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4‐Methylpyrazole Decreases 1,4‐Butanediol Toxicity by Blocking Its in Vivo Biotransformation to γ‐Hydroxybutyric Acid
Author(s) -
QUANG LAWRENCE S.,
DESAI MALHAR C.,
SHAN MICHAEL W.,
WOOLF ALAN D.,
MAHER TIMOTHY J.
Publication year - 2004
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1316.065
Subject(s) - righting reflex , toxicity , pharmacology , in vivo , chemistry , medicine , aldehyde dehydrogenase , antidote , anesthesia , reflex , biochemistry , biology , enzyme , microbiology and biotechnology
A bstract : 1,4‐Butanediol (1,4‐BD), a prodrug converted in vivo to γ‐hydroxybutyric acid by alcohol dehydrogenase, has resulted in life‐threatening overdoses and deaths. We investigated whether 4‐methylpyrazole (4‐MP), an alcohol dehydrogenase antagonist, can be used as an antidote in a murine model of 1,4‐BD overdose. CD‐1 mice were overdosed with 1,4‐BD, 600 mg/kg i.p. Mice then received 4‐MP, 25 mg/kg i.p., or control injections after 1 min, 5 min, and symptom appearance. Mice were then evaluated for toxicity by the righting reflex and rotarod test every 10 min after intervention. When 4‐MP was administered 1 and 5 min after 1,4‐BD overdose, mice completely maintained their righting reflex. Conversely, control mice lost their righting reflex for 110 and 130 min, respectively ( P = 0.05 ). When 4‐MP was administered after symptomatic 1,4‐BD overdose, mice lost their righting reflex but recovered it by 60 min. Conversely, control mice lost their righting reflex and recovered it by 140 min ( P = 0.05 ). When 4‐MP was administered at 1 min after 1,4‐BD overdose, mice never failed the rotarod test. Conversely, control mice failed the rotarod test for 210 min ( P = 0.05 ). When 4‐MP was administered 5 min after 1,4‐BD and after symptomatic 1,4‐BD overdose, mice failed the rotarod test for 100 and 110 min, respectively. Conversely, control mice failed the rotarod test for 210 and 180 min, respectively ( P = 0.05 ). In addition, treatment of mice with 4‐MP significantly attenuated increases in blood γ‐hydroxybutyric acid concentrations and prevented loss of the righting reflex and failure of the rotarod test. In this murine model of 1,4‐BD overdose, 4‐MP conferred antidotal effects by inhibiting alcohol dehydrogenase‐mediated biotransformation of 1,4‐BD to γ‐hydroxybutyric acid.