Oxidative metabolism of encainide: Polymorphism, pharmacokinetics and clinical considerations

摘要: The 8-h urinary metabolic profiles of encainide and its oxidized metabolites, O-desmethyl- (ODE), 3-methoxy-O-desmethyl- (MODE), N-desmethyl- (NDE) N, O-didesmethyl- (DDE) were studied in a group 112 normal Caucasians. Nine these subjects (8%) defective their ability to 4-hydroxylate debrisoquine. cumulative frequency distribution the recovery ratio encainide/ODE indicated two distinct populations complete concordance with debrisoquine phenotyping. an 'extensive metabolizer' (EM) phenotype had from 0.003 0.9 whereas PM values 7.4 48. In addition, no MODE was detected urine 'poor metabolizers' (PM). oxidative metabolism encainide, specifically O-demethylation pathway, is, therefore, polymorphically distributed controlled by same genetic factor(s) that determine 4-hydroxylation EM subjects, ODE are major metabolites plasma concentrations much greater than those unchanged drug. As is more potent antiarrhythmic agent at least equipotent, significantly contribute overall effect patients. low would be expected result inefficacious therapy when usual doses administered. However, such individuals, chronic oral results accumulation unmetabolized far higher levels subjects. itself has intrinsic activity concentrations, this generally desired clinical response. Despite pronounced interphenotypic differences encainide's disposition pharmacokinetics, polymorphic appears have limited consequences for drug's efficacy.