Pyrazoles as inhibitors of alcohol oxidation and as important tools in alcohol research: An approach to therapy against methanol poisoning

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Abstract
4-Methylpyrazole, in a dose producing inhibition of alcohol dehydrogenase (alcohol:NAD+ oxidoreductase, EC 1.1.1.1), was given alone or together with ethanol (10%) as sole drinking fluid to growing rats for up to 38 wk. Their weight curves remained normal. EM of liver, kidney and heart revealed no changes related to treatment. Hematologic analysis showed normal values for blood and bone marrow. Several clinical parameters showed no impairment of liver or kidney function, except for an enhancement of the microsomal drug-metabolizing activity after concurrent administration of 4-methylpyrazole and ethanol. A study on rats receiving 4-methylpyrazole and ethanol indicated a mutual interaction of the 2 compounds or the metabolites, leading to increased blood concentration of the compounds and reduced formation of 4-hydroxymethylpyrazole, the primary metabolite of 4-methylpyrazole. In monkeys [Macaca fascicularus], elimination of 4-methylpyrazole followed a linear course. 4-Hydroxymethylpyrazole accumulated to a level of approximately 10% of that 4-methylpyrazole. Concurrent methanol administration inhibited the elimination of 4-methylpyrazole .apprx. 25%, and 4-methylpyrazole produced a profound inhibition of methanol oxidation. 4-Methylpyrazole, at a level in the plasma of more than 10 .mu.M, prevented accumulation of the toxic metabolite formic acid in methanol-poisoned monkeys, and repeated injections of 4-methylpyrazole abolished methanol toxicity in monkeys receiving lethal doses of methanol. 4-Methylpyrazole, with its low toxicity and strong inhibition of alcohol oxidation, is a valuable tool for experimental studies of alcohol metabolism and its effects. It illustrates the usefulness of the monkey as a model to study 4-methylpyrazole activity and toxicity in light of its possible use for treating methanol poisoning in human beings.