A31: Antidotes in Depth

INTRODUCTION

Ethanol is used therapeutically as a competitive substrate for xenobiotics metabolized by alcohol dehydrogenase, thus limiting the bioactivation of those xenobiotics to toxic metabolites. Methanol and ethylene glycol are potentially lethal xenobiotics metabolized by this pathway.^11,12 Ethanol may also inhibit the metabolism of short chain polyethylene glycols, such as di- and triethylene glycol,⁵³ and possibly compete with monofluoroacetate and fluoroacetamide for binding to the tricarboxylic acid cycle. Ethanol also affects the cytochrome P450 CYP enzyme system, especially CYP2E1, for which it has biphasic properties as an inducer and an inhibitor similar to fomepizole and isoniazid. The competitive relationship of ethanol with potentially toxic xenobiotics can be used to therapeutic advantage, but the effect of ethanol on the CYP system often leads to unwanted drug interactions and pharmacokinetic tolerance after several days of administration.

HISTORY

Ethanol has been used as an antidote for methanol poisoning since the 1940s and for ethylene glycol since the 1960s.²

PHARMACOLOGY

Mechanism of Action

Ethanol works as a competitive substrate for alcohol dehydrogenase, inhibiting the metabolism of xenobiotics like methanol and ethylene glycol that use this enzyme.

Affinity for Alcohol Dehydrogenase

The dose of ethanol necessary to achieve competitive inhibition depends on the relative concentrations of the toxic alcohols and their affinity for the enzyme. An affinity constant, K_m, is used to express the degree of affinity: the lower the K_m value, the stronger the affinity. The following equates mmol or mg for alcohols: 1 mmol ethanol equals 46 mg, 1 mmol methanol equals 32 mg, and 1 mmol ethylene glycol equals 64 mg. A millimolar concentration means mmoles/L. A summary of in vitro experiments using human liver cells demonstrated a K_m of 30 mM for ethylene glycol, 7 mM for methanol, and 0.45 mM for ethanol.^29,42,43 This means that the molar affinity of ethanol for alcohol dehydrogenase is 67 times that of ethylene glycol and 15.5 times that of methanol. Studies in methanol-poisoned monkeys revealed that when ethanol was administered at a molar ethanol-to-methanol ratio (E:M) of 1:4, the metabolism of methanol was reduced by 70%; at a 1:1 E:M ratio, metabolism was reduced by greater than 90%.³² In these experiments, the dose of methanol was kept constant at about 1 g/kg (31 mmol/kg), whereas the dose of ethanol was varied. Although the serum methanol concentration was not measured, a calculation using this dose and a volume of distribution (Vd) of 0.6 L/kg would predict a serum concentration of about 166 mg/dL. Even in molar ratios as high as 1:8, methanol did not inhibit ethanol metabolism. When ethylene glycol and methanol are administered together in a 0.5:1 molar ratio, ethylene glycol did not inhibit methanol metabolism.³² When compared ...