title: A major pathway of mephenytoin metabolism in man. Aromatic hydroxylation to p-hydroxymephenytoin.
abstract: A major metabolite of the antiepileptic drug mephenytoin (3-methyl-5-ethyl-5-phenylhydantoin) has been identified in urine after a single oral dose of 100 mg of mephenytoin in man. Using chemical synthesis, gas chromatography-mass spectrometry, and nuclear magnetic resonance spectroscopy, we established its chemical structure 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 hr) 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, E-OH-M, or aliphatically hydroxylated 2-OH-ethyl-M) were not detectable under the conditions selected (less than 1 mumol/24 hr).
mesh_terms: D000328:Adult; D006801:Humans; D006827:Hydantoins / Q000378:metabolism*; D006900:Hydroxylation; D008297:Male; D008617:Mephenytoin / Q000378:metabolism* / Q000652:urine
chemical_list: D006827:Hydantoins; D008617:Mephenytoin