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目的:采用药动-药效结合模型观察普罗帕酮血浆浓度与心电图指标PR间期延长百分率的数量关系,并求算药效学参数。方法:选择健康汉族受试者10名,其中CYP2D6表型的快代谢型(EM)和中速代谢型(IM)各5名。受试者口服普罗帕酮片剂400mg,于给药后15h内抽取静脉血,并同步测定受试者PR间期。普罗帕酮浓度采用高效液相色谱分析法测定。采用CAPP软件对普罗帕酮血药浓度及PR间期延长百分率进行药动-药效结合模型计算。结果:10例健康志愿者的普罗帕酮血浆浓度与效应之间存在着滞后现象。经采用CAPP软件拟合数据,发现效应与浓度之间符合Sigmoid E_(max)模型。IM组的AUC(μg·h·L~(-1))明显高于EM组(5126±1030 vs2948±1230,P<0.05);相对应药效参数Ce_(50)IM组也比EM组大(P<0.05)。另外,效应曲线S线程度的参数γEM组大于IM组(P<0.05)。结论:CYP2D6遗传多态性不但对普罗帕酮的药动学有影响,而且对其药效学参数可能也有明显的影响。
OBJECTIVE: To observe the quantitative relationship between the plasma concentration of propafenone and the percentage of prolongation of PR interval of electrocardiogram (ECG) by pharmacokinetic-pharmacodynamic binding model and calculate pharmacodynamic parameters. Methods: Ten healthy Han subjects were selected, including 5 fast metabolome (EM) and moderately mesomorphic (IM) CYP2D6 phenotypes. Subjects were given propafenone 400 mg tablets intravenously within 15 h after administration of venous blood samples, and simultaneous determination of subjects PR interval. Propafenone concentrations were determined by high performance liquid chromatography. CAPP software was used to calculate the concentration of propafenone and the percentage of prolongation of PR interval. Results: There was a lag between propafenone plasma concentration and effect in 10 healthy volunteers. After fitting the data by using CAPP software, it was found that the effect and concentration accord with Sigmoid E max model. The AUC (μg · h · L -1) in IM group was significantly higher than that in EM group (5126 ± 1030 vs 2948 ± 1230, P <0.05) (P <0.05). In addition, the effect of the curve S-line parameters γEM group IM group (P <0.05). CONCLUSION: CYP2D6 genetic polymorphism not only affects the pharmacokinetics of propafenone, but also may have a significant effect on its pharmacodynamic parameters.