Jacobsen D, Sebastian C S, Dies D F, Breau R L, Spann E G, Barron S K, McMartin K E
Department of Pharmacology, Louisiana State University Medical Center, Shreveport 71130-3932, USA.
Alcohol Clin Exp Res. 1996 Aug;20(5):804-9. doi: 10.1111/j.1530-0277.1996.tb05255.x.
4-Methylpyrazole (4-MP), a potent inhibitor of alcohol dehydrogenase activity, is a candidate to replace ethanol as the antidote for methanol and ethylene glycol intoxications, because it has a longer duration of action and apparently fewer adverse effects. To study a probable mutual inhibitory effect between ethanol and 4-MP on their elimination, two studies were performed in healthy human volunteers using double-blind crossover designs. In study A1 4-MP in the presumed therapeutic dose range of 10 to 20 mg/kg caused a 40% reduction in the rate of elimination of ethanol in 12 subjects given 0.5 to 0.7 g/kg of ethanol. These 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-carboxypyrazole, the primary metabolite of 4-MP in humans. Data suggest that ethanol inhibits 4-MP metabolism, thereby increasing the duration of therapeutic blood levels of 4-MP in the body. This mutual interaction may have clinical implications, because most self-poisoned patients have also ingested ethanol. Theoretically, methanol and ethylene glycol might also show such interactions with 4-MP.
