普萘洛尔对映体的药代─药效学相关性研究

THE CORRELATION BETWEEN PHARMACOKINETICS AND PHARMACODYNAMICS OF PROPRANOLOL ENANTIOMERS

本文研究１２名健康志愿者口服多剂量普萘洛尔后，Ｓ（－）－型和Ｒ（＋）－型对映体的药代动力学和药效动力学特点，以及两种对映体的立体选择性差异对药效学的影响。负荷心电图、心率、Ｑ－Ｔｃ间期及血压作为药效学观察指标。稳态时普萘洛尔对映体的药代动力学特点为，Ｓ（－）－ＰＰＬ与Ｒ（＋）－ＰＰＬ的消除半衰期（Ｔ＿（１／２）Ｋｅ）基本一致，分别为４．７４±１．４０ｈ和４．５６±１．０５ｈ，Ｐ＞０．０５；但稳态的血药浓度较单剂量明显不同，Ｓ（－）／Ｒ（＋）的ＡＵＣ比值从单剂量１．５４±０．３６下降到稳态时１．３２±０．２４μｇ·ｈ（－１）·Ｌ（－１），Ｐ＜０．０５。稳态时药效动力学采用Ｓｉｇｍｏｉｄ模型描述。Ｓ（－）－ＰＰＬ抑制平均血压（ＭＢＰ）、运动心率（ＨＲ）和Ｑ－Ｔｃ间期效应的半效血药浓度分别为１８．９±１１．３μｇ／ｌ，１３．６±７．６μｇ／ｌ和８．７±６．１μｇ／ｌ，三者具有显著性差异（Ｐ＜０．０１）。Ｑ－Ｔｃ间期的浓度－效应曲线呈现明显的滞后现象。药代动力学与药效学结合分析时发现，当活性对映体以Ｓ（－）－ＰＰＬ在消旋药物总浓度中所占的比例逐渐增大时，ＰＰＬ的浓度－效应曲线呈现逆时针滞后环；而当活性对映体在总浓度?

The correlation between pharmacokinetics and pharmacodynamics of propranolol and its enantiotners were evaluated in 12 healthy subjects who received 40mg of racemate as a single dose and then consecutive administration for 4 days.Pharmacological response was assessed by use of standardized treadmill test, the heart-rate,Q-Tc interval and blood pressure were taken immediately following exercise. The pharmacokinetic characteristics of propranolol enantiomers at steady-state are that the half-life of elimination did not differ significantly between S(-)-propranolol and R(+)-propranolol(4.74±1. 40hversus 4.56± 1.05h, P>0.05), but the AUC ratio(S /R) decreased from 1.54 ±0.36 after single doses to 1. 32± 0. 24 μg·h(-1)·L(-1) at steady-state (P<0.05). Therefore, it was not oarallel for nonlinear accumulation in the two enantiomers. The pharmacodynamics at steady-state was depicted by Sigmoid model. The EC50,plasma concentrations of S(-)-propranolol producing 5%, maximal efficacy for the mean blood pressure (MBP), the heart-rate during exercise and the Q-Tc interval, were 18.9 ± 11.3μg /l, 13.6 ± 7. 6μg/l and 8. 7±6.1 μg/l respectively, the differences of the concentrations producing the three effects were significant(P< 0.01).Meanwhile, the hysteresis loops of the concentration-effect curves of the Q-Tc interval were observed. The concentration-effect curves and concentration-time courses for the drug and its enantiomers were simultancously analysed. When the active enantiomer S(-)-propranolol constitutes a greater portion of the total concentrations as time progresses after the drug adminlstration, the relationship between the plasma concentration of the racemate and its effect appeared a counterclockwise hysteresis, convcrxely,a smaller proportion of the active enantiomer in the total concentrations would result in a clockwise hysteresis.These resluts indieate that the pharmacodynamic differences of propranolol should be reevaluated from the aspect of stereoselcctive chemistry.