Antiarrhythmic activity, electrocardiographic effects and pharmacokinetics of the encainide metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide in man

Abstract

Although encainide is an effective antiarrhythmic agent, plasma concentrations and pharmacologic effects are not well correlated. One explanation is the generation of active metabolites: while in most patients (extensive metabolizers; EMs) concentrations of the metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (3MODE) are higher than those of encainide, a small subset (poor metabolizers: PMs) lack the ability to extensively biotransform encainide. Considerable data from studies in vitro and animal studies, as well as indirect evidence in patients, indicate that ODE and 3MODE produce the effects seen during long-term encainide therapy in EMs. We now report the initial direct evaluation of the pharmacologic actions of the metabolites of encainide in man. Nine patients with ventricular arrhythmias, seven of the EM phenotype and two of the PM phenotype, were studied. Chronic high-frequency ventricular arrhythmias were suppressed by encainide therapy in seven of nine; monitoring arrhythmia frequency during withdrawal of encainide allowed definition of plasma concentrations of encainide and metabolites associated with arrhythmia suppression. Intravenous infusions of both ODE and 3MODE suppressed chronic ventricular arrhythmias, while infusions of placebo had no effect. ODE clearance was a function of metabolizer phenotype, with higher clearance (mean 914 ml/min; range 554 to 1314) in EMs than in PMs (434, 298 ml/min); moreover, 3MODE was detected during ODE infusions in all seven EMs but in neither PM. 3MODE clearance was more uniform (mean 289 ml/min in EMs [range 180-410] vs 300 and 78 ml/min in the two PMs) and ODE was not detected in any subject during 3MODE infusion. Encainide itself was not detected after any infusion of ODE or 3MODE. During withdrawal of encainide therapy, ODE plasma concentration at the time of arrhythmia recurrence was 55 ± 40 ng/ml (mean ± SD), while ODE by infusion was effective at a concentration of 37 ± 15 ng/ml. Similarly, plasma concentration of 3MODE at the time of arrhythmia recurrence after withdrawal of chronic encainide was 116 ± 35 ng/ml and that during 3MODE infusion was 105 ± 50 ng/ml. While both compounds prolonged QRS duration, ODE was the more potent, increasing QRS by 9.2 ± 1.6% per 100 ng/ml vs 1.2 ± 0.5% per 100 ng/ml for 3MODE. On the other hand, 3MODE prolonged the corrected JT interval by 1.9 ± 0.6% per 100 ng/ml, while ODE shortened it by 2.7 ± 1.9% per 100 ng/ml. These data indicate that ODE and 3MODE are potent sodium channel-blockers that suppress arrhythmias at the low concentrations noted during long-term encainide therapy in EMs. The disposition of ODE was itself a function of metabolizer phenotype, while that of 3MODE was not strongly associated with metabolizer phenotype. These findings suggest that therapy with ODE would result in variable plasma concentrations, with particularly high values in PMs. 3MODE, however, appears to be a promising agent with different electrocardiographic characteristics than ODE and more uniform disposition, and it therefore merits further evaluation in man.