Genetically determined steady-state interaction between encainide and quinidine in patients with arrhythmias.
A genetically determined pharmacokinetic and pharmacodynamic interaction between quinidine and single doses of encainide in healthy volunteers has previously been described. In subjects with the extensive metabolizer phenotype, quinidine blunted encainide-induced QRS prolongation (a marker of sodium channel block) because it impaired encainide biotransformation to the potent active metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide. Therefore, the purpose of this study was to test the hypothesis that quinidine would inhibit sodium channel block (and by inference arrhythmia suppression) during encainide therapy in patients with the extensive metabolizer phenotype. Surprisingly, however, in eight extensive metabolizer patients, the extent of QRS prolongation during chronic encainide therapy was unaltered by quinidine (139 +/- 21 vs. 139 +/- 22 msec) whereas arrhythmia suppression was enhanced (64 +/- 22 to 77 +/- 19%; P = .05). Plasma concentration data demonstrated that although encainide metabolism to ODE was partially impaired by quinidine, subsequent 3-methoxy-O-desmethyl encainide formation from ODE was virtually completely inhibited; thus steady-state plasma ODE remained unchanged whereas plasma encainide increased 10-fold (21 +/- 30 to 240 +/- 118 ng/ml; P less than .05). In contrast, no changes in disposition or in pharmacodynamics were observed in two poor metabolizers. It is concluded that the effect of this drug interaction in patients is determined by differential sensitivities to inhibition by quinidine of encainide O-demethylation and subsequent ODE 3-methoxylation. Evaluation of potential drug interactions should include assessment of possible genetic factors as well as of steady-state effects.
Turgeon
J
J
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.
Pavlou
H N
HN
Wong
W
W
Funck-Brentano
C
C
Roden
D M
DM
D000368:Aged; D000813:Anilides / Q000378:metabolism* / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000378:metabolism; D003640:Dealkylation; D004347:Drug Interactions; D004562:Electrocardiography; D016700:Encainide; D005260:Female; D005823:Genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011802:Quinidine / Q000494:pharmacology*
D000813:Anilides; D011802:Quinidine; D016700:Encainide