美托洛尔在家兔和肾性高血压大鼠体内的药代动力学-药效学结合模型

正常家兔 im1 0 ,1 5mg· kg-1和肾性高血压大鼠 ig美托洛尔 ,研究药物在两种动物体内降低心率和血压效应与药代动力学之间的关系 ,用高效液相荧光检测药物浓度 ,结果显示 :美托洛尔血药浓度时间曲线均符合二室模型 ,其降低心率和血压的最大效应明显滞后于血药浓度 .应用 Sheiner等提出的药代动力学 -药效学结合模型 ,用多维函数一次搜寻法对效应室药物浓度 ( Ce)与抑制心率及降低血压效应进行拟合 ,得出美托洛尔在两种动物体内的Ce和抑制心率效应之间的关系符合 Sigmoid- Emax模型 ,而 Ce 和降低血压效应之间的关系符合 β-功能模型 ,以上效应的预测值和实测值拟合良好 ,因此认为以上数学模型可以应用于动物实验中效应的预测 .

Simultaneous pharmacokinetic and pharmacodynamic model of metoprolol in rabbits and renal hypertensive rats

After the rabbits were injected im with 10, 15 mg·kg^-1 and the renal hypertensive rats were administered ig with 10 mg·kg^-1 of metoprolol, the relationship between pharmacokinetics and pharmacodynamics (heart rate decrease and systolic pressure reduction) was described. The plasma drug concentration (C_p) was measured by HPLC. Results indicated that C_p time curves fitted two compartment open model, the maximum pharmacologic effects E_max of decreasing heart rate and artery systolic pressure were hysteretic clearly. By means of simultaneous pharmacokinetic and pharmacodynamic model (PK-PD model), proposed by Sheiner and coworkers, we fitted the relationship between the concentration of effect site (C_e) and its effects with the method of multidimensional function monosearching. The results showed that the relationship between C_e and the E_max on heart rate decrease fitted Sigmoid E_max model and the relationship between C_e and the E_max on systolic pressure reduction fitted β-function model. All the data of the predicted effect and the experimental effect fitted well. The results suggest that the mathematic model be used in predicting effects in animal experiments.