PT  - JOURNAL ARTICLE
AU  - Bridget L. Morse
AU  - Marilyn E. Morris
TI  - Toxicokinetics/Toxicodynamics of <em>γ</em>-Hydroxybutyrate-Ethanol Intoxication: Evaluation of Potential Treatment Strategies
AID  - 10.1124/jpet.113.206250
DP  - 2013 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 504--513
VI  - 346
IP  - 3
4099  - http://jpet.aspetjournals.org/content/346/3/504.short
4100  - http://jpet.aspetjournals.org/content/346/3/504.full
SO  - J Pharmacol Exp Ther2013 Sep 01; 346
AB  - 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 0.1–0.2% and 0.3–0.4% (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 0.1–0.2% (4 of 10) and 0.3–0.4% (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 0.1–0.2% (0 of 10) and 0.3–0.4% ethanol (5 of 10). Treatment with a GABAB receptor antagonist completely prevented fatality at 0.3–0.4% (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.