Disposition kinetics of encainide and metabolites.
Interpretation of plasma concentration data during encainide therapy is predicated on an understanding of the role of active metabolites during treatment. In over 90% of patients, encainide is rapidly biotransformed to O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (3-MODE), which persist in plasma hours after encainide itself is undetectable. This metabolism occurs in the liver, and encainide clearance is sufficiently high that a significant first-pass effect is seen during oral therapy (bioavailability 30 +/- 7%). In these extensive metabolizers, ODE and 3-MODE appear to mediate the arrhythmia suppression and electrocardiographic changes seen during encainide therapy. In less than 10% of patients, a genetic defect prevents expression of the enzyme responsible for the rapid biotransformation of encainide. In this poor metabolizer subset, the systemic clearance of encainide is 10-fold lower than in extensive metabolizers (0.18 +/- .002 vs 1.9 +/- 0.2 liters/min), the first-pass effect is virtually absent (bioavailability 83% to 88%), plasma concentrations are higher and an antiarrhythmic effect may be seen at usual encainide doses. Minimally effective plasma concentrations appear to be 35 ng/ml (ODE), 100 ng/ml (3-MODE) and 300 ng/ml (encainide), making ODE one of the most potent sodium channel blockers yet used in man. The elimination half-life of encainide is 2.3 +/- 0.3 hours in extensive metabolizer patients. Despite this rapid elimination, encainide can be administered every 8 to 12 hours in both extensive and poor metabolizer subsets; this is because of slowly eliminated metabolites in extensive metabolizers and slower elimination of encainide itself (11.3 +/- 0.3 hours) in poor metabolizers.(ABSTRACT TRUNCATED AT 250 WORDS)
D000813:Anilides / Q000097:blood* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000097:blood / Q000188:drug therapy; D001682:Biological Availability; D001711:Biotransformation; D016700:Encainide / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000097:blood; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000097:blood; D011247:Pregnancy
D000813:Anilides; C033635:O-demethylencainide; C033636:3-methoxy-O-demethylencainide; D016700:Encainide