4-methylpyrazole decreases 1,4-butanediol toxicity by blocking its in vivo biotransformation to gamma-hydroxybutyric acid.
1,4-Butanediol (1,4-BD), a prodrug converted in vivo to gamma-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 gamma-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 gamma-hydroxybutyric acid.
Quang
Lawrence S
LS
Division of Emergency Medicine, Children's Hospital Boston/Harvard Medical School, Boston, Massachusetts, USA. lsq1@cwru.edu
Desai
Malhar C
MC
Shannon
Michael W
MW
Woolf
Alan D
AD
Maher
Timothy J
TJ
D000818:Animals; D001711:Biotransformation / Q000187:drug effects / Q000502:physiology; D002072:Butylene Glycols / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity*; D000077604:Fomepizole; D006885:Hydroxybutyrates / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D045442:Rotarod Performance Test / Q000379:methods
D002072:Butylene Glycols; D006885:Hydroxybutyrates; D011720:Pyrazoles; C111420:4-hydroxybutyric acid; C039681:1,4-butanediol; D000077604:Fomepizole