Kinetic interactions between 4-methylpyrazole and ethanol in healthy humans.
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.
Jacobsen
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D
Department of Pharmacology, Louisiana State University Medical Center, Shreveport 71130-3932, USA.
Sebastian
C S
CS
Dies
D F
DF
Breau
R L
RL
Spann
E G
EG
Barron
S K
SK
McMartin
K E
KE
D000328:Adult; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors*; D000428:Alcohol Drinking / Q000097:blood*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000431:Ethanol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019855:Ethylene Glycol; D005026:Ethylene Glycols / Q000493:pharmacokinetics; D000077604:Fomepizole; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D000432:Methanol / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*
D005026:Ethylene Glycols; D011720:Pyrazoles; D000431:Ethanol; D000077604:Fomepizole; D000426:Alcohol Dehydrogenase; D019855:Ethylene Glycol; D000432:Methanol