美托洛尔光学异构体在犬体内的药动学-药效学结合模型

PHARMACOKINETIC PHARMACODYNAMIC MODELING OF METOPROLOL ENANTIOMERS IN THE DOG

用麻醉犬研究美托洛尔（Ｍｅｔ）光学异构体药动学—药效学结合模型。结果表明，ｉｇ（＋）Ｍｅｔ或（－）Ｍｅｔ后，其药动学符合二室模型，药动学参数Ｖｄ／Ｆ，ＣＬｓ／Ｆ和ＡＵＣ在两种Ｍｅｔ之间有显著性差异。（＋）Ｍｅｔ和（－）Ｍｅｔ的效应和血药浓度关系呈逆时针滞后环。引入效应室理论后，药效和效应室浓度之间的关系符合ＳｉｇｍｏｉｄＥｍａｘ模型。应用ＣＡＰＰ软件进行模型拟合，血药浓度的预测值和药效的预测值皆与其实测值较为接近。（＋）Ｍｅｔ抑制Ｖｍａｘ，ｄｐ／ｄｔｍａｘ及ＨＲ效应的Ｃｅ５０分别是（－）Ｍｅｔ的３７，６８，６３倍，证实（－）Ｍｅｔ对犬心脏的抑制作用强于（＋）Ｍｅｔ。

The PK PD model of (+) Met and (-) Met was studied in anesthetized dogs. The plasma drug concentration time profiles were most adequately described by two compartment model. Significant differences of V d/ F , CL s/ F and AUC between (+) Met and (-) Met were observed. The peak times of plasma (+) Met and (-) Met concentration in dogs were 24±5 and 30±5 min, respectively. But the peak times of drug inhibitory effects on V max , d p /d t max , LVSP, SBP and HR were about 90～120 min, showing the hysteresis loops. When using the effect compartment model, the counterclock wise hysteresis collapsed and the relationships between the effects and concentration in effect compartment were fit by using Sigmoid E max model. The C e 50 values of inhibitory effects on V max , d p /d t max and HR of (+) Met were 250±80, 450±210, 520±210 μg·L -1 and those of (-) Met were 70±30, 70±40 and 82±27 μg·L -1 , respectively. Significant differences of C e 50 of (+) Met and (-) Met were found. The values of C e 50+ / C e 50- were 3 7, 6 8 and 6 3, indicating that the inhibitory effects on V max , d p /d t max and HR of (-) Met were stronger than those of (+) Met in dogs.