Ellinwood E H, Heatherly D G, Nikaido A M, Bjornsson T D, Kilts C
Psychopharmacology (Berl). 1985;86(4):392-9. doi: 10.1007/BF00427897.
The contribution of differential absorption-distribution pharmacokinetics to drug activity can be partially determined by comparing simultaneous estimates of drug serum level with pharmacodynamic effects. In the present paper we have contrasted the effects of clinically equipotent doses of lorazepam, alprazolam, and diazepam on the performance of tracking and digit symbol substitution tasks. Eight young males were tested for 12 h after ingesting the drug. The three benzodiazepines and placebo were administered to each subject according to a balanced double-blind Latin square design. A model is presented that describes the relationship between drug concentration and the degree of impairment across time after the final peak effect. Exponential rate constants were determined for each drug using a Marquardt nonlinear fit of the pooled data. Basically, the constants relate offset serum drug values to the impairment curves at a time when serum-brain equilibrium is assumed to have occurred. The values indicate markedly rapid acute tolerance for alprazolam and diazepam but relatively little acute tolerance for lorazepam. Whether these constants reflect adaptation or differential association-dissociation receptor rate constants cannot be determined, but they do highlight the need to consider receptor kinetics as an important factor in benzodiazepine pharmacodynamics.
通过比较药物血清水平与药效学效应的同步估计值，可以部分确定差异吸收-分布药代动力学对药物活性的贡献。在本文中，我们对比了临床等效剂量的劳拉西泮、阿普唑仑和地西泮对追踪和数字符号替换任务表现的影响。八名年轻男性在服用药物后接受了12小时的测试。根据平衡双盲拉丁方设计，将三种苯二氮䓬类药物和安慰剂给予每个受试者。提出了一个模型，该模型描述了最终峰值效应后药物浓度与随时间的损害程度之间的关系。使用合并数据的Marquardt非线性拟合为每种药物确定指数速率常数。基本上，这些常数将血清药物抵消值与假定发生血清-脑平衡时的损害曲线相关联。这些值表明阿普唑仑和地西泮有明显快速的急性耐受性，而劳拉西泮的急性耐受性相对较小。这些常数是否反映适应性或差异结合-解离受体速率常数尚无法确定，但它们确实突出了将受体动力学视为苯二氮䓬类药物药效学重要因素的必要性。
