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 card iac dysrhythmia during a restricted sensitive period. In order to further e lucidate this theory, PHT was administered to Sprague-Dawley rats on gestat ion 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 In satellite animals blood samples were withdrawn (0.5-24 h after dose) and total and fr ee maternal plasma concentrations of PHT were measured. Pharmacokinetic dat a correlated well with pregnancy outcome data. At 150 mg/kg ip high concent rations of long duration (C-max 240 mu M and AUC 5300 mu Mhl(-1) - total) a nd marked developmental toxicity (embryonic death, decreased fetal weights, and orofacial clefts) were observed. After 100 mg/kg ip (C-max 150 mu M, A UC 2600 mu Mhl(-1) - total) only slight developmental toxicity (decreased f etal 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 adver se effects at all were observed. In separate experiments the effect of diff erent concentrations of PHT on the embryonic heart was studied by adding PH T 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 administra tion 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 sugge st that the development toxicity of PHT is caused by concentration-dependen t induction of embryonic dysrhythmia and hypoxia related damage. (C) 2000 a cademic Press.