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Genetically determined stereoselective excretion of encainide in humans and electrophysiologic effects of its enantiomers in canine cardiac Purkinje fibers.
- Source :
-
Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 1991 May; Vol. 49 (5), pp. 488-96. - Publication Year :
- 1991
-
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.
- Subjects :
- Action Potentials drug effects
Anilides chemistry
Anilides pharmacokinetics
Anilides pharmacology
Animals
Anti-Arrhythmia Agents chemistry
Anti-Arrhythmia Agents pharmacokinetics
Anti-Arrhythmia Agents pharmacology
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System metabolism
Dogs
Drug Evaluation, Preclinical
Drug Interactions
Encainide
Phenotype
Quinidine pharmacokinetics
Quinidine pharmacology
Stereoisomerism
Anilides urine
Anti-Arrhythmia Agents urine
Purkinje Fibers drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0009-9236
- Volume :
- 49
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 1903098
- Full Text :
- https://doi.org/10.1038/clpt.1991.59