Fomepizole has a molecular weight of 82 Da, and a pKa of 2.91 at low concentrations and a pKa of 3.0 at high concentrations. The free base is used in the United States, whereas the salts are used in Europe. The free base is chemically equivalent to the chloride and sulfate salts at physiologic pH.24
Fomepizole works by being a potent inhibitor of ADH thereby blocking the metabolism of methanol and ethylene glycol to their respective toxic metabolites.
Values for Km have been estimated for the toxic alcohols and the Ki with fomepizole. The smaller the Km, the higher the affinity of the substrate (alcohol) for the enzyme, and the lower the concentration of the substrate to achieve saturation of 50% of the enzyme. Studies in monkey and human liver tissue demonstrate that fomepizole is a competitive inhibitor of alcohol dehydrogenase.65,82 In monkey liver, fomepizole demonstrated very similar Kis for both ethanol and methanol at 7.5 and 9.1 μmol/L, respectively.65 The affinity was 10 times higher when human liver was used.81 Studies in monkeys demonstrate that a fomepizole concentration of 9 to 10 μmol/L (0.74–0.8 µg/mL) is needed to inhibit the metabolism of methanol to formate.13,74 In human liver, the concentration needed to achieve inhibition is about 0.9 to 1 μmol/L.61,81 The most recent trial using intravenous (IV) fomepizole attempted to maintain a serum fomepizole concentration above 10 μmol/L. Current dosing calls for a serum fomepizole concentration of 100 to 300 μmol/L to ensure a margin of safety.1
CYP2E1 oxidizes ethanol and a number of other xenobiotics, including acetaminophen, carbon tetrachloride, nitrosamines, and benzene to toxic metabolites. Fomepizole, like ethanol and isoniazid, induces CYP2E1 in rat liver and kidney, but not in the lung, through a posttranscriptional mechanism via stabilization and not involving increased messenger RNA.76 However, when fomepizole is present, CYP2E1 is inhibited. It is not until after fomepizole is eliminated that the consequences of induction are manifest.16,95,96 In hepatocyte culture, fomepizole stabilizes and maintains the induced metabolic activity of the isoenzyme for about one week.97
The volume of distribution of fomepizole is about 0.6 to 1 L/kg; it is metabolized to 4-carboxypyrazole, an inactive metabolite that accounts for 80% to 85% of the administered dose.71,76 In healthy human volunteers, oral doses of fomepizole are rapidly absorbed and demonstrate saturation and nonlinear kinetics.44,67,76 The Km was estimated to be 75 μmol/L in two studies, and 0.94 μmol/L at a dose of 15 mg/kg to 2.49 μmol/L at a dose of 7 mg/kg in the two most recent analyses, although the reason for the discrepancy is not known.44,67,68,76 First-order kinetics were exhibited at concentrations below the Km, whereas zero-order elimination occurred at concentrations 100% to 200% of the Km.44 Thus, elimination of fomepizole at doses of 10, 20, 50, and 100 mg/kg was 3.66, 5.05, 10.3, and 14.9 μmol/L/h, respectively.44 Classical Michaelis-Menten kinetics would predict that the elimination rate should be comparable at the two higher doses. The authors speculate that the differences are attributable to the existence of other metabolic pathways with different affinities that predominate at different fomepizole concentrations. Following multiple doses, the elimination of fomepizole increases at 36 to 48 hours, most likely because of autoinduction.76 After 96 hours fomepizole elimination apparently changed to first order elimination with a half-life of 1.5 to 2 hours, from zero order elimination. At a single dose of 20 mg/kg, the apparent half-life of fomepizole calculated from the linear portion of the curve was 5.2 hours and occurred when serum concentrations were less than 100 μmol/L. Peak concentrations after oral administration were achieved within 2 hours and were 132, 326, 759, and 1425 μmol/L following 10, 20, 50, and 100 mg/kg doses, respectively. Every increase of 10 mg/kg in the oral dose of fomepizole raised the serum concentration 130 to 160 μmol/L.44 The renal clearance was low (0.016 mL/min/kg), and only 3% of the administered dose was excreted unchanged in the urine.44
In the two most recent pharmacokinetic studies in healthy volunteers, oral administration produced similar serum concentrations to IV fomepizole.67,76 The pharmacokinetics of IV fomepizole were studied in 14 patients being treated for ethylene glycol toxicity.52 A mean peak concentration of 342 μmol/L (200–400 μmol/L) was achieved following a loading dose of 15 mg/kg (183 μmol/kg).71,86 A significant weakness of the study involving toxicokinetic data is that the effect of simultaneous serum ethanol concentrations was not analyzed. The lowest serum fomepizole concentration of 105 μmol/L was present at 8 hours after the loading dose. The rate of elimination was determined to be zero order at 16 μmol/L/h compared with a first-order elimination half-life of 3 hours during hemodialysis. Other authors have reported similar fomepizole clearances (12.99 μmol/L/h).21 A recent pharmacokinetic analysis in patients poisoned with methanol or ethylene glycol demonstrated a mean peak fomepizole concentration of 226 μmol/L (19 µg/mL), an apparent half-life of 14.5 hours (in the presence of methanol or ethylene glycol), and an apparent half-life of 40 hours in the presence of ethanol, and methanol or ethylene glycol. In the sole death, hepatic tissue contained 12 µg/g of fomepizole, even when the serum concentration was less than 1 µg/mL (12 μmol/L).93
The hemodialysis clearance of fomepizole ranges from 50 mL/min to 137 mL/min.30,51 An analysis using determinations of dialysis fluid revealed an extraction ratio of approximately 75% and a dialysance of 117 mL/min, which was very similar to a simultaneous ethylene glycol determination.30 The dialysance was similar to urea in a pig model and suggests no significant protein binding of fomepizole.45
The pharmacokinetic interactions between fomepizole and ethanol were studied in a double-blind crossover design in healthy human volunteers.49 Fomepizole was given orally in doses of 10, 15, and 20 mg/kg 1 hour prior to oral ethanol at 0.5 to 0.7 g/kg as a 20% solution in orange juice. Fomepizole decreased the elimination rate of ethanol by approximately 40%, from 12 to 16 mg/dL/h to about 7 to 9.5 mg/dL/h. When IV fomepizole was administered at 5 mg/kg over 30 minutes and ethanol was administered orally at doses to achieve a concentration of 50 to 150 mg/dL for 6 hours beginning at the end of the fomepizole infusion, the elimination of fomepizole was decreased by approximately 50%.49 This decrease occurred without a change in the amount or fraction of unchanged fomepizole appearing in the urine. The authors suggested that the ethanol probably inhibited the metabolism of fomepizole to 4-carboxypyrazole. A single low dose of fomepizole given to humans had a maximal effect on ethanol metabolism at 1.5 to 2 hours.12 Thus, ethanol and fomepizole mutually inhibit the elimination of the other, thereby maintaining higher serum concentrations than otherwise expected.66,72 Methanol also decreases the elimination of fomepizole by approximately 25% in the monkey.74