Phenytoin causes phalangeal hypoplasia in the rabbit fetus at clinically relevant free plasma concentrations

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Abstract
New Zealand White robbits were treated orally with 0 (controls), 50, 100, or 150 mg/kg phenytoin on days 14‐16 of pregnacy. Total and free plasma concentrations of phenytoin were determined in maternal plasma 2, 6, and 24 hr after the final dose in all aimals. In addition, after administration of 150 mg/kg maternal plasma concentrations were also determined after 12 and 48 hr, the concentrations in amniotic fluid after 6 hr and those in fetal tissue 6 and 24 hr after the final treatment. A high degree of plasma protein binding was observed in maternal blood. Treatment with 50 mg/kg resulted in free plasma concentrations of up to 5.0 μmol/1 during the 24 hr period following the final dose. Significantly higher free plasma concentrations were observed at the two higher dose levels; up to 9.7 μmol/1 at 100 mg/kg and 12.7 μmol/1 at 150 mg/kg. Digital hypoplasia was not seen in the control group or the animals treated with 50 mg/kg. However, treatment with 100 mg/kg resulted in hypoplasia in a single or a few digits in approximately 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 used therapeutically, the resulting free concentrations of phenytoin are similar to those which are associated wth the some type of defects in humans. These data indicate that the pharmacologically induced fetal hypoxia/ischemia and vascular disruption preceding malformations of this type, which were observed in a previous study in rabbits, may be of human relevance.