Phenytoin-Induced Depletion of Folate in Rats Originates in Liver and Involves a Mechanism That Does Not Discriminate Folate Form ,

Abstract

The anticonvulsant phenytoin causes a decrease in plasma concentrations of folate in epileptic patients. The mechanism underlying this depletion is unknown. To study this mechanism, phenytoin was administered to rats by addition to the diet (3 g phenytoin/kg diet) for up to 8 wk. At selected times during phenytoin administration (0, 3, 7, 10, 14, 28, 42 and 56 d), the composition of the folate pools of intestinal mucosa, liver, bile and brain was determined. The 0-d administration served as the control group. The controls were fed the same diet without phenytoin for the eight weeks of the experiment. Phenytoin administration had minimal effect on either the folate concentration or the composition of the folate pool in intestinal mucosa. Phenytoin administration did, however, cause a depletion of total hepatic folate to about 50% of control, causing the pentaglutamate derivatives of each of the pteridine derivatives to decline rapidly, with the formyl and dihydro derivatives of the pteridine moiety falling more rapidly than the methyl and methylene + tetrahydro derivatives. The monoglutamate of the methylene + unsubstituted tetrahydro derivative increased significantly with time of phenytoin treatment. The mono- and di-glutamate derivatives of the methyltetrahydrofolate increased transiently and significantly in the bile, and the polyglutamate chain length increased significantly in the brain with time of phenytoin treatment. We conclude that phenytoin inhibits the formation of polyglutamyl folates in rat liver.

Effect of folic acid and vitamin B12 administration on phenytoin induced toxicity in rats

“…Group 1 animals served as the control and were gavaged normal saline (1.0 ml). Groups 2, 3, 4, and 5 received phenytoin, phenytoin + folic acid, phenytoin + vitamin B 12 and phenytoin + vitamin B 12 + folic acid respectively.…”

“…Commercially available phenytoin capsules were obtained from Parke-Davis Hoofireg; Vitamin B 12 and folic acid tablets were obtained from Vitabiotics (Nig) Ltd, Lagos, Nigeria. The choice of commercial products was to reflect the condition of those under the medication of these drugs.…”

“…Phenytoin: 5mg/ kg body weight of rat, folic acid: 70 microgram/kg body weight of rat and vitamin B 12 : 15 microgram/kg body weight of rat. Phenytoin and folic acid were administered daily by oral intubations whilst vitamin B 12 was administered intraperitoneally twice a week. Treatment lasted for 4 weeks.…”

“…Several suggestions have been made in an attempt to deduce the mechanism by which phenytoin alter folate metabolism (11,12). Porter and Meldrum (13), proposed that phenytoin causes mal-absorption of dietary folate by inhibiting a conjugase, an enzyme that converts the polyglutamate form of folate to the absorbable monoglutamate.…”

“…Also it causes depletion of total hepatic folate to about 50% (12). There are several reports on the effect of drugs on liver function and phenytoin is included.…”