Stereoselective genetically-determined interaction between chronic flecainide and quinidine in patients with arrhythmias.
1. Recent reports have indicated a role for the P450IID6 polymorphism in the stereoselective disposition of single doses of the antiarrhythmic flecainide. 2. In this study, we evaluated the effects of adding low dose quinidine, a potent inhibitor of P450IID6, to chronic flecainide therapy in patients with arrhythmias. 3. In five extensive metabolizer patients, quinidine significantly reduced the clearance of R-(-)-flecainide, from 395 +/- 121 (s.d.) to 335 +/- 88 ml min-1. This change was attributable to a decrease in metabolic clearance, was accompanied by decreased formation of the two major metabolites of flecainide and was not observed in a poor metabolizer subject. The renal clearance of R-(-)-flecainide rose significantly. 4. Quinidine did not alter the clearance of S-(+)-flecainide. 5. The pharmacologic effects of flecainide therapy (QRS widening, % arrhythmia suppression) were slightly, but not significantly, increased. 6. In extensive metabolizer patients receiving chronic flecainide, increased plasma concentrations will develop if P450IID6 is inhibited.
Birgersdotter
U M
UM
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.
Wong
W
W
Turgeon
J
J
Roden
D M
DM
D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004347:Drug Interactions; D005424:Flecainide / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics; D011110:Polymorphism, Genetic; D011802:Quinidine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; D005424:Flecainide