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Fomepizole is a competitive inhibitor of alcohol dehydrogenase (ADH) that prevents the formation of toxic metabolites from ethylene glycol and methanol. It may also have a role in halting the disulfiram—ethanol reaction, and in limiting the toxicity from a variety of xenobiotics that rely on ADH for metabolism to toxic metabolites. In addition, as both an inducer and an inhibitor of certain cytochrome P450 (CYP) isoenzymes, the presence of fomepizole may lead to drug interactions.

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In 1963, Theorell and associates described the inhibiting effect of pyrazole on the horse ADH-NAD+ (nicotinamide adenine dinucleotide) enzyme—coenzyme system.78 They noted that pyrazole blocked ADH by complexation, and that the administration of pyrazole to animals poisoned with methanol and ethylene glycol improved survival.79 However, pyrazole also inhibited other liver enzymes, including catalase and the microsomal ethanol-oxidizing system.55 Additional adverse effects of pyrazole administration resulted in bone marrow, liver, and renal toxicity, and these effects increased in the presence of ethanol and methanol.66 These factors led to the search for less-toxic compounds with comparable mechanisms of action.

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In 1969, Li and Theorell found that both pyrazole and 4-methylpyrazole (fomepizole) inhibited ADH in human liver preparations,54 and studies in rodents found that fomepizole, unlike pyrazole, was relatively nontoxic regardless of the presence or absence of ethanol.11 Subsequent studies of fomepizole in monkeys and humans poisoned with methanol and ethylene glycol confirmed both the inhibitory effect and relative safety of fomepizole.16,17,66

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Fomepizole has a molecular weight (MW) of 82 daltons, 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.21

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Values for Km (Michaelis-Menten dissociation constant; substrate concentration where the rate of metabolism is half the maximum) have been estimated for the toxic alcohols, along with the value for Ki (dissociation of enzyme-inhibitor complex inhibition constant) 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 that is needed to half saturate the enzyme. Studies in monkey and human liver tissue demonstrate that fomepizole is a competitive inhibitor of alcohol dehydrogenase.58,73 In monkey liver, fomepizole demonstrated very similar Kis for both ethanol and methanol at 7.5 and 9.1 μmol/L, respectively.58 The affinity was 10 times higher when human liver was used.72 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.11,66 In human liver, the concentration needed to achieve inhibition is about 0.9 to 1 μmol/L.54,72 The most recent trial using intravenous fomepizole attempted ...

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