title: Variable disposition kinetics and electrocardiographic effects of flecainide during repeated dosing in humans: contribution of genetic factors, dose-dependent clearance, and interaction with amiodarone.
abstract: We studied the influence of cytochrome P450 2D6 (CYP2D6) on the steady-state disposition kinetics and the electrocardiographic effects of flecainide at two doses and during combination with amiodarone. Seven extensive and five poor metabolizers of dextromethorphan were studied during a three-period crossover study. All subjects received 50 mg flecainide every 12 hours, alone or together with 200 mg amiodarone every 12 hours, and 100 mg flecainide every 12 hours for 5 days. Mean steady-state plasma concentration of flecainide and QRS change from predrug value did not differ significantly among extensive and poor metabolizer subjects during each study period. Except for a shortened elimination half-life and nonlinear kinetics in extensive metabolizer subjects, phenotype had no significant influence on flecainide pharmacokinetics. Combination with amiodarone resulted in an increase in mean flecainide plasma concentration and effect in subjects with both phenotypes. Our findings indicate that CYP2D6 phenotype predicts flecainide nonlinear kinetics and flecainide half-life but has no influence on electrocardiographic effects during repeated administration of flecainide or on the extent of the amiodarone-flecainide interaction.
authors.affiliation: Clinical Pharmacology Unit, Saint-Antoine University Hospital, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Funck-Brentano
authors.forename: L
authors.initials: L
authors.lastname: Becquemont
authors.forename: H K
authors.initials: HK
authors.lastname: Kroemer
authors.forename: K
authors.initials: K
authors.lastname: Bühl
authors.forename: N G
authors.initials: NG
authors.lastname: Knebel
authors.forename: M
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: P
authors.initials: P
authors.lastname: Jaillon
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000638:Amiodarone / Q000494:pharmacology*; D000704:Analysis of Variance; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects*; D005424:Flecainide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010641:Phenotype; D012016:Reference Values
chemical_list: D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D005424:Flecainide; D000638:Amiodarone