylene glycol poisoning[1]. It works by inhibiting the enzyme alcohol dehydrogenase, which is responsible for converting methanol and ethylene glycol into their toxic metabolites. Fomepizole is administered intravenously and may be used alone or in combination with hemodialysis[1].

Common side effects associated with fomepizole use include headache, nausea, sleepiness, and unsteadiness[1]. It is unclear if use during pregnancy causes risk to a fetus. Fomepizole was approved for medical use in the United States in 1997 and is on the World Health Organization's List of Essential Medicines[1].

In addition to its medical uses, 4-methylpyrazole has been studied for its role in coordination chemistry[1]. It has been shown to be effective in treating methanol and ethylene glycol intoxications, and its slower elimination rate and lesser degree of toxicity make it a preferable treatment option compared to ethanol[3].

Fomepizole distributes rapidly into total body water, with a volume of distribution 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 it has not been calculated[1].

Fomepizole is metabolized in the liver, with the primary metabolite being 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[1].

In healthy volunteers, 1.0 to 3.5% of an administered dose was excreted unchanged in the urine. The metabolites are also excreted unchanged in the urine. Fomepizole is dialyzable[1].

A placebo-controlled, double-blind, single-dose, randomized, sequential, ascending-dose study was performed in healthy volunteers to determine the tolerance of 4-methylpyrazole at dose levels of 10, 20, 50, and 100 mg/kg. No side effects were reported at the 10 and 20 mg/kg levels, but at the 50 mg/kg level, three out of four subjects experienced slight to moderate nausea and dizziness. At the 100 mg/kg level, all three subjects reported side effects like nausea, dizziness, and vertigo[2].

Another study found that a slight, transient elevation in one or both serum transaminase values was observed in 6 of the 15 subjects treated with 4-methylpyrazole. This effect was not dose-related nor apparently mediated through a hypersensitivity reaction. Serum triglyceride levels were increased in 30% of 4-methylpyrazole-treated subjects, but also in 25% of the placebo subjects[3].

Fomepizole is available in various dosage forms, including injection, solution, and powder, and is manufactured by several companies, including Alliance Medical Products, Ben Venue Laboratories Inc., Bioniche Pharma, Emcure Pharmaceuticals Ltd., Generamedix Inc., Jazz Pharmaceuticals, Orphan Medical Inc., Paladin Laboratories Usa Inc., Pharmaforce Inc., Sandoz, and X-Gen Pharmaceuticals[4].

The prices of fomepizole vary depending on the dosage form and manufacturer, with a 1.5 gm/1.5 ml vial costing around $1849.80 USD[4].

Citations:

[1] https://en.wikipedia.org/wiki/Fomepizole

[2] https://pubmed.ncbi.nlm.nih.gov/3056073/

[3] https://pubmed.ncbi.nlm.nih.gov/2212566/

[4] https://go.drugbank.com/drugs/DB01213

[5] https://www.sigmaaldrich.com/US/en/product/aldrich/222569