Pharmacokinetic data support pharmacologically induced embryonic dysrhythmia as explanation to fetal hydantoin syndrome in rats

New studies suggest that the teratogenicity of phenytoin (PHT) is linked to its membrane-stabilizing pharmacological action via the rapid component of the delayed rectified potassium channel (lkr), resulting in embryonic cardiac dysrhythmia during a restricted sensitive period. In order to further elucidate this theory, PHT was administered to Sprague-Dawley rats on gestation day (GD) 11 with either a single dose of 150 or 100 mg/kg ip or 150 mg/kg po and developmental toxicity at term (GD 21) was studied. In satellite animals blood samples were withdrawn (0.5-24 h after dose) and total and free maternal plasma concentrations of PHT were measured. Pharmacokinetic data correlated well with pregnancy outcome data. At 150 mg/kg ip high concentrations of long duration (C-max 240 mu M and AUC 5300 mu Mhl(-1) - total) and marked developmental toxicity (embryonic death, decreased fetal weights, and orofacial clefts) were observed. After 100 mg/kg ip (C-max 150 mu M, AUC 2600 mu Mhl(-1) - total) only slight developmental toxicity (decreased fetal weights) was recorded and after 150 mg/kg po the plasma concentrations were even lower (C-max 63 PM and AUC 1100 mu Mhl(-1) - total) and no adverse effects at all were observed. In separate experiments the effect of different concentrations of PHT on the embryonic heart was studied by adding PHT to GD 11 rat embryos cultured in vitro or by culturing GD 11 embryos from exposed dams. The decrease in heart rates was 3, 16, and 32% after culture with 50, 100, and 200 mu M of PHT, respectively. After maternal administration of 150 mg/kg ip or po, the embryonic heart rate in vitro decreased by 25 and 7%, respectively, compared to controls. Altogether the results suggest that the development toxicity of PHT is caused by concentration-dependent induction of embryonic dysrhythmia and hypoxia related damage. (C) 2000 academic Press.