美托洛尔和厄贝沙坦降压效应的药代动力学-药效学结合模型研究

目的 β₁受体阻断剂联合血管紧张素Ⅱ受体拮抗剂在高血压治疗指南中，不做为优先推荐，但临床联合用药比较常见。选取美托洛尔(Metoprolol)为代表的选择性β₁受体阻断剂，和厄贝沙坦(Irbesartan)为代表的非肽类血管紧张素Ⅱ受体AT₁的拮抗药，研究它们在高血压患者体内的药代动力学-药效学结合模型，探讨二者降压作用特征，为临床个体化合理用药提供依据。 方法 将24例高血压患者分为2组，分别口服美托洛尔和厄贝沙坦，测定服药后不同时间的血药浓度和血压，计算药代动力学参数，采用Sheiner等提出的药动学药效学结合模型计算药效学参数，比较降压作用的实测值和预测值。 结果 高血压患者口服美托洛尔和厄贝沙坦体内代谢分别呈一室和二室模型，两药降压效应均滞后于血药浓度，存在逆时针滞后环，应用Sigmoid-Emax药效动力学模型研究效应室浓度与降压作用关系，美托洛尔和厄贝沙坦Ce (50)和Keo分别为(130.2±68.4)μg/L、(0.051±0.025)/min以及(380±140)μg/L、(0.54±0.08)/h，其降压作用的实测值和模型预测值接近。 结论 应用药动学、药效学结合模型研究美托洛尔和厄贝沙坦降压作用，可为其临床合理用药提供参考。 

Pharmacokinetic-pharmacodynamicsmodeling antihypertensive effect of metoprolol and irbesartan

Objective In hypertension treatment guidelines,Beta-1 receptor antagonist combined with angiotensin Ⅱ receptor antagonist are not be recommended for priority.But it is common for the combination of both medicines in clinical practice.In order to provide evidence for the rational use of clinical drug,metoprolol were selected as selective beta 1 receptor blocker,Irbesartan was chosen as the representative of the angiotensin receptor Ⅱ.In patients with high blood pressure,a pharmacokinetic pharmacodynamics-combination model was established,to discuss the antihypertensive effect characteristics of the two drugs. Methods A total number of 24 patients with hypertension were divided into two groups,one group was given metoprolol,another group were given Irbesartan.The blood drug concentration and blood pressure were measured.To calculate the pharmacokinetic parameters,the blood drug concentration and blood pressure were measured at different time.The pharmacodynamics parameters were also determined using combined pharmacokinetic-pharmacodynamics(PK-PD) model presented by Sheiner et al.The data of reduced blood pressure were determined and compared with the predicted data. Results The pharmacokinetic profiles of metoprolol and irbesartan were fitted to one and two compartment model respectively.There was an anticlockwise hysteresis loop between antihypertensive effect and plasma concentrations of the agents.The relationship between antihypertensive effect and concentration of effect compartment of the agents was investigated using Sigmoid-Emax model.The data of Ce(50) and Keo for metoprolol and irbesartan were (130.2±68.4)μg/L,(0.051±0.025)/min and (380±140)μg/L,(0.54±0.08)/h,respectively.The determined data of the antihypertensive effect was close to those predicted. Conclusion To Study the antihypertensive effect of metoprolol and irbesartan with PK-PD model may be more rational for the clinical medication.