Co-inheritance of the polymorphic metabolism of encainide and debrisoquin

Abstract

O-demethylation of the investigational antiarrhythmic encainide was found to be correlated with the genetically determined hydroxylation of debrisoquin in 20 randomly selected and unrelated subjects and in five members of one family. Extensive metabolizers of debrisoquin had a mean (+/- SD) encainide elimination t1/2 of 1.19 +/- 0.98 hours (range 0.25 to 3.4 hours). Poor metabolizers of debrisoquin (two normal subjects and three family members) had a mean t1/2 of 13.2 +/- 0.73 hours (range 7.8 to 22.4 hours). The elimination rate constant of encainide and the fractional excretion of O-desmethyl encainide in urine were linearly related to the fractional urinary excretion of 4-hydroxy-debrisoquin. Poor metabolizers could be identified after a 50 mg dose of encainide by the fractional excretion of O-desmethyl encainide in urine or the absence of (1) measurable ECG changes or (2) O-desmethyl encainide in plasma. The correlation between excretion of O-desmethyl encainide and 4-hydroxy-debrisoquin suggests that significant numbers of the caucasian population (7% to 9%) are likely to be poor metabolizers of encainide and to have markedly different pharmacokinetics and plasma concentration-response relationships than extensive metabolizers.