Phenytoin: an evaluation of several potential teratogenic mechanisms.

The effect of pharmacological doses of phenytoin (DPH) administered for a maximum of 28 days was studied in pregnant and nonpregnant rats as well as in 14- and 21-day fetuses. The following parameters were monitored in the adult rats: maximal electroshock seizures, serum DPH and folate, liver microsomal P-450, and 14C-DPH tissue distribution. 14C-DPH distribution was also evaluated in fetal tissues. Pregnant animals demonstrated an increase in anticonvulsant activity as well as increased serum concentrations of DPH throughout pregnancy and on the 7th post-partum day. Brain concentrations of DPH increased during pregnancy but had returned to the values in the nonpregnant group at the 7th post-partum day. Liver microsomal P-450 was decreased in pregnant animals receiving DPH at days 7 and 14 of pregnancy. Serum folate also decreased at day 14 of pregnancy in animals receiving DPH. Fetal tissue binding of DPH appeared to be related to serum concentrations of the drug at day 14. Teratogenic effects of DPH could be related to the increased serum and tissue concentrations of the drug observed during pregnancy as well as its effect on serum folate at day 14 of gestation.