MAJOR PATHWAY OF MEPHENYTOIN METABOLISM IN MAN - AROMATIC HYDROXYLATION TO PARA-HYDROXYMEPHENYTOIN

Abstract

A major metabolite of the antiepileptic drug mephenytoin (3-methyl-5-ethyl-5-phenylhydantoin) was identified in urine after a single oral dose of 100 mg of mephenytoin in man. Using chemical synthesis, gas chromatography-mass spectrometry and NMR spectroscopy, its chemical structure was established as 3-methyl-5-ethyl-5-(4-hydroxyphenyl)hydantoin (4-OH-M) which is a product of aromatic hydroxylation of mephenytoin in man. Quantitative determinations of 4-OH-M in urine of 10 volunteers showed that 43 .+-. 7% (SD) of a single oral dose of 100 mg of mephenytoin were eliminated as the glucuronide of this metabolite. Urinary elimination of the demethylated metabolite, 5-ethyl-5-phenylhydantoin (Nirvanol), was low (1% of the dose per 24 h) emphasizing the importance of 4-OH-M as the major metabolite after a single oral dose of mephenytoin. Other products of mephenytoin hydroxylation (2-OH-M, 3-OH-ethyl-M, or aliphatically hydroxylated 2-OH-ethyl-M) were not detectable under the conditions selected (< 1 .mu.mol/24 h).