A30: Antidotes in Depth

INTRODUCTION

Fomepizole, a competitive inhibitor of alcohol dehydrogenase (ADH), 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 enzymes, the presence of fomepizole may lead to drug interactions.

HISTORY

In 1963, Theorell described the inhibiting effect of pyrazole on the horse ADH nicotinamide adenine dinucleotide (NAD⁺) enzyme–coenzyme system.^70,89 Pyrazole blocked ADH by complexation, and the administration of pyrazole to animals poisoned with methanol and ethylene glycol improved survival.⁹⁰ However, pyrazole also inhibited other liver enzymes, including catalase and the microsomal ethanol oxidizing system.⁶² Additional adverse effects of pyrazole administration resulted in bone marrow, liver, and kidney toxicity, and these effects increased in the presence of ethanol and methanol.⁷⁴ These factors led to the search for less toxic compounds with comparable mechanisms of action.

In 1969, Li and Theorell found that both pyrazole and 4-methylpyrazole (fomepizole) inhibited ADH in human liver preparations,⁶¹ and studies in rodents found that fomepizole, unlike pyrazole, was relatively nontoxic regardless of the presence or absence of ethanol.¹³ Subsequent studies of fomepizole in monkeys and humans poisoned with methanol and ethylene glycol confirmed both the inhibitory effect and relative safety of fomepizole.^19,20,74

PHARMACOLOGY

Chemistry

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

Mechanism of Action

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 K_m have been estimated for the toxic alcohols and the K_i with fomepizole. The smaller the K_m, 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 K_is 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 ...