Metabolic interactions of phenytoin in the rat: effect of coadministration with the anticonvulsant drugs sodium valproate, sulthiame, ethosuximide or phenobarbital

Rats were administered with 50 mg/kg phenytoin (PHT), twice a day, for five consecutive days and with a second anticonvulsant drug in addition for a further five days. Analysis of 24 hr urine samples for content of unmetabolized PHT and its major metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (pHPPH) indicates that PHT hydroxylation was significantly inhibited by sulthiame coadministration since during the test period (days 6-10) the concentrations of PHT and pHPPH in urine were significantly increased and decreased respectively. In contrast, sodium valproate, ethosuximide and phenobarbital had no significant effect on the urinary excretion pattern of PHT. These data correlate with changes in plasma and brain PHT concentrations.