title: Genetically determined stereoselective excretion of encainide in humans and electrophysiologic effects of its enantiomers in canine cardiac Purkinje fibers.
abstract: Encainide metabolism is mediated by the polymorphically distributed cytochrome P450IID6, which displays stereoselectivity for some substrates. In this study we found that urinary recovery during steady-state encainide in three poor metabolizers was high (49% to 80%), consisted mainly of unchanged encainide, was nonstereoselective (+/- ratio, 0.985 to 1.049), and was unchanged by quinidine, a potent inhibitor of P450IID6. In contrast, in seven extensive metabolizers the +/- urinary ratios were 1.20 +/- 0.06 for encainide and 0.81 +/- 0.06 (both p less than 0.01) for the cytochrome P450IID6 products O-desmethylencainide plus 3-methoxy-O-desmethylencainide; with quinidine the total percentage recovery rose from 4% +/- 4% to 37% +/- 9% because of increased recovery of unchanged encainide and became non-stereoselective (+/- ratio, 0.84 +/- 0.08 [encainide alone] versus 0.97 +/- 0.05 [encainide plus quinidine]). In vitro, encainide enantiomers depressed the maximum rate of metabolism with similar frequency and concentration dependence. We conclude that (-)-encainide undergoes preferential metabolism by cytochrome P450IID6; however, this genetically determined stereoselective disposition is unlikely to play a major role in mediating the clinical actions of encainide.
authors.affiliation: Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232-6602.
authors.forename: J
authors.initials: J
authors.lastname: Turgeon
authors.forename: C
authors.initials: C
authors.lastname: Funck-Brentano
authors.forename: H T
authors.initials: HT
authors.lastname: Gray
authors.forename: H N
authors.initials: HN
authors.lastname: Pavlou
authors.forename: C
authors.initials: C
authors.lastname: Prakash
authors.forename: I A
authors.initials: IA
authors.lastname: Blair
authors.forename: D M
authors.initials: DM
authors.lastname: Roden
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000813:Anilides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D016700:Encainide; D010641:Phenotype; D011690:Purkinje Fibers / Q000187:drug effects*; D011802:Quinidine / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D000813:Anilides; D000889:Anti-Arrhythmia Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D011802:Quinidine; D016700:Encainide