title: Relationship between gamma-hydroxybutyrate plasma concentrations and its electroencephalographic effects in the rat.
abstract: In view of the potential interest in an objective parameter for the depth of coma in intoxications with the recreational drug gamma-hydroxybutyrate (GHB), we have studied the relationship between the plasma concentrations and the electroencephalographic (EEG) changes induced by GHB in the rat. Fifteen rats randomly received either 150 (n = 3), 200 (n = 6) or 300 mg kg(-1) (n = 6) GHB over 5 min, followed by a supramaximal dose of 450 mg kg(-1) over 5 min at the end of the experiment. Plasma concentrations were determined with HPLC. The EEG was continuously recorded and the amplitude in the 15.5-30 Hz frequency band was quantified using aperiodic analysis. The plasma concentration-time profiles were fitted to a two-compartment model with Michaelis-Menten elimination. The pharmacokinetic parameters Vmax, Km and the apparent volume of distribution (Vd) proved to be independent of the dose and the mean pooled values were Vmax 2068 +/- 140 microg min(-1) kg(-1), Km 58 +/- 16 microg mL(-1) and Vd 476 +/- 12 mL kg(-1). The EEG amplitude in the 15.5-30 Hz frequency band displayed a monophasic inhibition and the effect-plasma concentration curve showed hysteresis. This hysteresis between EEG effect and plasma concentrations was minimized by simultaneous calculation of hypothetical effect-site concentrations and fitting the effect vs effect-site concentration curve to a sigmoid inhibitory Emax model. The descriptors of this Emax model (Emax, EC50, k(e,0), gamma and E0) were independent of the dose with an equilibration half-life t1/2k(e,0) of 5.6 +/- 0.3 min (mean value of the pooled results of the 5-min treatment groups). To investigate the origin of this hysteresis, a dose of 600 mg kg(-1) GHB was infused over either 45 or 60 min each in three animals. The hysteresis was much less pronounced with 45 min than with 5 min and was absent with 60-min infusions. This indicated that the hysteresis was due to a distribution delay between the central compartment and the effect site. This study showed that the concentration-effect relationship of GHB could be characterized in individual rats using aperiodic analysis in the 15.5-30 Hz frequency band.
authors.affiliation: Heymans Institute of Pharmacology, Ghent University, Faculty of Medicine and Health Sciences, Belgium. diederik.vansassenbroeck@rug.ac.be
authors.forename: D K
authors.initials: DK
authors.lastname: Van Sassenbroeck
authors.forename: P
authors.initials: P
authors.lastname: De Paepe
authors.forename: F M
authors.initials: FM
authors.lastname: Belpaire
authors.forename: M T
authors.initials: MT
authors.lastname: Rosseel
authors.forename: P
authors.initials: P
authors.lastname: Martens
authors.forename: P A
authors.initials: PA
authors.lastname: Boon
authors.forename: W A
authors.initials: WA
authors.lastname: Buylaert
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects*; D013287:Illicit Drugs / Q000633:toxicity*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012978:Sodium Oxybate / Q000097:blood / Q000633:toxicity*
chemical_list: D013287:Illicit Drugs; D012978:Sodium Oxybate