Influence of hypovolemia on the pharmacokinetics and electroencephalographic effect of gamma-hydroxybutyrate in the rat.

Abstract

Hypovolemia alters the effect of propofol in the rat by influencing the pharmacokinetics and the end organ sensitivity. We now studied the effect of hypovolemia on the anesthetic gamma-hydroxybutyrate (GHB) because in contrast with propofol it increases blood pressure. Thirty-two rats were randomly assigned to undergo moderate hypovolemia or a control procedure. Each rat received either an infusion of sodium-GHB (390 mg x kg(-1) x 5 min(-1)) or the same volume of an equimolar solution of sodium chloride (6.9%). Plasma samples were taken for GHB assay (high-performance liquid chromatography) and the electroencephalography and blood pressure values were recorded. A two-compartment model with Michaelis-Menten elimination was fitted to the concentration-time data and a sigmoid E(max) model to the electroencephalographic effect effect site concentration curve allowing the study of the end organ sensitivity. Plasma concentration-time curves and the total volume of distribution in hypovolemic and normovolemic rats were comparable with only small but significant differences in central volume of distribution and the intercompartmental clearance. There was no significant difference either in the distribution from the plasma to the brain (k(e0)) or in the end organ sensitivity (EC50 = 335 +/- 76 microg/ml in control vs. 341 +/- 89 microg/ml in hypovolemic rats). GHB temporarily increased mean arterial pressure in both groups, which cannot be explained by the sodium salt alone. Hypovolemia does not influence the overall concentration-time curve of GHB and induces no changes in the electroencephalographic effect of GHB in the rat. This difference with propofol may be due to the fact that it increases blood pressure but also due to its different pharmacokinetic properties.