COMPARATIVE PHARMACOKINETICS AND PHARMACODYNAMICS OF LORAZEPAM, ALPRAZOLAM AND DIAZEPAM
COMPARATIVE PHARMACOKINETICS AND PHARMACODYNAMICS OF LORAZEPAM, ALPRAZOLAM AND DIAZEPAM
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DOI：
10.1007/bf00427897
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发表时间：
1985-01-01
影响因子：
3.4
通讯作者：
KILTS, C
中科院分区：
文献类型：
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作者：
ELLINWOOD, EH;HEATHERLY, DG;KILTS, C
差异吸收-分布药代动力学对药物活性的贡献可以通过比较药物血清水平的同时估计值与药效学效应来部分确定。比较临床等效剂量的劳拉西泮、阿普唑仑和地西泮对跟踪和数字符号替换任务表现的影响。 8 名年轻男性在服用该药物后 12 小时内接受了测试。根据平衡双盲拉丁方设计，对每个受试者施用 3 种苯二氮卓类药物和安慰剂。提出了一个模型，描述药物浓度与最终峰值效应后随时间的损害程度之间的关系。使用汇总数据的 Marquardt 非线性拟合确定每种药物的指数速率常数。基本上，这些常数将血清药物偏移值与假设发生血清-脑平衡时的损伤曲线相关联。这些值表明对阿普唑仑和地西泮具有显着快速的急性耐受性，但对劳拉西泮的急性耐受性相对较低。无法确定这些常数是否反映了适应或差异缔合-解离受体速率常数，但它们确实强调需要考虑受体动力学作为苯二氮卓药效学的重要因素。
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. The effects of clinically equipotent doses of lorazepam, alprazolam, and diazepam were contrasted on the performance of tracking and digit symbol substitution tasks. Eight young males were tested for 12 h after ingesting the drug. The 3 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 adapatation 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.