Danhof M, Mandema J W
Center for Bio-Pharmaceutical Sciences, Sylvius Laboratory Leiden, The Netherlands.
Int J Clin Pharmacol Ther Toxicol. 1992 Nov;30(11):516-9.
The pharmacodynamics and pharmacodynamic interactions of benzodiazepines have been determined using amplitudes in the 12-30 Hz frequency band of the EEG as a measure of the pharmacological response. Following the administration of a single intravenous dose, plasma concentration and pharmacological effect versus time profiles were determined and subjected to simultaneous pharmacokinetic-pharmacodynamic modelling to derive individual concentration EEG effect relationships. For flunitrazepam, midazolam, oxazepam and clobazam the concentration EEG effect relationships could be characterized on basis of the sigmoid Emax model. The values of the EC50 differed widely. A close correlation between the value of the EC50 and the affinity to the nanomolar benzodiazepine receptor in vitro was observed. For midazolam, bretazenil, flumazenil and Ro 19-4603 in addition to differences in potency also widely different values of the Emax were observed, which are in agreement with the known pharmacological properties of these compounds. The pharmacodynamic interaction between midazolam and flumazenil was characterized both under steady-state and non steady-state conditions. It was found that the effects of combined treatment with these drugs can be described and predicted on the basis of a competitive interaction model. The findings of these studies demonstrate that on the basis of an integrated pharmacokinetic-pharmacodynamic approach, important information on the pharmacodynamics and pharmacodynamic interactions of CNS active drugs can be obtained.
苯二氮䓬类药物的药效学及药效学相互作用已通过将脑电图（EEG）12 - 30Hz频段的振幅作为药理反应的指标来确定。单次静脉给药后，测定血浆浓度和药理效应随时间的变化曲线，并进行同时的药代动力学 - 药效学建模，以得出个体浓度 - EEG效应关系。对于氟硝西泮、咪达唑仑、奥沙西泮和氯巴占，浓度 - EEG效应关系可基于S形Emax模型进行表征。EC50值差异很大。观察到EC50值与体外对纳摩尔级苯二氮䓬受体的亲和力之间存在密切相关性。对于咪达唑仑、布雷他西尼、氟马西尼和Ro 19 - 4603，除了效价差异外，还观察到Emax值差异很大，这与这些化合物已知的药理特性一致。在稳态和非稳态条件下均对咪达唑仑和氟马西尼之间的药效学相互作用进行了表征。发现基于竞争性相互作用模型可以描述和预测这些药物联合治疗的效果。这些研究结果表明，基于综合的药代动力学 - 药效学方法，可以获得关于中枢神经系统活性药物药效学及药效学相互作用的重要信息。
