Van Sassenbroeck D K, De Paepe P, Belpaire F M, Rosseel M T, Martens P, Boon P A, Buylaert W A
Heymans Institute of Pharmacology, Ghent University, Faculty of Medicine and Health Sciences, Belgium.
J Pharm Pharmacol. 2001 Dec;53(12):1687-96. doi: 10.1211/0022357011778089.
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.
鉴于人们可能对娱乐性药物γ-羟基丁酸（GHB）中毒时昏迷深度的客观参数感兴趣，我们研究了大鼠血浆浓度与GHB诱导的脑电图（EEG）变化之间的关系。15只大鼠随机在5分钟内接受150（n = 3）、200（n = 6）或300 mg·kg⁻¹（n = 6）的GHB，然后在实验结束时在5分钟内接受450 mg·kg⁻¹的超大剂量。用高效液相色谱法测定血浆浓度。持续记录脑电图，并使用非周期性分析对15.5 - 30 Hz频段的振幅进行量化。血浆浓度-时间曲线拟合为具有米氏消除的二室模型。药代动力学参数Vmax、Km和表观分布容积（Vd）被证明与剂量无关，平均合并值为Vmax 2068 ± 140 μg·min⁻¹·kg⁻¹、Km 58 ± 16 μg·mL⁻¹和Vd 476 ± 12 mL·kg⁻¹。15.5 - 30 Hz频段的脑电图振幅呈现单相抑制作用，效应-血浆浓度曲线显示滞后现象。通过同时计算假设的效应部位浓度，并将效应与效应部位浓度曲线拟合为S形抑制性Emax模型，可使脑电图效应与血浆浓度之间的这种滞后现象最小化。该Emax模型的描述符（Emax、EC50、k(e,0)、γ和E0）与剂量无关，平衡半衰期t1/2k(e,0)为5.6 ± 0.3分钟（5分钟治疗组合并结果的平均值）。为了研究这种滞后现象的起源，分别在三只动物中以45分钟或60分钟的时间输注600 mg·kg⁻¹的GHB。45分钟输注时的滞后现象比5分钟输注时明显减轻，60分钟输注时则不存在滞后现象。这表明滞后现象是由于中央室与效应部位之间的分布延迟所致。本研究表明，使用15.5 - 30 Hz频段的非周期性分析可以在个体大鼠中表征GHB的浓度-效应关系。
