Della Paschoa O E, Mandema J W, Voskuyl R A, Danhof M
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, University of Leiden, University of Leiden, P.O. Box. 9503, 2300 RA Leiden, The Netherlands.
J Pharmacol Exp Ther. 1998 Feb;284(2):460-6.
In this study a pharmacokinetic-pharmacodynamic model is proposed for drugs with nonlinear elimination kinetics. We applied such an integrated approach to characterize the pharmacokinetic-pharmacodynamic relationship of phenytoin. In parallel, the anticonvulsant effect and the electroencephalogram (EEG) effect were used to determine the pharmacodynamics. Male Wistar-derived rats received a single intravenous dose of 40 mg . kg-1 phenytoin. The increase in the threshold for generalized seizure activity (TGS) was used as the anticonvulsant effect and the increase in the total number of waves in the 11.5 to 30 Hz frequency band was taken as the EEG effect measure. Phenytoin pharmacokinetics was described by a saturation kinetics model with Michaelis-Menten elimination. Vmax and Km values were, respectively, 386 +/- 31 microg . min-1 and 15.4 +/- 2.2 microg . ml-1 for the anticonvulsant effect in the cortical stimulation model and 272 +/- 31 microg . min-1 and 5.9 +/- 0.7 microg . ml-1 for the EEG effect. In both groups, a delay to the onset of the effect was observed relative to plasma concentrations. The relationship between phenytoin plasma concentrations and effect site was estimated by an equilibration kinetics routine, yielding mean ke0 values of 0.108 and 0.077 min-1 for the anticonvulsant and EEG effects, respectively. The EEG changes in the total number of waves could be fitted by the sigmoid Emax model, but Emax values could not be estimated for the nonlinear relationship between concentration and the increase in TGS. An exponential equation (E = E0 + Bn . Cn) derived from the sigmoid Emax model was applied to describe the concentration-anticonvulsant effect relationship, under the assumption that Emax values cannot be reached within acceptable electric stimulation levels. This approach yielded a coefficient (B) of 2.0 +/- 0.4 microA . ml . microg-1 and an exponent (n) of 2.7 +/- 0.9. The derived EC50 value of 12.5 +/- 1. 3 microg . ml-1 for the EEG effect coincides with the "therapeutic range" in humans.
在本研究中，针对具有非线性消除动力学的药物提出了一种药代动力学-药效学模型。我们应用这种综合方法来表征苯妥英的药代动力学-药效学关系。同时，使用抗惊厥作用和脑电图（EEG）效应来确定药效学。雄性Wistar大鼠静脉注射单次剂量40mg·kg⁻¹苯妥英。将全身性癫痫发作活动阈值（TGS）的升高用作抗惊厥作用，将11.5至30Hz频段内总波数的增加作为EEG效应指标。苯妥英的药代动力学用具有米氏消除的饱和动力学模型描述。在皮质刺激模型中，对于抗惊厥作用，Vmax和Km值分别为386±31μg·min⁻¹和15.4±2.2μg·ml⁻¹；对于EEG效应，Vmax和Km值分别为272±31μg·min⁻¹和5.9±0.7μg·ml⁻¹。在两组中，相对于血浆浓度均观察到效应起效延迟。通过平衡动力学程序估计苯妥英血浆浓度与效应部位之间的关系，抗惊厥和EEG效应的平均ke0值分别为0.108和0.077min⁻¹。EEG总波数的变化可用S形Emax模型拟合，但由于浓度与TGS升高之间的非线性关系，无法估计Emax值。在假设在可接受的电刺激水平内无法达到Emax值的情况下，应用从S形Emax模型导出的指数方程（E = E0 + Bⁿ·Cⁿ）来描述浓度-抗惊厥效应关系。该方法得出系数（B）为2.0±0.4μA·ml·μg⁻¹，指数（n）为2.7±0.9。EEG效应的推导EC50值为12.5±1.3μg·ml⁻¹，与人类的“治疗范围”一致。
