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考察8名汉族男性健康志愿者口服80mg和静滴5mg外消旋维拉帕米的心血管效应(心率、血压和PR间期),并结合对映体药代动力学分析其药效学特性。以三甲基-β-环糊精为手性选择剂,毛细管电泳法测定维拉帕米对映体血浆浓度。用药代动力学-药效学结合模型,即二房室模型加效应室,估算以维拉帕米总浓度和S-(-)-维拉帕米浓度对PR间期延长百分率的药效学参数。口服给药时,以维拉帕米总浓度估算的药效学参数Emax(%),CE50(μg·L-1),Keo和γ分别为43.7±21.1,69.4±30.3,3.64±4.7和2.85±2.01;以S-(-)-维拉帕米估算的药效学参数分别为47.7±26.9,14.3±8.5,5.23±5.5和3.24±1.8。静脉给药时,以维拉帕米总浓度估算的药效学参数分别为35.2±13.3,29.7±12.9,6.36±3.2和2.28±1.6;以S-(-)-维拉帕米估算的药效学参数分别为35.7±17.2,13.4±8.41,7.13±3.42和2.52±1.52。因此,在不同给药途径下或对映体比率的个体间差异较大时,以S-(-)-维拉帕米浓度与效应拟合药效学参数,较总浓度更有临床意义。
The cardiovascular effects (heart rate, blood pressure and PR interval) of oral administration of 80 mg and intravenous infusion of 5 mg racemic verapamil in 8 Han male volunteers were investigated and their pharmacodynamic properties were analyzed in combination with enantiomer pharmacokinetics . The enantiomeric plasma concentrations of verapamil were determined by capillary electrophoresis with trimethyl-β-cyclodextrin as chiral selector. A pharmacokinetic-pharmacodynamic model, a two-compartment model with an effect chamber, was used to estimate the pharmacodynamic parameters of the verapamil total concentration and the S - (-) - verapamil concentration for the percentage of prolongation of the PR interval . At oral administration, the pharmacodynamic parameters Emax (%), CE50 (μg · L-1), Keo and γ estimated at the total concentration of verapamil were 43.7 ± 21.1 and 69.4 ± 30 .3, 3.64 ± 4.7 and 2.85 ± 2.01, respectively. The pharmacodynamic parameters estimated by S - (-) - verapamil were 47.7 ± 26.9 and 14.3 ± 8.5, 5.23 ± 5.5 and 3.24 ± 1.8. Pharmacodynamic parameters estimated at the total verapamil concentration of 35.2 ± 13.3, 29.7 ± 12.9, 6.36 ± 3.2 and 2.28 ± 1, respectively, for intravenous administration. 6; the pharmacodynamic parameters estimated with S - (-) - verapamil were 35.7 ± 17.2, 13.4 ± 8.41, 7.13 ± 3.42 and 2.52 ± 1 .52. Therefore, the pharmacodynamic parameters fitted by S - (-) - verapamil concentration and effect were more significant than the total concentration when there were significant differences between individuals under different routes of administration or enantiomeric ratios.