Chronic treatment of rats with primidone causes depletion of pteroylpentaglutamates in liver.

Anticonvulsants have been shown to cause folacin deficiency in chronically treated epileptic patients. However, a mechanism for this depletion has not been established. In the present study, the effects of chronic primidone treatment on folates in the rat were investigated. Using a continuously protective relatively nontoxic regimen of oral administration, it was found that primidone (100 mg/kg, twice per day) caused a decrease of pteroylpentaglutamates in the liver to less than half the control value within 1 wk. Total liver folacin concentration decreased by 30% in the first week followed by a slow gradual further decline with continuing treatment. Plasma folacin exhibited essentially the same pattern but no effect was observed on brain folacin concentration. Primidone was not detectable in plasma 12 h after gavage but phenobarbital was detectable. These data are consistent with the hypothesis that the anticonvulsant primidone (and/or phenobarbital) cause folate depletion via interaction with folate metabolism.