Mephenytoin hydroxylation deficiency: Kinetics after repeated doses

Adrian Küpfer, Paul Desmond, Rashmi Patwardhan, Steven Schenker, Robert A. Branch

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Deficient aromatic hydroxylotion of S-mephenytoin Was observed in an index subject durbig a kinetic study of stereoselective metobolism of mephenytoin. A genetic basis, for this defect was suggested by decreased urinary recover. of 3-methly-5-(4-bydroxyphenyl)-5-thylhydantoin (4-OH-M) in the 24 hr after oral racemic mephenytoin in two brothers of the propositus. The parents and a third brother held urinary recoveries of 4-OH-M of the same order as in a group of 20 normal subjects. The kinetic implications of this defect were studied in the index subject and compared with tour normal subjects after a single oral close of differentially radiolabeled pseudoracemic mephenytoin (5 μCi of 14C-S-mephenytoin. 45 μCi of H3-R-mephenytoin, and 11.5 μmol/kg of both S- and R-mephenytoin) followed by single oral doses of 1.4 mmol of unlabeled racemic mephenytoin daily the nest 4 days In normal subjects, there was substrate stereoselective metabolism with the S-enantiomer rapidly excreted (is 4-OH-M and the R-enantiomer slowly excreted as 5-phenyl-5-ethylhydantoin (PEH). Stereoselective metabolism persisted daring repeated closing. In the hydroxylation-defecient subject, there was no evidence of stereoselective metabolism, recovery, of 4-OH-M was low, and both enantiomers were slowly excreted, predominantly as PEH. Plasma PEH concentrations and urinary PEH excretion rates were approximately twice that in normal subjects. Thus a genetic deficiency in ability to hydroxylate S-mephenytoin results in the S-enantiomer inetabolization by the alternate route of demethylation to PEH that cumulates thereby, in comparison to the normal, effectively doubting the close of total hydantoin.

Original languageEnglish (US)
Pages (from-to)33-39
Number of pages7
JournalClinical Pharmacology and Therapeutics
Volume35
Issue number1
DOIs
StatePublished - Jan 1984
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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