EFFECT OF LOW-DOSE QUINIDINE ON ENCAINIDE PHARMACOKINETICS AND PHARMACODYNAMICS - INFLUENCE OF GENETIC-POLYMORPHISM

  • 1 April 1989
    • journal article
    • research article
    • Vol. 249  (1) , 134-142
Abstract
Encainide biotransformation to its active metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide cosegregates with the polymorphic oxidation of debrisoquine. Because quinidine has been reported recently to be a potent inhibitor of the enzyme responsible for this polymorphism (cytochrome P450db1), we tested the hypothesis that quinidine would selectively inhibit encainide metabolism and alter its effects in subjects with the extensive metabolism phenotype for debrisoquine oxidation. Seven subjects with the extensive and four subjects with the poor metabolism phenotype received encainide (60 mg p.o. and 4.5 mg of [14C]encainide i.v. administered simultaneously) alone and during chronic treatment with low dose quinidine (50 mg q 6 hr) in a randomized, crossover design. In extensive metabolizers, quinidine decreased encainide systemic clearance from 935 .+-. 541 to 190 .+-. 77 ml/min and encainide nonrenal clearance from 782 .+-. 474 to 95 .+-. 32 ml/min (both P < .02). In this population, quinidine significantly increased encainide elimination half-life from 1.8 .+-. 1.2 to 7.7 .+-. 2.4 hr and fractional urinary recovery of unchanged encainide from 17.5 .+-. 7.6 to 47.4 .+-. 7.8% (both < .001). The extent to which quinidine altered these indices of encainide disposition was highly correlated with the metabolic ratio for debrisoquine oxidation (r = 0.62-0.95). Moreover, poor metabolism and QRS prolongation during encainide were blunted by addition of quinidine; the extent of quinidine-induced reversal of encainide-related ECG changes was also correlated with degrisoquine ratio (r = 0.91). In contrast, in poor metabolizers, quinidine did not change encainide disposition kinetics and neither encainide alone nor encainide plus quinidine significantly altered electrocardiographic intervals. We conclude that selective inhibition of cytochrome P450dbr by quinidine is the major determinant of both the pharmacokinetic and pharmacodynamic consequences of this potentially important drug interaction.