PHENYTOIN CAUSES PHALANGEAL HYPOPLASIA IN THE RABBIT FETUS AT CLINICALLY RELEVANT FREE PLASMA-CONCENTRATIONS

New Zealand White rabbits were treated orally with 0 (controls), 50, 1 00, or 150 mg/kg phenytoin on days 14-16 of pregnancy. Total and free plasma concentrations of phenytoin were determined in maternal plasma 2, 6, and 24 hr after the final dose in all animals. In addition, afte r administration of 150 mg/kg maternal plasma concentrations were also determined after 12 and 48 hr, the concentrations in amniotic fluid a fter 6 hr, and those in fetal tissue 6 and 24 hr after the final treat ment. A high degree of plasma protein binding was observed in maternal blood. Treatment with 50 mg/kg resulted in free plasma concentrations of vp to 5.0 mu mol/l during the 24 hr period following the final dos e. Significantly higher free plasma concentrations were observed at th e two higher dose levels; up to 9.7 mu mol/l at 100 mg/kg and 12.7 mu mol/l at 150 mg/kg. Digital hypoplasia was not seen in the control gro up or the animals treated with 50 mg/kg. However, treatment with 100 m g/kg resulted in hypoplasia in a single or a few digits in approximate ly 50% of the fetuses, and 150 mg/kg provoked hypoplasia in almost all digits in all fetuses. These results show that even though the doses which caused digital defects in rabbits are much higher than those use d therapeutically, the resulting free concentrations of phenytoin are similar to those which are associated with the same type of defects in humans. These data indicate that the pharmacologically induced fetal hypoxia/ischemia and vascular disruption preceding malformations of th is type, which were observed in a previous study in rabbits, may be of human relevance. (C) 1995 Wiley-Liss, Inc.