Encainide and its metabolites. Comparative effects in man on ventricular arrhythmia and electrocardiographic intervals.

Carey, Edmund L.; Duff, Henry J.; Roden, Dan M.; Primm, R.Kirby; Wilkinson, Grant R.; Wang, T; Oates, John A.; Woosley, Raymond L.

doi:10.1172/jci111241

Cited by 63 publications

(11 citation statements)

References 28 publications

(25 reference statements)

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“…Thus, the parent drug accumulates with the result that pharmacological effects, such as arrhythmia suppression and QRS prolongation, are seen (Carey et al 1984).…”

Section: Encainide Disposition In Healthy Subjectsmentioning

confidence: 99%

“…Interestingly, encainide, ODE and MODE produce qualitatively different electrophysiological changes. In most studies, ODE is a more potent depressor of sodium channels and cardiac conduction (evidenced in patients by QRS widening) than either encainide or MODE (Carey et al 1984;Fain et al 1986). However, MODE is more potent than encainide or ODE in prolonging ventricular refractoriness in dogs (Fain et al 1986) and QT interval in humans (Barbey et al 1986), and unlike encainide and ODE, does not raise energy requirements for defibrillation in dogs (Fain et al 1986).…”

Section: Encainide Disposition In Healthy Subjectsmentioning

confidence: 99%

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Clinical Pharmacokinetics of Encainide

Roden

Woosley

1988

Clinical Pharmacokinetics

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The disposition kinetics of the new antiarrhythmic agent encainide are a function of the genetic polymorphism which also controls debrisoquin 4-hydroxylation. In the majority of subjects (extensive metabolisers) encainide undergoes extensive first-pass hepatic biotransformation to the active metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (MODE). The plasma concentrations of these metabolites are higher than those of encainide, and pharmacological effects correlate better with plasma metabolite concentrations than they do with those of encainide itself. In poor metabolisers, who make up to 7% of the population, a first-pass effect is absent, encainide clearance is lower, and plasma encainide concentrations are higher than those in extensive metabolisers. In poor metabolisers, plasma concentrations of active metabolites are low or undetectable, and the effects of encainide therapy can be closely correlated with plasma concentrations of the parent drug. Despite the marked differences in encainide disposition between extensive and poor metabolisers, the dosages which produce pharmacological effects (QRS prolongation and arrhythmia suppression) are similar in both groups. Encainide biotransformation is impaired in hepatic disease, but no major dosage changes are required. On the other hand, excretion of encainide and its metabolites is impaired in individuals with renal disease, and starting dosages should be decreased. The time required to achieve steady-state concentrations of metabolites (in extensive metabolisers) and of encainide itself (in poor metabolisers) is similar (3 to 5 days); therefore, the dosage should be increased no more often than every 3 to 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Thus, the parent drug accumulates with the result that pharmacological effects, such as arrhythmia suppression and QRS prolongation, are seen (Carey et al 1984).…”

Section: Encainide Disposition In Healthy Subjectsmentioning

confidence: 99%

Section: Encainide Disposition In Healthy Subjectsmentioning

confidence: 99%

Clinical Pharmacokinetics of Encainide

Roden

Woosley

1988

Clinical Pharmacokinetics

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“…The other 10% produce very little or no ODE or MODE, but produce measurable amounts of third metabolite, N-desmethyl encainide (NDE). All of these metabolites possess potent class 1 antiarrhythmic actions of their own (Carey et al, 1984;Davy et al, 1986;Barbey et al, 1988). Because they have longer elimination half-lives than encainide, MODE and ODE tend to accumulate in the plasma of patients on chronic oral therapy and reach concentrations well in excess of the parent compound (Kates et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

“…Because they have longer elimination half-lives than encainide, MODE and ODE tend to accumulate in the plasma of patients on chronic oral therapy and reach concentrations well in excess of the parent compound (Kates et al, 1982). Furthermore, it has been suggested that ODE in particular, may contribute significantly to the clinical effects of encainide (Carey et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Depression of maximum rate of depolarization of guinea‐pig ventricular action potentials by metabolites of encainide

Hemsworth

Campbell

1989

British J Pharmacology

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1 Standard microelectrode methods have been used to record action potentials from guinea-pig ventricular myocardium and dog Purkinje fibres, and to study the effects of the two major metabolites of encainide, 0-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (MODE). 2 In concentrations similar to those found in patients during chronic encainide therapy, neither ODE nor MODE produced significant depression of maximum rate of depolarization (P,..X) of action potentials in unstimulated tissue. Repetitive stimulation, however, was associated with depression of J, which increased with increasing driving rates (rate-dependent block, RDB). At the fastest rate studied (interstimulus interval = 300 ms) ODE 1 gM depressed P,., by 47.5 + 5.7%and MODE 1 gM, reduced Vx by 52.2 + 12%.3 The onset and offset kinetics of this rate-dependent block were very slow. Full development of RDB during a train required over 100 action potentials and the time constants of recovery of VP.,X from RDB were 86.4 + 37 s for ODE and 100.4 + 18 s for MODE. The amount of RDB and its rate of onset increased with drug concentration. The recovery time constants were independent of interstimulus interval or drug concentration. Both metabolites also produced rate-dependent depression of conduction velocity in canine Purkinje fibres, but no evidence of selective depression of conduction of interpolated premature potentials was seen. 4 Early afterdepolarizations occurred spontaneously in three preparations in the presence of MODE, 1 gM and one preparation in ODE, 1 gM. 5 It is concluded that these metabolites of encainide may play a role in producing both its antiarrhythmic and its proarrhythmic effects.

