Mephenytoin hydroxylation polymorphism

Characterization of the enzymatic deficiency in liver microsomes of poor metabolizers phenotyped in vivo

U. Thomas Meier, Pierre Dayer, Pierre Jean Male, Thomas Kronbach, Urs A. Meyer

Research output: Contribution to journalArticle

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Abstract

The rate of 4-hydroxylation and of N-demethylation of S- and R-mephenytoin was determined in liver microsomes of 13 extensive (EM) and two poor (PM) metabolizers of mephenytoin. Detailed kinetic studies were performed in microsomes of eight EMs and the two PMs. Microsomal mephenytoin metabolism in PMs was characterized by an increased Km (150.6 and 180.6 vs. a mean [± SD] 37.8 ± 9.6 μmol/L S-mephenytoin in 8 EMs), a decreased maximum rate of metabolism for S-mephenytoin hydroxylation (0.76 and 0.69 vs 4.85 ± 1.65 ntnol 4-hydroxymephenytoin per milligram protein per hour), and loss of stereoselectivity for the hydroxylation of the R- and S-enantiomers of mephenytoin ( R S ratio: 1.10 and 0.76 vs. 0.11 ± 0.04 in 13 EMs). The formation of 4-OH-mephenytoin from R-mephenytoin and the demethylation reaction remained unaffected. These results support our hypothesis that the mephenytoin polymorphism is caused by a partial or complete absence or inactivity of a cytochrome P-450 isozyme with high affinity for S-mephenytoin.

Original languageEnglish (US)
Pages (from-to)488-494
Number of pages7
JournalClinical Pharmacology and Therapeutics
Volume38
Issue number5
StatePublished - Nov 1 1985
Externally publishedYes

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Mephenytoin
Liver Microsomes
Hydroxylation
Microsomes
Cytochrome P-450 Enzyme System
Isoenzymes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Mephenytoin hydroxylation polymorphism : Characterization of the enzymatic deficiency in liver microsomes of poor metabolizers phenotyped in vivo. / Meier, U. Thomas; Dayer, Pierre; Male, Pierre Jean; Kronbach, Thomas; Meyer, Urs A.

In: Clinical Pharmacology and Therapeutics, Vol. 38, No. 5, 01.11.1985, p. 488-494.

Research output: Contribution to journalArticle

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