Methanol poisoning I. The role of formic acid in the development of metabolic acidosis in the monkey and the reversal by 4-methylpyrazole

Abstract

The administration of methanol (3 g/kg) to rhesus and pigtail monkeys produced signs and symptoms similar to those described for methanol poisoning in man. These were a mild central nervous system depression, a latent period of 8–12 hr when no signs were observed, followed by a severe metabolic acidosis leading to coma and death 12–33 hr after the initial administration. The gradual development of metabolic acidosis coincided with the accumulation of formic acid in the blood, and the decrease of bicarbonate in the plasma. There was an increase in the anion gap during the period of metabolic acidosis, and formic acid concentration accounted for about one-half of the increase observed. Therefore, formic acid was a major, but not the only, determinant of the metabolic acidosis. Administration of 4-methylpyrazole (50 mg/kg), a potent inhibitor of monkey hepatic alcohol dehydrogenase, produced a 75% inhibition of the rate of [ 14C]methanol metabolism to 14CO 2 in the monkey. During the first 36 hr following the administration of 4-methylpyrazole and methanol, no metabolic acidosis developed, no formate accumulated in the blood, and no signs of toxicity were observed. After a single dose of 4-methylpyrazole and methanol, the toxic syndrome was delayed by about 36 hr in the monkey, after which time the onset of metabolic acidosis and the accumulation of formic in blood was noted. The use of the monkey as a model for the study of methanol poisoning is presented, and the possible use of 4-methylpyrazole in the treatment of methanol poisoning is implicit.