4-Methylpyrazole Decreases 1,4-Butanediol Toxicity by Blocking Its in Vivo Biotransformation to {gamma}-Hydroxybutyric Acid

doi:10.1196/annals.1316.065

1,4-Butanediol (1,4-BD), a prodrug converted in vivo to ${gamma}$ -hydroxybutyricacid by alcohol dehydrogenase, has resulted in life-threateningoverdoses and deaths. We investigated whether 4-methylpyrazole(4-MP), an alcohol dehydrogenase antagonist, can be used asan antidote in a murine model of 1,4-BD overdose. CD-1 micewere overdosed with 1,4-BD, 600 mg/kg i.p. Mice then received4-MP, 25 mg/kg i.p., or control injections after 1 min, 5 min,and symptom appearance. Mice were then evaluated for toxicityby 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 aftersymptomatic 1,4-BD overdose, mice lost their righting reflexbut recovered it by 60 min. Conversely, control mice lost theirrighting reflex and recovered it by 140 min (P < 0.05). When4-MP was administered at 1 min after 1,4-BD overdose, mice neverfailed the rotarod test. Conversely, control mice failed therotarod test for 210 min (P < 0.05). When 4-MP was administered5 min after 1,4-BD and after symptomatic 1,4-BD overdose, micefailed 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 significantlyattenuated increases in blood ${gamma}$ -hydroxybutyric acid concentrationsand prevented loss of the righting reflex and failure of therotarod test. In this murine model of 1,4-BD overdose, 4-MPconferred antidotal effects by inhibiting alcohol dehydrogenase-mediatedbiotransformation of 1,4-BD to ${gamma}$ -hydroxybutyric acid.