Fomepizole

Fomepizole is a competitive inhibitor of alcohol dehydrogenase. Alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde. Alcohol dehydrogenase also catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites.

Fomepizole has been shown in vitro and in vivo to block alcohol dehydrogenase enzyme activity in dog, monkey, and human liver. The relative affinity of fomepizole for human ADH is 80,000 times greater than that of methanol and ethylene glycol, and 8,000 times greater than that of ethanol (3, 18, 30). The concentration of fomepizole at which alcohol dehydrogenase is inhibited by 50% in vitro is approximately 0.1 μmol/L. The plasma concentrations achieved in humans with the proposed dosage regimen are well above this, with peak concentrations of fomepizole between 100-300 μmol/L (8.6-24.6 mg/L). These levels are achieved with oral or i.v. fomepizole doses of 10-20 mg/kg. Fomepizole is most effective when given in close proximity to the ethylene glycol or methanol ingestion before significant target organ damage occurs.

The plasma half-life of fomepizole varies with dose, even in patients with normal renal function, and has not been calculated.

Distribution

After intravenous infusion, fomepizole rapidly distributes to total body water. The volume of distribution is between 0.6 L/kg and 1.02 L/kg.

Metabolism

In healthy volunteers, only 1-3.5% of the administered dose of fomepizole (7-20 mg/kg oral and IV) was excreted unchanged in the urine, indicating that metabolism is the major route of elimination. In humans, the primary metabolite of fomepizole is 4-carboxypyrazole (approximately 80-85% of administered dose), which is excreted in the urine. Other metabolites of fomepizole observed in the urine are 4-hydroxymethylpyrazole and the N-glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole.

Excretion

After a single dose, the elimination of fomepizole is best characterized by Michaelis-Menten kinetics with saturable elimination occurring at plasma concentrations of 100-300 μmol/L, 8.2-24.6 mg/L.

With multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system, which produces a significant increase in the elimination rate after about 30-40 hours. After enzyme induction, elimination follows first-order kinetics.

Special populations

No special pharmacokinetic studies have been performed with respect to pediatric, geriatric, hepatically-impaired, or renally-impaired patients. Possible gender differences to recommend dose adjustments for patient subgroups were not investigated.

Fomepizole has been shown in vitro and in vivo to block alcohol dehydrogenase enzyme activity in dog, monkey, and human liver. The relative affinity of fomepizole for human ADH is 80,000 times greater than that of methanol and ethylene glycol, and 8,000 times greater than that of ethanol (3, 18, 30).

Fomepizole has been shown to inhibit ethylene glycol toxicity in rats (8), dogs (11, 17, 13), monkeys (9), and cats (12). Fomepizole has been shown to inhibit methanol toxicity in monkeys (4, 5, 24, 25, 26). Fomepizole is most effective when given in close proximity to the exposure of ethylene glycol or methanol, before significant renal damage or visual disturbance has occurred. When used in sufficient doses, fomepizole inhibits the metabolism of ethylene glycol or methanol to their toxic metabolites and ameliorates metabolic acidosis before significant target organ damage develops in relevant animal models.

Animal and in vitro studies indicate that the main metabolite, 4-carboxypyrazole, is not active pharmacologically nor are any of the minor metabolites active at concentrations found following therapeutic doses of fomepizole.

In a study of dogs given a lethal dose of ethylene glycol, three animals each were administered fomepizole, ethanol, or left untreated (control group). The three animals in the untreated group became progressively obtunded, moribund, and died. At necropsy, all three dogs had severe renal tubular damage. Fomepizole or ethanol, given 3 hours after ethylene glycol ingestion, attenuated the metabolic acidosis and prevented the renal tubular damage associated with ethylene glycol intoxication.

Several studies have demonstrated that fomepizole plasma concentrations of approximately 10 μmol/L (0.82 mg/L) in monkeys are sufficient to inhibit methanol metabolism to formate, which is also mediated by alcohol dehydrogenase. Based on these results, peak plasma concentrations of fomepizole in humans in the range of 100 to 300 μmol/L (8.6-24.6 mg/L) have been targeted to assure adequate plasma concentrations for the effective inhibition of alcohol dehydrogenase.