KINETIC INTERACTIONS BETWEEN 4-METHYLPYRAZOLE AND ETHANOL IN HEALTHY HUMANS

4-Methylpyrazole (4-MP), a potent inhibitor of alcohol dehydrogenase a ctivity, is a candidate to replace ethanol as the antidote for methano l and ethylene glycol intoxications, because it has a longer duration of action and apparently fewer adverse effects. To study a probable mu tual inhibitory effect between ethanol and 4-MP on their elimination, two studies were performed in healthy human volunteers using double-bl ind crossover designs. In study A, 4-MP in the presumed therapeutic do se range of ID to 20 mg/kg caused a 40% reduction in the rate of elimi nation of ethanol in 12 subjects given 0.5 to 0.7 g/kg of ethanol. The se data suggest that such doses of 4-MP inhibit alcohol dehydrogenase activity in humans in vivo and would be effective at blocking methanol or ethylene glycol metabolism. In study B, ethanol (0.6 g/kg followed by 0.2 g/kg twice) significantly decreased the rate of elimination of 4-MP (5 mg/kg, given intravenously to four subjects). These moderate doses of ethanol also inhibited the rate of urinary excretion of 4-car boxypyrazole, the primary metabolite of 4-MP in humans. Data suggest t hat ethanol inhibits 4-MP metabolism, thereby increasing the duration of therapeutic blood levels of 4-MP in the body. This mutual interacti on may have clinical implications, because most self-poisoned patients have also ingested ethanol. Theoretically, methanol and ethylene glyc ol might also show such interactions with 4-MP.