Hoogerkamp A, Arends R H, Bomers A M, Mandema J W, Voskuyl R A, Danhof M
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, The Netherlands.
J Pharmacol Exp Ther. 1996 Nov;279(2):803-12.
The in vivo concentration-anticonvulsant effect relationships of six benzodiazepines, midazolam, clonazepam, oxazepam, flunitrazepam, diazepam and clobazam were quantified in individual rats and correlated with the affinity to the GABAA-benzodiazepine receptor complex. Furthermore the interaction between midazolam and the benzodiazepine antagonist flumazenil was characterized. All benzodiazepines exhibited a nonlinear relationship between concentration and anticonvulsant effect without ceiling of the effect at higher concentration. The potency of most benzodiazepines was similar with values of the EC250, between 0.067 +/- 0.01 mg. l-1 for midazolam and 0.21 +/- 0.03 mg. l-1 for diazepam. The EC250,u of clobazam was 2.8 +/- 0.9 mg. l-1. These values were considerably larger than the Ki for binding at the GABAA-benzodiazepine receptor complex. No correlation was observed between EC250,u and Ki. Antagonism of the anticonvulsant effect of midazolam by flumazenil was associated with a remarkable change in the concentration-anticonvulsant effect relationship. Analysis of these data on basis of a composite model provided evidence for two separate effects of which only one is antagonized by flumazenil. The anticonvulsant effect at low midazolam concentration was characterized on basis of the sigmoid E maximal effect pharmacodynamic model. The value of the EC50,u was 0.0086 +/- 0.0013 mg. l-1 which is similar to the Ki for binding at the GABAA-benzodiazepine receptor complex. The second more pronounced anticonvulsant effect occurred at higher concentration and was described by an exponential function. The findings of this study indicate that the effect of benzodiazepines against seizures induced by cortical stimulation in vivo cannot be fully accounted for by an interaction at the GABAA-benzodiazepine receptor complex.
在个体大鼠中对六种苯二氮䓬类药物（咪达唑仑、氯硝西泮、奥沙西泮、氟硝西泮、地西泮和氯巴占）的体内浓度 - 抗惊厥作用关系进行了量化，并将其与对GABAA - 苯二氮䓬受体复合物的亲和力相关联。此外，还对咪达唑仑与苯二氮䓬拮抗剂氟马西尼之间的相互作用进行了表征。所有苯二氮䓬类药物在浓度与抗惊厥作用之间均呈现非线性关系，且在较高浓度时效应无上限。大多数苯二氮䓬类药物的效价相似，咪达唑仑的EC250值为0.067±0.01mg·l-1，地西泮的EC250值为0.21±0.03mg·l-1。氯巴占的EC250,u为2.8±0.9mg·l-1。这些值远大于在GABAA - 苯二氮䓬受体复合物上结合的Ki值。未观察到EC250,u与Ki之间的相关性。氟马西尼对咪达唑仑抗惊厥作用的拮抗与浓度 - 抗惊厥作用关系的显著变化相关。基于复合模型对这些数据的分析提供了证据，表明存在两种独立的效应，其中只有一种可被氟马西尼拮抗。低浓度咪达唑仑的抗惊厥作用基于S形E最大效应药效学模型进行表征。EC50,u值为0.0086±0.0013mg·l-1，这与在GABAA - 苯二氮䓬受体复合物上结合的Ki值相似。第二种更明显的抗惊厥作用发生在较高浓度时，可用指数函数描述。本研究结果表明，苯二氮䓬类药物在体内对皮质刺激诱导的癫痫发作的作用不能完全通过在GABAA - 苯二氮䓬受体复合物上的相互作用来解释。
