Phenytoin treatment and folate supplementation affect concentrations of folates in tissues of cobalamin-deficient rats.

To further define the mechanism of interaction among phenytoin, folates and cobalamins in rats, we studied the effect of phenytoin (60 mg/(kg.day)) with or without folic acid supplementation and with or without cobalamin deficiency, as well as the effect of supplementing with folic acid (200 mg/kg diet) with or without a cobalamin deficiency, on the tissue concentrations of folates and phenytoin (determined respectively by HPLC and fluorescence polarization). The major tissues (liver, intestinal mucosae, blood and brain) were studied. A folic acid overload (estimated at about 2 mg/day) increased folate levels in the liver, the intestinal mucosae and blood, while there was no effect on cerebral levels. Phenytoin had no significant effect on folate tissue concentration. The major finding was that a folic acid overload caused a considerable decrease in the hepatic and cerebral concentrations of phenytoin. This decrease could be responsible for the increased frequency of epileptic fits in patients treated with this anticonvulsant drug when combined with a folic acid supplement. Concentration changes of the drug in cobalamin-replete or -deficient rats, with or without folic acid supplementation, suggest that the interaction between the anticonvulsant and the two vitamins (folates and cobalamins) occurs at the level of transmethylation reactions.