PHENOTYPIC DIFFERENCES IN MEPHENYTOIN PHARMACOKINETICS IN NORMAL SUBJECTS

Abstract

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 seveal 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 (< 5%) of unchanged mephenytoin was excreted in the urine regardless of phenotype. In EMs, almost 50% of the dose was excreted over 4 days as 4-hydroxymephenytoin with only 5 to 15% being eliminated as PEH over 14 days. On the other hand, PMs eliminated negligible amounts of the 4-hydroxy metabolite and PEH excretion accounted for 35 to 40% of the administered dose. Negligible plasma concentrations of both S-mephenytoin and S-PEH were present in an EM subject given 100 mg of racemic mephenytoin daily for 14 days. By contrast, R-mephenytoin accumulated over 8 to 10 days, but the level then declined by about 25% over the next 4 to 6 days. Also, R-PEH increased progressively to concentrations almost 3-fold higher than unchanged enantiomer, and there was no indication of these leveling off over the dosing period. Detectable amounts of R-PEH were still present in the plasma 25 days after stopping drug administration. Stereoselective and interphenotypic differences in the metabolism of the enantiomers of mephenytoin, therefore, have a profound effect on the plasma concentration/time profile of unchanged drug and its pharmacologically active metabolite, PEH. Such large differences would be expected to have clinical consequences for both desired and untoward effects.