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“…In a minority of patients (approximately 7% of caucasians and blacks), the specific hepatic cytochrome P450 responsible for encainide O-demethylation is functionally absent on a genetic basis.14,l5 In such "poor metabolizers,," encainide clearance is markedly reduced, ODE plasma concentrations are low, MODE is not detected in plasma, and encainide itself accumulates to antiarrhythmic concentrations. [14][15][16] Many drugs, including the antihypertensive debrisoquin, have been used as probes for the presence of this cytochrome, termed P450dbl. [17][18][19] We have previously shown that the metabolism of ODE to MODE is dependent on the same genetic polymorphism as that controlling encainide O-demethylation.13 Thus, long-term administration of ODE to patients with the poor metabolizer phenotype might lead to undesirable accumulation of this very potent sodium channel blocker.…”

mentioning

confidence: 99%

Antiarrhythmic efficacy, clinical electrophysiology, and pharmacokinetics of 3-methoxy-O-desmethyl encainide (MODE) in patients with inducible ventricular tachycardia or fibrillation.

et al. 1989

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In most patients, the clinical effects of therapy with encainide are mediated by the generation of the active metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide (MODE). Data from in vitro and animal studies have indicated that MODE has electrophysiologic and pharmacokinetic features that make its further evaluation desirable; in earlier studies, we found that MODE suppressed chronic high-frequency nonsustained ventricular arrhythmias at plasma concentrations of 50-160 ng/ml. We now report the clinical electrophysiology, antiarrhythmic activity, and pharmacokinetics of MODE in 17 patients with inducible ventricular tachyarrhythmias (VTs) in whom programmed electrical stimulation was performed before drug administration and after one or two sequences of loading and maintenance infusions of MODE. Because the relation between plasma concentration and effect had been incompletely defined, a dose-titration approach was adopted: available pharmacokinetic data were used to construct loading and maintenance infusion regimens that were predicted to attain low plasma concentrations in initial patients while higher infusion rates were evaluated in subsequent patients. MODE prevented VT induction in three of 17 patients and VT cycle length was increased by .100 msec in a further seven of 17; most responses to MODE occurred at plasma concentrations >556 ng/ml (>1 SD above mean plasma MODE during encainide therapy). Response to MODE did not predict subsequent response to oral therapy with encainide. MODE increased intracardiac conduction times, QT intervals during atrial and ventricular pacing, and right ventricular efective refractory periods (RVERP); changes in RVERP were most prominent at rapid pacing rates, while changes in intracardiac conduction were rate-independent at cycle lengths between 400 and 600 msec. Plasma MODE concentrations measured during electrophysiology study correlated well with those predicted by the pharmacokinetic simulations (r=0.91, p<0.001). Serial plasma sampling after programmed electrical stimulation indicated a minimum MODE elimination half-life of 8.2+5.4 hours. Side effects were confined to three instances of asymptomatic conduction system depression in subjects with latent conduction system disturbances. We conclude that MODE slows intracardiac conduction, delays repolarization, and can suppress or substantially modify inducible VT. Moreover, it was only with the adoption of the dose-titration strategy that we were able to safely demonstrate that plasma MODE concentrations higher than those routinely observed during encainide therapy were required to substantially alter cardiac electrophysiology. (Circulation 1989;80:1247-1258 I n most patients, the antiarrhythmic agent encainthose of encainide.1-5 Both metabolites have pharide is rapidly cleared to the active metabolites macologic activity equal to or more than the parent O-desmethyl encainide (ODE) and 3 -methoxydrug in a variety of in vitro and in vivo settings6-13; O-desmethyl encainide (MODE) (Figure 1), which thus,...

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Encainide and its metabolites. Comparative effects in man on ventricular arrhythmia and electrocardiographic intervals.

Cited by 63 publications

References 28 publications

Clinical Pharmacokinetics of Encainide

Clinical Pharmacokinetics of Encainide

Depression of maximum rate of depolarization of guinea‐pig ventricular action potentials by metabolites of encainide

Antiarrhythmic efficacy, clinical electrophysiology, and pharmacokinetics of 3-methoxy-O-desmethyl encainide (MODE) in patients with inducible ventricular tachycardia or fibrillation.

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