美托洛尔在正常大鼠和自发性高血压大鼠体内的药代动力学-药效学结合模型

用麻醉正常大鼠(NR)和麻醉自发性高血压大鼠(SHR)研究美托洛尔混旋体(Met)药动学-药效学之间的关系. Sig Met后, Met在NR及大多数SHR上的血药浓度-时间曲线呈二室模型. 药动学参数k_a, k_e，t_1/2ka，t_1/2α，t_1/2β在两种大鼠间有显著性差异. Met抑制SHR和NR的V_max，dp/dt_max，LVSP, SBP及HR效应和血药浓度之间存在着逆时针滞后环. 引入效应室理论后, 药效和效应室浓度间的关系符合Sigmoid-E_max模型. Met抑制V_max, dp/dt_max, LVSP及SBP作用在SHR上的C_ss50分别是NR的1.6, 3.2, 4.3和3.0倍, 而减慢SHR心率的作用仅为NR的28%.

Simultaneous modeling of metoprolol pharmacokinetics and pharmacodynamics in normotensive and spontaneously hypertensive rats

The combined pharmacokinetic and pharmacodynamic relationships of metoprolol (±)-Met] were studied in anesthetized normotensive rats (NR) and spontaneously hypertensive rats (SHR). After ig (±)-Met, the plasma (±)-Met concentration- time profiles of NR and most of SHR were adequately described by a two compartment model. Significant#O&;differences of pharmacokinetic parameters k_a, k_e, t_1/2ka, t_1/2α, and t_1/2β between NR and SHR were found. The peak times of plasma (±)-Met concentration in SHR and NR were 13.0±1.2 and 12.3±2.0 min, respectively, but the peak times of (±)-Met inhibitory effects on V_max, dp/dt_max, LVSP, SBP and HR were about 30-40 min, showing the hysteresis of effect-plasma concentration. When the effect compartment model was used, the counterclockwise hysteresis disappeared and the relationships between the effects and concentration in effect compartment were fit by using Sigmoid-E_max model. The C_ss50 values (x±s) of V_max, dp/dt_max, LVSP, SBP and HR in SHR were 0.24±0.11, 0.25±0.10, 0.32±0.20, 0.30±0.17, and 0.68±0.38 mg·L^-1, while those in NR were 0.37±0.10, 0.81±0.12, 1.34±0.41, 0.89±0.34, and 0.19±0.09 mg·L^-1, respectively, demonstrating that the former four inhibitory effects in SHR were 1.6, 3.2, 4.3, 3.0 times as strong as those in NR, and the HR inhibitory effect in SHR was only 28% of that in NR.