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

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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 μg/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 μg/ml) and GHB (200–1400 μg/ml). For the righting reflex, synergy was observed at high ethanol concentrations (>2000 μg/ml) and additivity at lower concentrations. For the startle reflex, it was antagonistic at ethanol concentrations below 1000 μg/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.

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