EFFECTS OF LOW-DOSE PHENYTOIN ADMINISTERED TO NEWBORN MICE ON DEVELOPING CEREBELLUM

To examine correlations between dose levels of phenytoin (PHT) and neu rotoxic effects on cerebellar development, we administered 10, 17.5, 2 5, and 35 mg/kg PHT suspended in sesame oil orally to newborn Jcl:ICR mice once a day during postnatal days 2-4 and determined plasma PHT co ncentrations during the administration period. Mortality rates were 12 .5% and 35.2% in males and 15.3% and 33.3% in females for the 25 and 3 5 mg/kg PHT-treated groups during the PHT treatment, respectively. In the 25 and 35 mg/kg PHT-treated groups, total brain weight, the size o f the cerebellum and cerebellar weight were significantly reduced on p ostnatal day 21. However, in the 10 and 17.5 mg/kg PHT-treated groups, total brain weight and the size and weight of the cerebellum did not differ from those of the control group. Histologically, the number of pyknotic cells in the external granular layer (EGL) in the 25 and 35 m g/kg PHT-treated groups was increased on postnatal day 5, and the EGL was thicker than in the control group on postnatal day 14. Some of the Purkinje cells in the 35 mg/kg PHT-treated group showed degeneration. Plasma PHT levels were 10.7 +/- 2.2 and 24.6 +/- 2.6 mu g/ml in the 2 5 and 35 mg/kg PHT groups on the third day of PHT treatment, respectiv ely. In the 25 mg/kg PHT group, plasma PHT level was found to be in th e therapeutic range for humans, 10-20 mu g/ml. Accordingly, during pre gnancy, epileptic women should be carefully given PHT at the lowest ef fective dose while plasma PHT levels are monitored properly. These fin dings emphasize the importance of pharmacokinetics in evaluating of ph enytoin-induced developmental neurotoxicity. (C) 1997 Elsevier Science Inc.