INFLUENCE OF GENETIC-POLYMORPHISM ON THE METABOLISM AND DISPOSITION OF ENCAINIDE IN MAN

Abstract

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. The disposition of encainide and known metabolites was investigated after simultaneous acute i.v. (radiolabeled) and single and multiple oral (nonradiolabeled) dosing to 2 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-h urinary excretion of encainide and metabolites were observed between the 2 phenotypes. In the EM group, the oral bioavailability of encainide was only about 25-30% because of extensive presystemic (1st-pass) metabolism, and no accumulation occurred after multiple oral dosing with 50 mg every 8 h for 3 days, as the elimination half-life of the drug was about 2.5 h. The major metabolite formed was O-desmethylencainide which accounted for almost 1/2 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 the PM group, encainide plasma concentrations were 10- to 20-fold higher than in the EM after both oral and i.v. administration and the elimination half-life was 3- to 4-fold longer. Only a small 1st-pass effect was present after oral dosing and significant accumulation of unchanged drug occurred after multiple oral administration. These pronounced differences were caused by an impaired ability to metabolize encainide as almost 40% of unchanged drug was excreted in the urine compared with only 5% in the EM group. O-desmethylencainide formation in particular was affected such that its plasma concentrations were at the most 1/10 those of parent drug after a single dose and 1/5 after multiple dosing. Its urinary recovery was only about 3% compared with .apprx. 10% in the EM group. No 3-methoxy-O-desmethylencainide was apparently formed in PM; instead, N-desmethylencainide was present in both the plasma and urine in significant amounts and accumulation occurred during multiple oral dosing. The differences in metabolism and disposition had significant pharmacodynamic consequences. In the PM group no changes in the ECG were observed during multiple dosing; however, in 6 of the 8 EM subjects the QRS interval increased from 18 to 58% compared with its base-line value. This is consistent with reports showing the metabolites of encainide having cardiovascular activity equal or greater than the parent drug. These findings show the pronounced differences in the metabolism of encainide and pharmacological response that are present in deficient metabolizers. The incidence of this genetically determined trait is about 8-10% in American Caucasians and it affects the oxidative metabolism of a large number of drugs other than encainide. Knowledge of a phenotype of an individual with regard to this and other separately inherited traits may have therapeutic and investigative potential.