Kinetic interactions between 4-methylpyrazole and ethanol in healthy humans

D. Jacobsen, C. S. Sebastian, D. F. Dies, R. L. Breau, E. G. Spann, S. K. Barron, K. E. McMartin

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

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 A, 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.

Original languageEnglish (US)
Pages (from-to)804-809
Number of pages6
JournalAlcoholism: Clinical and Experimental Research
Volume20
Issue number5
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

Keywords

  • Alcohol Dehydrogenase
  • Cytochrome P-450
  • Drug Metabolism
  • Ethylene Glycol Poisoning
  • Methanol Poisoning

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

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