Stereoselective metabolism and disposition of the enantiomers of mephenytoin during chronic oral administration of the racemic drug in man

A. Kupfer, P. V. Desmond, S. Schenker, R. A. Branch

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Abstract

The stereospecific disposition of the enantiomers of mephenytoin has been investigated during chronic oral administration of racemic mephenytoin (23 μmol/kg/day) for 14 days in four normal subjects. On days 1 and 11, 5 μCi of [14C]-S-mephenytoin and 45 μCi of [3H]-R-mephenytoin were administered concomitantly with unlabeled racemic mephenytoin. Plasma mephenytoin concentrations reached a peak on the 2nd day of administration, then declined to a plateau between the 7th and 14th day. Mephenytoin was metabolized to two major metabolites. Firstly, 4-hydroxylation of the phenyl ring [3-methyl-5-(4-hydroxy phenyl)-5-ethylhydantoin; 4-OH-M) yielded a metabolite which was rapidly eliminated in urine to quantitatively account for almost half of the racemic dose administered. This amount remained constant during chronic therapy. The second metabolic route was demethylation to 5-phenyl-5-ethylhydantoin (PEH). The renal clearance for this metabolite was lower than its synthesis rate; thus, the initial low plasma level of PEH accumulated until it achieved a 10:1 ratio in excess of parent drug after 12 days of therapy. As urinary clearance of PEH remained constant, daily urinary excretion increased in a similar time profile to that observed in plasma. The initial radiotracer study confirmed stereoselective 4-hydroxylation of S- but not R-mephenytoin. S-Mephenytoin was rapidly and quantitatively converted to 4-OH-M and excreted in urine within the dosage interval. The tritium label on R-mephenytoin was slowly excreted in urine in the form R-PEH and minor unidentified phenolic metabolites other than 4-OH-M or 4-OH-PEH. The second radiotracer study confirmed that the stereospecificity of hydroxylation of S-mephenytoin persisted and suggested that the rate of synthesis of R-PEH increased. The possibility of autoinduction was supported by a study in a single subject, who received only R-mephenytoin on day 1 and 11, but racemic mephenytoin on days 2 to 10 and 12 to 14. In this subjects, apparent oral clearance of R-mephenytoin increased from 33 to 106 ml/min. In conclusion, with daily oral administration of racemic mephenytoin, S-mephenytoin is eliminated as 4-OH-M within each dosage interval and will not accumulate to make a significant contribution to the therapeutically effective hydantoin, whereas R-mephenytoin is converted to R-PEG which is the major contribution to the therapeutic response.

Original languageEnglish (US)
Pages (from-to)590-597
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume221
Issue number3
StatePublished - 1982
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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