Studies on the metabolic interactions between 4-methylpyrazole and methanol using the monkey as an animal model

Abstract

Young cynomolgus monkeys, Macaca fascicularis, were chosen as a model to investigate the metabolism of 4-methylpyrazole and its interaction with methanol. Following a single dose of 4-methylpyrazole, the elimination of 4-methylpyrazole from the plasma followed a linear course; at a dose of 50 mg/kg (424 μmol/kg) the constant rate of elimination of 4-methylpyrazole was approximately 13 μmol/kg/h with disappearance of the dose within 35 h. This rate of elimination was slower when the smaller dose of 20 mg 4-methylpyrazole was administered. The primary metabolite of 4-methylpyrazole, 4-hydroxymethylpyrazole, accumulated to levels at most 10% of those of 4-methylpyrazole and did not persist in the plasma after the elimination of 4-methylpyrazole. The concurrent administration of methanol with 4-methylpyrazole inhibited the disappearance of 4-methylpyrazole from the plasma about 25%, which suggested an interaction between the metabolism of the two compounds. As expected from its potent inhibitory effect on alcohol dehydrogenase, 4-methylpyrazole produced a profound and dose-dependent inhibition of the rate of elimination of methanol from the plasma. In addition, 4-methylpyrazole at a plasma level of greater than 10 μ m was capable of preventing the accumulation of formic acid in methanol poisoned monkeys. In such a way 4-methylpyrazole repeatedly injected in various dose combinations was able to reverse methanol toxicity in the monkey. These studies indicated the usefulness of the monkey as a model to study 4-methylpyrazole activity and toxicity in light of its possible use to treat methanol poisoning in man.