Encainide and its metabolites. Comparative effects in man on ventricular arrhythmia and electrocardiographic intervals.
Encainide and its metabolites. Comparative effects in man on ventricular arrhythmia and electrocardiographic intervals.
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恩卡尼及其代谢物。
DOI：
10.1172/jci111241
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发表时间：
1984
期刊：
影响因子：
--
通讯作者：
Woosley,RL
中科院分区：
文献类型：
--
作者：
CareyJr,EL;Duff,HJ;Roden,DM;Primm,RK;Wilkinson,GR;Wang,T;Oates,JA;Woosley,RL
为了评估恩卡尼及其代谢产物O-去甲基恩卡尼（ODE）和3-甲氧基-O-去甲基恩卡尼（3 MODE）对药物药理作用的相对贡献，我们比较了两组表型不同的患者（恩卡尼的快代谢者和慢代谢者）的静脉输注和持续口服治疗。与慢代谢者不同，快代谢者血浆中可检测到相当数量的两种代谢物，恩卡尼的消除半衰期缩短四倍。通过定量心电图间期、心律失常频率和血浆浓度，我们发现，在弱代谢者中，心律失常抑制和心室综合征（QRS）延长与恩卡尼浓度呈正相关（r大于或等于0.570，P小于0.014）。在这两个主题中，恩卡尼的抗组胺浓度（大于265 ng/ml）至少比在稳态口服治疗期间的6个强代谢者中持续的浓度高5倍。在快代谢者中，恩卡尼浓度与效应无关。快代谢型患者的心律失常抑制和QRS延长与ODE相关性最好（r ≥ 0.816，P <0.001）; QTc变化与3 MODE和ODE均呈正相关。心律失常抑制与QRS延长之间的关系在两个表型组中相似。在大多数患者中，强代谢型，恩卡尼在口服治疗期间的作用是由代谢物介导的，可能是ODE。
To assess the relative contributions of encainide and its putatively active metabolites, O-demethyl encainide (ODE) and 3 methoxy-O-demethyl encainide (3MODE), to the drug's pharmacologic effects, we compared intravenous infusions and sustained oral therapy in two phenotypically distinct groups of patients, extensive and poor metabolizers of encainide. Unlike poor metabolizers, extensive metabolizers had appreciable quantities of both metabolites detectable in plasma and had fourfold shorter elimination half-lives for encainide. By quantitating electrocardiogram intervals, arrhythmia frequency, and plasma concentrations, we found that, in poor metabolizers, arrhythmia suppression and ventricular complex (QRS) prolongation were correlated positively with encainide concentrations (r greater than or equal to 0.570, P less than 0.014). In these two subjects, antiarrhythmic concentrations of encainide (greater than 265 ng/ml) were at least fivefold higher than those sustained in the six extensive metabolizers during steady state oral therapy. In extensive metabolizers, encainide concentrations were uncorrelated with effects. Arrhythmia suppression and QRS prolongation in extensive metabolizers correlated best with ODE (r greater than or equal to 0.816, P less than 0.001); QTc change correlated positively with both 3MODE and ODE. Arrhythmia suppression paralleled QRS prolongation; the relationship between them appeared similar in both phenotypic groups. In most patients, extensive metabolizers, encainide effects during oral therapy are mediated by metabolites, probably ODE.