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

• Published in: Archives of biochemistry and biophysics Vol. 199; no. 2; pp. 606 - 614
• Main Authors: McMartin, Kenneth E., Hedström, Karl-Göran, Tolf, Bo-Ragnar, Östling-Wintzell, Helene, Blomstrand, Rolf
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.1980
• Subjects: Alcohol Oxidoreductases - antagonists & inhibitors; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Haplorhini; Liver - enzymology; Macaca - metabolism; Macaca fascicularis - metabolism; Methanol - metabolism; Methanol - poisoning; Pyrazoles - metabolism; Pyrazoles - therapeutic use; Pyrazoles - toxicity
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/0003-9861(80)90318-5

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.