Evidence for an arene-3,4-oxide as a metabolic intermediate in the meta- and para-hydroxylation of phenytoin in the dog.

To investigate the potential involvement of an arene oxide-NIH shift pathway in the meta- and para-hydroxylation of phenytoin, (R,S)-5-(2-deuteriophenyl)-5-phenylhydantoin (2-2H-DPH), (R,S)-5-(3-deuteriophenyl)-5-phenylhydantoin (3-2H-DPH), and (R,S)-5-(4-deuteriophenyl)-5-phenylhydantoin (4-2H-DPH) were subjected to in vivo metabolic experiments in the dog. After enzymatic hydrolysis of the urine, meta- and para-hydroxy metabolites were isolated by HPLC and deuterium retentions were determined by GC/MS. The metahydroxy metabolites had 100, 52, and 80-82% retained of their initial deuterium content after oral administration of (R,S)-2-, 3-, and 4-2H-DPH, respectively. Similarly, in the case of the para-hydroxy metabolites, the percentages of deuterium retained were 100, 92, and 71-72%. These results exclude the intermediacy of a DPH-2,3-oxide in the production of meta-hydroxy metabolites but are consistent with the existence of DPH-3,4-oxide as intermediate in the production of both meta- and para-hydroxy metabolites. The stereoselectivity of the meta- and para-hydroxylation has been determined by GC/MS analyses of the urinary metabolites after administration of (R)-5-(3-deuteriophenyl)-5-phenylhydantoin [(R)-3-2H-DPH], and the measurements are in agreement with previous determinations in the literature obtained by optical methods. The overall results of 2H retention are compared with those obtained in the rabbit, rat, and man.