Quinidine-enhanced beta-blockade during treatment with propafenone in extensive metabolizer human subjects.
Propafenone, a sodium channel blocking antiarrhythmic drug with beta-blocking properties, is metabolized to non-beta-blocking metabolites in part by cytochrome P4502D6. Subtherapeutic doses of quinidine inhibit P4502D6 and increase plasma propafenone in extensive metabolizer subjects, in whom the active enzyme is present. In this study we tested the hypothesis that quinidine would enhance beta-blockade in extensive metabolizers receiving propafenone. Seven extensive and two poor metabolizers received propafenone (225 mg orally every 8 hours) plus quinidine sulfate (60 mg orally every 8 hours) or propafenone plus placebo for 7 days in a randomized, double-blind, crossover fashion. In extensive metabolizers, the coadministration of quinidine significantly increased the extent of propafenone-induced beta-blockade, assessed by a decrease in exercise heart rate and by sensitivity to isoproterenol. We conclude that low-dose quinidine enhances propafenone-induced beta-blockade in extensive metabolizers. Thus the polymorphic patterns of drug metabolism can result in clinically significant drug interactions on a genetic basis.
Mörike
K E
KE
Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232-6602.
Roden
D M
DM
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000502:physiology; D004311:Double-Blind Method; D004357:Drug Synergism; D015444:Exercise / Q000502:physiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D011405:Propafenone / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011802:Quinidine / Q000494:pharmacology* / Q000627:therapeutic use; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D011405:Propafenone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; D007545:Isoproterenol