Phenytoin metabolism in mice.

The effect of dose on the metabolism of phenytoin (5,5-diphenylhydantoin, DPH) was investigated. A single ip injection of 14C-DPH (1, 20, or 100 mg/kg) was given to adult male mice, and urine and feces were collected over 72 hr. DPH and its metabolites excreted in urine were separated and analyzed by HPLC after beta-glucuronidase hydrolysis and extraction with ethyl acetate. The drug-related products measured in urine included: DPH, 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin, (DHD), 5-(3-methoxy-4-hydroxyphenyl)-5-phenylhydantoin (OMCAT), and diphenylhydantoic acid (DPHA). The percentage of the dose appearing as unchanged DPH and DPHA increased with dose, whereas that excreted as OMCAT decreased at higher doses. In contrast, the excretion of p-HPPH (approximately 30%) and DHD (approximately 12%) was independent of dose. The constant ratio of p-HPPH/DHD excreted in urine suggests that these metabolites have a common precursor, probably an arene oxide. Studies of the fate of DPH metabolites showed that a small fraction of a dose of p-HPPH or of DHD was converted to OMCAT. The catechol metabolite of DPH, therefore, arises via two different mechanisms.