Oxidative metabolism of encainide: polymorphism, pharmacokinetics and clinical considerations.

The 8-h urinary metabolic profiles of encainide and its oxidized metabolites, O-desmethyl- (ODE), 3-methoxy-O-desmethyl- (MODE), N-desmethyl- (NDE) and N, O-didesmethyl- (DDE) encainide were studied in a group of 112 normal Caucasians. Nine of these subjects (8%) were defective in their ability to 4-hydroxylate debrisoquine. The cumulative frequency distribution of the 8-h recovery ratio of encainide/ODE indicated two distinct populations in complete concordance with the debrisoquine phenotyping. The subjects with an 'extensive metabolizer' (EM) phenotype had a ratio from 0.003 to 0.9 whereas the PM group had values from 7.4 to 48. In addition, no MODE was detected in the urine from 'poor metabolizers' (PM). The oxidative metabolism of encainide, specifically the O-demethylation pathway, is, therefore, polymorphically distributed and controlled by the same genetic factor(s) that determine the 4-hydroxylation of debrisoquine. In EM subjects, ODE and MODE are the major metabolites in plasma and their concentrations are much greater than those of unchanged drug. As ODE is a more potent antiarrhythmic agent than encainide and MODE is at least equipotent, these metabolites significantly contribute to the overall antiarrhythmic effect in EM patients. The low plasma concentrations of ODE and MODE in PM subjects would be expected to result in inefficacious therapy when usual doses of encainide are administered. However, in such individuals, chronic oral therapy results in accumulation of unmetabolized encainide to far higher levels than in EM subjects. As encainide itself has intrinsic antiarrhythmic activity at these concentrations, this generally results in the desired clinical response. Despite pronounced interphenotypic differences in encainide's disposition and pharmacokinetics, the polymorphic oxidative metabolism appears to have limited consequences for the drug's clinical efficacy.

Phenotypic differences in mephenytoin pharmacokinetics in normal subjects.

The urinary metabolic profile of mephenytoin and its oxidative metabolites indicates significant stereoselective metabolism of its two enantiomers. Also, polymorphic oxidation, which is present in about 2 to 5% of the Caucasian population, has been demonstrated by an impaired ability to 4-hydroxylate this anticonvulsant. In order to determine the consequences of such metabolism, the plasma concentration/time profiles of the enantiomers of mephenytoin and its N-demethylated metabolite, phenylethylhydantoin (PEH), were investigated after a single p.o. dose of racemic mephenytoin in normal subjects with different metabolizing ability for mephenytoin [extensive metabolizer (EM) vs. poor metabolizer (PM) phenotypes]. In the EM subjects, the disposition of S- and R-mephenytoin was markedly different with a 100- to 200-fold difference in mean oral clearance (4.7 vs. 0.027 liters/min) and a 30- to 40-fold difference in elimination half-life (2.1 vs. 76 hr). In these same subjects, R-PEH concentrations significantly accumulated over several days and then very slowly declined with an apparent half-life of about 200 hr. Plasma levels of S-PEH were essentially negligible. In contrast, the stereoselective elimination of mephenytoin was reduced markedly in subjects of the PM phenotype, with the disposition of the S-enantiomer being the same as that for R-mephenytoin, which in turn was similar to that observed for this enantiomer in EMs. Almost comparable plasma levels of S- and R-PEH were also present in PMs. Only a small amount (less than 5%) of unchanged mephenytoin was excreted in the urine regardless of phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism.

The ability of normal subjects to hydroxylate mephenytoin (100 mg) or debrisoquine (10 mg) after oral dosing was investigated in 156 unrelated Caucasians living in middle Tennessee. Urinary recovery of 4-hydroxymephenytoin (4-OH-M) and the urinary S:R enantiomeric ratio of mephenytoin measured in an 8-hr urine sample were investigated as phenotypic traits for mephenytoin, and the urinary metabolic ratio of debrisoquine was used to determine the debrisoquine hydroxylase phenotype. Both urinary 4-OH-M and the S:R ratio of mephenytoin discriminated between extensive (EM) and poor (PM) metabolizers of mephenytoin. The frequencies of PMs for mephenytoin and debrisoquine hydroxylation activity were 2.6% and 7.0%. These two defects in oxidative metabolism were not observed in the same subjects, which suggests that 4-hydroxylation of mephenytoin is a new polymorphism independent of that for debrisoquine.