Cleton A, Mazee D, Voskuyl R A, Danhof M
Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.
Br J Pharmacol. 1999 May;127(1):227-35. doi: 10.1038/sj.bjp.0702499.
The objective of this investigation was to characterize quantitatively the influence of the rate of increase in blood concentrations on the pharmacodynamics of midazolam in rats. The pharmacodynamics of midazolam were quantified by an integrated pharmacokinetic-pharmacodynamic modelling approach. Using a computer controlled infusion technique, a linear increase in blood concentrations up to 80 ng ml(-1) was obtained over different time intervals of 16 h, resulting in rates of rise of the blood concentrations of respectively, 1.25, 1.00, 0.87, 0.46, 0.34 and 0.20 ng ml(-1) min(-1). In one group of rats the midazolam concentration was immediately brought to 80 ng ml(-1) and maintained at that level for 4 h. Immediately after the pretreatment an intravenous bolus dose was given to determine the time course of the EEG effect in conjunction with the decline of midazolam concentrations. The increase in beta activity (11.5-30 Hz) of the EEG was used as pharmacodynamic endpoint. For each individual animal the relationship between blood concentration and the EEG effect could be described by the sigmoidal Emax model. After placebo, the values of the pharmacodynamic parameter estimates were Emax = 82+/-5 microV, EC50,u = 6.4+/-0.8 ng ml(-1) and Hill factor = 1.4+/-0.1. A bell-shaped relationship between the rate of change of midazolam concentration and the value of EC50,u was observed with a maximum of 21+/-5.0 ng ml(-1) at a rate of change of 0.46 ng ml(-1) min(-1); lower values of EC50,u were observed at both higher and lower rates. The findings of this study show that the rate of change in plasma concentrations is an important determinant of the pharmacodynamics of midazolam in rats.
本研究的目的是定量表征血药浓度上升速率对大鼠咪达唑仑药效学的影响。采用药代动力学-药效学整合建模方法对咪达唑仑的药效学进行定量分析。利用计算机控制输注技术，在16小时的不同时间间隔内使血药浓度线性上升至80 ng/ml，血药浓度上升速率分别为1.25、1.00、0.87、0.46、0.34和0.20 ng/(ml·min)。在一组大鼠中，将咪达唑仑浓度立即升至80 ng/ml并维持4小时。预处理后立即静脉注射推注剂量以确定脑电图效应的时间进程以及咪达唑仑浓度的下降情况。脑电图β波活动（11.5 - 30 Hz）的增加用作药效学终点。对于每只动物，血药浓度与脑电图效应之间的关系可用S型Emax模型描述。给予安慰剂后，药效学参数估计值为Emax = 82±5 μV，EC50,u = 6.4±0.8 ng/ml，希尔系数 = 1.4±0.1。观察到咪达唑仑浓度变化率与EC50,u值之间呈钟形关系，在变化率为0.46 ng/(ml·min)时最大值为21±5.0 ng/ml；在较高和较低变化率时均观察到较低的EC50,u值。本研究结果表明，血浆浓度变化率是大鼠咪达唑仑药效学的重要决定因素。
