Characterization of the Pharmacokinetic and Pharmacodynamic Interaction between Gamma-Hydroxybutyrate and Ethanol in the Rat

Abstract

It has been reported that ethanol enhances the hypnotic effect of gamma-hydroxybutyrate (GHB). In order to clarify the nature of this interaction we studied the pharmacokinetics and pharmacodynamics of combinations of GHB and ethanol in rats. Intraperitoneal injections of the GHB precursor gamma-butyrolactone (300 mg/kg) together with ethanol (3000 mg/kg) (n = 4) resulted in a longer "sleeping time" than the sum of the individual times (n = 8). Pharmacokinetic analysis of GHB concentrations with a two-compartment model with Michaelis-Menten (M-M) elimination in rats receiving a bolus of GHB (400 mg/kg, i.v.) in addition to steady-state ethanol concentrations (300-3000 microg/ml) (n = 12) or saline (n = 15) showed no marked differences in the area under the curve. The nature of the pharmacodynamic interaction was studied using isobolographs and an interaction model for the loss of the startle and righting reflex and a reaction to a painful tail clamp in rats receiving combinations of steady state concentrations of ethanol (1000-3000 microg/ml) and GHB (200-1400 microg/ml). For the righting reflex, synergy was observed at high ethanol concentrations (>2000 microg/ml) and additivity at lower concentrations. For the startle reflex, it was antagonistic at ethanol concentrations below 1000 microg/ml, and additivity was seen at higher concentrations. For the tail clamp reaction, a slight but significant antagonism was found at all combined concentrations. It is concluded that ethanol prolongs the sleeping time induced by GHB in the rat, which may not be due to a pharmacokinetic interaction. Pharmacodynamic interactions between GHB and ethanol in the rat occur, and the nature varies with the reflex studied and the concentration of ethanol used.

Toxicokinetics/Toxicodynamics ofγ-Hydroxybutyrate-Ethanol Intoxication: Evaluation of Potential Treatment Strategies

“…Regarding the toxicokinetic interaction between GHB and ethanol, our study indicates no effect of intravenous ethanol administration on the clearance of GHB, as previously reported (Van Sassenbroeck et al, 2003;Fung et al, 2008). A lack of effect of GHB on ethanol toxicokinetics was also confirmed in these previous studies and was therefore not evaluated in the current study.…”

“…McCabe et al (1971) reported a longer sleep time with GHB-ethanol coadministration than the sum of the sleep times with either agent alone, as we observed in our study. Van Sassenbroeck et al (2003) reported similar effects on sleep time, concluding that there was a synergistic interaction between the two drugs at high concentrations of ethanol. Studies in rodents have demonstrated the involvement of GABA A receptors in the sedative effect of ethanol and the involvement of GABA B receptors in the sedative effect of GHB (Liljequist and Engel, 1982;Beleslin et al, 1997;Carai et al, 2001).…”

“…Available literature supports minimal toxicokinetic interaction between GHB and ethanol when the two are administered at high intravenous doses or at low oral doses (Van Sassenbroeck et al, 2003;Thai et al, 2006;Fung et al, 2008). In contrast, significant toxicodynamic interactions between GHB and ethanol have been reported with an array of toxicodynamic endpoints (Van Sassenbroeck et al, 2003;Cook et al, 2006;Thai et al, 2006).…”

“…Available literature supports minimal toxicokinetic interaction between GHB and ethanol when the two are administered at high intravenous doses or at low oral doses (Van Sassenbroeck et al, 2003;Thai et al, 2006;Fung et al, 2008). In contrast, significant toxicodynamic interactions between GHB and ethanol have been reported with an array of toxicodynamic endpoints (Van Sassenbroeck et al, 2003;Cook et al, 2006;Thai et al, 2006). These toxicodynamic interactions may be attributed to different pharmacological actions; whereas GHB's effects are attributed to action at GABA B receptors, effects of ethanol are mainly attributed to action at GABA A receptors (Adinoff et al, 1988;Carai et al, 2001;Morse et al, 2012).…”

“…Clinically, overdose of both GHB and ethanol can produce profound sedation and respiratory depression, potentially resulting in fatality (Altose and Hudgel, 1986;Adinoff et al, 1988;Zvosec et al, 2011). Although multiple studies have assessed the effect of GHB-ethanol administration on sedation (McCabe et al, 1971;Van Sassenbroeck et al, 2003;Cook et al, 2006), the effect of ethanol on respiration during GHB overdose has not been evaluated. We predict that, like sedation, GHBinduced respiratory depression is potentiated by the presence of ethanol.…”