Evidence for an arene oxide-NIH shift pathway in the metabolic conversion of phenytoin to 5-(4-hydroxyphenyl)-5-phenylhydantoin in the rat and in man.
To determine whether the hydroxylation of 5,5-diphenylhydantoin (DPH) to 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) occurs by an arene oxide-NIH shift process, racemic 5-(4-deuteriophenyl)-5-phenylhydantoin (p-2H-DPH) was subjected to in vivo metabolic experiments in the rat and in man. After enzymatic hydrolysis of the urine, para-hydroxylated metabolites were separated by HPLC. Deuterium retention in the isolated metabolites determined by gas chromatography-mass spectrometry, was 68-72%. The results are interpreted as the predominance of an arene oxide-NIH shift pathway in those two metabolic systems. Induction of rats with phenobarbital or 3-methylcholanthrene showed no effect on the value of deuterium retention.
D000328:Adult; D000818:Animals; D003903:Deuterium; D004988:Ethers, Cyclic / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D008297:Male; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D004988:Ethers, Cyclic; C001419:hydroxyphenytoin; D010672:Phenytoin; D003903:Deuterium