Mandema J W, Veng-Pedersen P, Danhof M
Center for Bio-Pharmaceutical Sciences, Sylvius Laboratory, University of Leiden, The Netherlands.
J Pharmacokinet Biopharm. 1991 Dec;19(6):617-34. doi: 10.1007/BF01080870.
The time delay between drug plasma concentrations and effect has been modeled most commonly by the effect compartment approach, assuming first-order monoexponential equilibrium kinetics between plasma and effect site. So far this assumption has not been rigorously probed. The purpose of the present investigation was to model the delay between amobarbital plasma concentrations and EEG effect using a new approach based on system analysis principles. This approach models the equilibrium between plasma and effect site without assuming a specific kinetic structure. Assuming linear distribution kinetics between plasma and effect site, the relationship between the two variables may be described by a convolution type of linear operation, involving a conductance function phi(t), which is approximated by a sum of exponentials. Six male Wistar-derived rats received an iv infusion of amobarbital at a rate of 10 mg/kg per min until isoelectric periods of 5 sec or longer appeared on the EEG. Frequent arterial blood samples were obtained and EEG was continuously quantified using aperiodic analysis. The amplitudes in the 2.5-30 Hz frequency band were used as EEG effect measure. The delay between plasma concentrations and EEG effect was best modeled by a biexponential conductance function. The use of a biexponential conductance function resulted in a significant further reduction (41 +/- 10%) in hysteresis when compared to a monoexponential function, indicating that the assumption of simple first-order monoexponential equilibration kinetics is inadequate. The use of a biexponential conductance function also resulted in a significantly different shape of the effect site concentration-EEG effect relationship and hence the estimated pharmacodynamic parameters, when compared with a monoexponential function. This relationship showed a biphasic behavior, with EEG effects being maximal at amobarbital concentrations of 29.6 +/- 1.3 mg/L. At 80.2 +/- 2.0 mg/L the EEG effect was reduced 50% below baseline values. A comparison was made with the equilibration between amobarbital plasma and cerebrospinal fluid (CSF) concentrations. Six male Wistar-derived rats received an iv infusion of amobarbital, 10 mg per min for 15 min. Arterial blood and CSF samples were taken simultaneously at regular intervals. The equilibration between plasma and CSF concentrations was best fitted by a monoexponential conductance function. Significant differences in equilibration profiles of CSF and effect site with the plasma site were observed. To reach 50% equilibrium the effect site requires 2.5 +/- 0.3 min and the CSF 3.5 +/- 0.2 min, to reach 95% the values were, respectively, 90 +/- 27 and 15 +/- 1 min. This suggests that CSF is kinetically distinguishable from the effect site.
药物血浆浓度与效应之间的时间延迟最常通过效应室方法进行建模，该方法假定血浆与效应部位之间存在一级单指数平衡动力学。到目前为止，这一假设尚未得到严格验证。本研究的目的是使用一种基于系统分析原理的新方法，对异戊巴比妥血浆浓度与脑电图（EEG）效应之间的延迟进行建模。这种方法对血浆与效应部位之间的平衡进行建模，而不假定特定的动力学结构。假定血浆与效应部位之间存在线性分布动力学，则这两个变量之间的关系可以用卷积类型的线性运算来描述，其中涉及一个电导函数phi(t)，该函数可用指数之和来近似。六只雄性Wistar大鼠以每分钟10mg/kg的速率静脉输注异戊巴比妥，直至脑电图上出现5秒或更长时间的等电位期。频繁采集动脉血样，并使用非周期分析对脑电图进行连续定量。使用2.5 - 30Hz频段的振幅作为脑电图效应指标。与单指数电导函数相比，双指数电导函数能更好地模拟血浆浓度与脑电图效应之间的延迟。与单指数函数相比，使用双指数电导函数可使滞后现象进一步显著降低（41±10%），这表明简单的一级单指数平衡动力学假设是不充分的。与单指数函数相比，使用双指数电导函数还导致效应部位浓度 - 脑电图效应关系的形状以及由此估计的药效学参数有显著差异。这种关系呈现双相行为，异戊巴比妥浓度为29.6±1.3mg/L时脑电图效应最大。在80.2±2.0mg/L时，脑电图效应比基线值降低50%。对异戊巴比妥血浆与脑脊液（CSF）浓度之间的平衡进行了比较。六只雄性Wistar大鼠静脉输注异戊巴比妥，每分钟10mg，持续15分钟。定期同时采集动脉血和脑脊液样本。血浆与脑脊液浓度之间的平衡最适合用单指数电导函数拟合。观察到脑脊液和效应部位与血浆部位的平衡曲线存在显著差异。效应部位达到50%平衡需要2.5±0.3分钟，脑脊液需要3.5±0.2分钟；达到95%平衡时，相应的值分别为90±27分钟和15±1分钟。这表明脑脊液在动力学上与效应部位可区分。
