RT Journal Article
SR Electronic
T1 Phenotypic differences in mephenytoin pharmacokinetics in normal subjects.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 662
OP 669
VO 234
IS 3
A1 P J Wedlund
A1 W S Aslanian
A1 E Jacqz
A1 C B McAllister
A1 R A Branch
A1 G R Wilkinson
YR 1985
UL http://jpet.aspetjournals.org/content/234/3/662.abstract
AB 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)