Pretreatment of CD-1 mice with 4-methylpyrazole blocks toxicity from the gamma-hydroxybutyrate precursor, 1,4-butanediol

Abstract

1,4-Butanediol (1,4-BD) is the dihydroxy precursor of gamma-hydroxybutyrate (GHB), a popular recreational drug that has been banned by the United States Food and Drug Administration (FDA) and controlled as a federal schedule I drug. 1,4-BD is enzymatically converted in vivo to GHB by alcohol dehydrogenase (ADH), and overdoses can result in coma, severe respiratory depression, bradycardia, hypothermia, seizures, and death. Presently, there is no antidote. We pretreated CD-1 mice with the ADH antagonist, 4-methylpyrazole (4-MP), to determine if blocking ADH can prevent or decrease toxicity from 1,4-BD overdose. Pretreatment with 4-MP increased the Toxic Dose-50 (TD(50)) of 1,4-BD for the righting reflex from 585 mg/kg (95% CI, 484-707 mg/kg) in control mice to 5,550 mg/kg (95% CI, 5,353-5,756 mg/kg) in pretreated mice. Pretreatment with 4-MP also increased the TD(50) of 1,4-BD for the rotarod test from 163 mg/kg (95% CI, 136-196 mg/kg) in control mice to 4,900 mg/kg (95% CI, 4,812-4,989 mg/kg) in pretreated mice. Pretreatment with 4-MP significantly decreased the toxicity of 1,4-BD in CD-1 mice, presumably by inhibiting its ADH biotransformation to GHB. 4-MP warrants further investigation as a potential antidote for this increasingly abused drug.