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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 the two most lethal xenobiotics metabolized by this pathway.8,9 Ethanol may also inhibit the metabolism of short-chain polyethylene glycols, such as di- and triethylene glycol,50 as well as compete with monofluoroacetate and fluoroacetamide for binding to the tricarboxylic acid cycle via the formation of acetate. Ethanol also affects the cytochrome P450 (CYP) enzyme system, especially CYP2E1, for which it has biphasic properties as an inducer/inhibitor similar to fomepizole and isoniazid. The competitive relationship of ethanol with potentially toxic xenobiotics are 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.

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, Km, is used to express the degree of affinity: the lower the Km value, the stronger the affinity. A summary of in vitro experiments using human liver cells demonstrated a Km of 30 mM for ethylene glycol, 7 mM for methanol, and 0.45 mM for ethanol.26,39,40 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%.29 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 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.29 When compared to methanol smaller amounts of ethanol are required to block the metabolism of ethylene glycol, as the affinity of ethylene glycol for alcohol dehydrogenase is less than that of methanol.19,26,39,40,42,48 Most authors1,19,48 recommend either a serum ethanol concentration of 100 mg/dL, or at least a 1:4 molar ratio of ethanol to methanol or ethylene glycol, whichever is greater. Using this ratio, 100 mg/dL (∼22 mmol/L) of ethanol protects against 88 mmol/L (286 mg/dL) of methanol or 88 mmol/L (546 mg/dL) of ethylene glycol. Inhibiting the metabolism of methanol and ethylene glycol impedes the formation of toxic metabolites and prevents the development of metabolic acidosis.10,13,18,48 After this ...

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