Oxidative metabolism of encainide: Polymorphism, pharmacokinetics and clinical considerations

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Abstract
1. The 8-h urinary metabolic profiles of encainide and its oxidized metabolites, O-desmethyl- (ODE), 3-methoxy-O-desmethyl- (MODE), N-desmethyl-(NDE) and N, O-didesmethyl- (DDE) encainide were studied in a group of 112 normal Caucasians. Nine of these subjects (8%) were defective in their ability to 4-hydroxylate debrisoquine. 2. The cumulative frequency distribution of the 8-h recovery ratio of encainide/ODE indicated two distinct populations in complete concordance with the debrisoquine pheno-typing. The subjects with an ‘extensive metabolizer’ (EM) phenotype had a ratio from 0·003 to 0·9 whereas the PM group had values from 7·4 to 48. In addition, no MODE was detected in the urine from ‘poor metabolizers’ (PM). 3. The oxidative metabolism of encainide, specifically the O-demethylation pathway, is, therefore, polymorphically distributed and controlled by the same genetic factor(s) that determine the 4-hydroxylation of debrisoquine. 4. In EM subjects, ODE and MODE are the major metabolites in plasma and their concentrations are much greater than those of unchanged drug. As ODE is a more potent antiarrhythmic agent than encainide and MODE is at least equipotent, these metabolites significantly contribute to the overall antiarrhythmic effect in EM patients. 5. The low plasma concentrations of ODE and MODE in PM subjects would be expected to result in inefficacious therapy when usual doses of encainide are administered. However, in such individuals, chronic oral therapy results in accumulation of unmetabolized encainide to far higher levels than in EM subjects. As encainide itself has intrinsic antiarrhythmic activity at these concentrations, this generally results in the desired clinical response. 6. Despite pronounced interphenotypic differences in encainide's disposition and pharmacokinetics, the polymorphic oxidative metabolism appears to have limited consequences for the drug's clinical efficacy.
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