Simultaneous modeling of pharmacokinetics and pharmacodynamics of propafenone in healthy subjects  

普罗帕酮在健康受试者中的药动-药效学结合模型研究(英文)

作　　者：蔡卫民[1] 张银娣 陈冰 蔡明虹 罗建平 凌树森[2] 

机构地区：[1]Fellow in College of Phamacy,University of Kenucky,USA postdoctoral [2]南京金陵医院临床药理科,南京中国210029 [3]南京医科大学临床药理研究所

出　　处：《Acta Pharmacologica Sinica》2001年第10期956-960,共5页中国药理学报（英文版）

摘　　要：AIM: To study the simultaneous modeling of pharmacokinetics and pharmacodynamics (PK-PD) of propafenone (Pro) in healthy subjects. METHODS: Ten healthy Chinese volunteers, 5 extensive metabolizers (EM) and 5 intermediate metabolizers ( IM) of CYP2D6, received a single dose (400 mg) of Pro hydrochloride. The blood samples and electrocardiogram (ECG) measurements were taken after administration over 15 h period. The concentrations of Pro in plasma were measured by a reverse-phase HPLC. PR interval was used as an average value of 10 PR interval measurements. RESULTS: There was a delay between Pro level and percentage of PR interval prolongation. After PK-PD simulating, the relationship between effect concentration (Ce) and the effect met the sigmoid Emax model. CYP2D6 (EM & M) played an important role in both pharmacokinetics and pharmacodynamics which produced by Pro. The AUC (μg·h·L-1) of M group was significantly higher than that of EM group (5126 ± 1030 vs 2948 ± 1230, P < 0.05). Whereas Cex (μg/L) was also greater in IM group than in EM group (747 ± 281 vs 359 ± 123, P < 0.05). On the other hand, r of EM group was about one fold larger than that of IM group (P <0.05). CONCLUSION: CYP2D6 phenotype of human may influence not only pharmacokinetic of Pro but also its pharmacological effects.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。

关 键 词：PROPAFENONE PHARMACOKINETICS MODELS cytochrome P-450 CYP2D6 

分 类 号：R96[医药卫生—药理学]