Influence of genetic polymorphism on the metabolism and disposition of encainide in man.
The metabolism of the new, highly effective antiarrhythmic agent, encainide, appears to be polymorphically distributed in a similar fashion to the genetically determined oxidative biotransformation of debrisoquine. Accordingly, the disposition of encainide and known metabolites was investigated after simultaneous acute i.v. (radiolabeled) and single and multiple oral (nonradiolabeled) dosing to two groups of normal subjects characterized as "poor" (PM) and "extensive" (EM) metabolizers of debrisoquine. Pronounced differences in both the plasma concentration/time curves and the 24-hr urinary excretion of encainide and metabolites were observed between the two phenotypes. In the EM group, the oral bioavailability of encainide was only about 25 to 30% because of extensive presystemic (first-pass) metabolism, and no accumulation occurred after multiple oral dosing with 50 mg every 8 hr for 3 days, as the elimination half-life of the drug was about 2.5 hr. The major metabolite formed was O-desmethylencainide which accounted for almost half of the identified urinary metabolites and represented about 10% of the administered dose. This metabolite was present in 5- to 10-fold higher concentrations in the plasma than unchanged drug and accumulated almost 2-fold after multiple oral dosing. 3-Methoxy-O-desmethylencainide also was present at higher concentrations than encainide and accumulated on multiple dosing similarly to O-desmethylencainide. N,O-didesmethylencainide was a minor metabolite only detectable in the urine and N-desmethylencainide was not measurable in either plasma or urine. In contrast, in the PM group, encainide plasma concentrations were 10- to 20-fold higher than in the EMs after both oral and i.v. administration and the elimination half-life was 3- to 4-fold longer.(ABSTRACT TRUNCATED AT 250 WORDS)
D000328:Adult; D000813:Anilides / Q000378:metabolism*; D000889:Anti-Arrhythmia Agents / Q000378:metabolism*; D001711:Biotransformation; D016700:Encainide; D006801:Humans; D008297:Male; D010084:Oxidation-Reduction; D010641:Phenotype; D011110:Polymorphism, Genetic
D000813:Anilides; D000889:Anti-Arrhythmia Agents; D016700:Encainide