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Genetically determined stereoselective excretion of encainide in humans and electrophysiologic effects of its enantiomers in canine cardiac Purkinje fibers
Author(s) -
Turgeon Jacques,
FunckBrentano Christian,
Gray Holly T,
Pavlou Harris N,
Prakash Chandra,
Blair Ian A,
Roden Dan M
Publication year - 1991
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1991.59
Subject(s) - quinidine , stereoselectivity , chemistry , enantiomer , pharmacokinetics , pharmacology , debrisoquine , metabolism , medicine , cytochrome p450 , endocrinology , cyp2d6 , biochemistry , stereochemistry , catalysis
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 < 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 nonstereoselective (± 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. Clinical Pharmacology and Therapeutics (1991) 49, 488–496; doi: 10.1038/clpt.1991.59