Kinetics and metabolism of fomepizole in healthy humans

Fomepizole, a potent inhibitor of alcohol dehydrogenase, has replaced ethanol as antidote for methanol and ethylene glycol intoxications because of a longer duration of action and fewer adverse effects. Prior human studies have indicated that single doses of fomepizole are eliminated by Michaelis-Menten kinetics, but two studies in poisoned patients have suggested that first order elimination occurs after multiple doses. Because of the contrast in fomepizole kinetics among existing studies and the lack of information regarding its metabolism in humans, kinetic and metabolic studies were conducted after single doses and after multiple oral doses in healthy human subjects.

In a single-dose, crossover study, healthy humans received fomepizole IV or orally (7 mg/kg). Also to define the metabolism and kinetics of fomepizole when administered over the presumed antidotal period, subjects were divided into three groups, which were given oral loading doses of 10-15 mg/kg, followed by supplemental doses of 3-10 mg/kg/12 h through 96 hours.

The single dose study confirmed that fomepizole was eliminated by saturable, nonlinear kinetics, primarily by metabolism, and subsequent renal excretion of the metabolite 4-carboxypyrazole (4-CP). In the multi-dose study, the zero order elimination rate of fomepizole increased with increasing duration of treatment (from mean of 3 μmol/L/h after first dose to 14 μmol/L/h after 72 hours). Consistent with the enhanced elimination of fomepizole, the rate of urinary excretion of 4-CP increased with time. After 96 hours, fomepizole elimination apparently changed to first order kinetics with a t(½) of 1.5-2 hours.

The results suggest that fomepizole induces its own metabolism via cytochrome P-450, leading to enhanced fomepizole elimination and 4-CP excretion. Thus, to maintain relatively constant plasma levels of fomepizole during therapy, increased supplemental doses at about 36-48 hours are needed to overcome the increased elimination of fomepizole. As such, these kinetic evaluations in healthy humans support the current dosing recommendations for fomepizole.