@article {Morse504, author = {Bridget L. Morse and Marilyn E. Morris}, title = {Toxicokinetics/Toxicodynamics of γ-Hydroxybutyrate-Ethanol Intoxication: Evaluation of Potential Treatment Strategies}, volume = {346}, number = {3}, pages = {504--513}, year = {2013}, doi = {10.1124/jpet.113.206250}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {γ-Hydroxybutyrate (GHB), a common drug of abuse, is often coingested with ethanol. Increasing renal clearance via monocarboxylate transporter (MCT) inhibition represents a potential therapeutic strategy in GHB overdose, as does inhibition of GABAB receptors. In this study, we investigate toxicokinetic/toxicodynamic interactions between GHB-ethanol and efficacy of treatment options for GHB-ethanol intoxication in rats. Sedation was assessed using the endpoint of return-to-righting reflex. Respiration was assessed using plethysmography. Coadministration of 2.0 g/kg ethanol i.v. with 600 mg/kg GHB i.v. increased sleep time compared with GHB alone. Administration of ethanol to steady-state concentrations of 0.1{\textendash}0.2\% and 0.3{\textendash}0.4\% (w/v) did not affect toxicokinetics of 600 mg/kg GHB i.v., or respiratory rate, but did result in significantly lower peak tidal volumes compared with GHB alone. Oral administration of 2.5 g/kg ethanol had no significant effect on toxicokinetics of 1500 mg/kg orally administered GHB. Pretreatment with specific receptor inhibitors indicated no effect of GABAA receptor inhibition on sleep time or respiratory depression in GHB-ethanol intoxication. GABAB receptor inhibition partially prevented sedation and completely prevented respiratory depression. Ethanol increased fatality when administered at 0.1{\textendash}0.2\% (4 of 10) and 0.3{\textendash}0.4\% (9 of 10) versus 1500 mg/kg GHB i.v. alone (0 of 10). Treatment with the MCT inhibitor, l-lactate, significantly decreased sleep time after GHB-ethanol and decreased fatality at 0.1{\textendash}0.2\% (0 of 10) and 0.3{\textendash}0.4\% ethanol (5 of 10). Treatment with a GABAB receptor antagonist completely prevented fatality at 0.3{\textendash}0.4\% (0 of 10). These data indicate that ethanol potentiates the sedative and respiratory depressant effects of GHB, increasing the risk of fatality. MCT and GABAB receptor inhibition represent potentially effective treatments in GHB-ethanol intoxication.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/346/3/504}, eprint = {https://jpet.aspetjournals.org/content/346/3/504.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }