Developmental toxicity and pharmacokinetics of phenytoin in the rhesus macaque: an interspecies comparison

The developmental toxicity and pharmacokinetic fate of phenytoin in the pregnant rhesus macaque (Macaca mulatta) were examined. Oral administration of 60 to 600 mg/kg phenytoin once daily from gestational day 21 to 50 resulted in dose-dependent maternal toxicity of the central nervous system and gastrointestinal tract and an increase in embryonic loss, but no teratogenic insult. Sustained plasma levels as high as 40 micrograms/mL of total phenytoin occurred at the beginning of the treatment period. However, significant increases in the rate of elimination resulted in the reduction of total phenytoin exposure as treatment progressed. This was evidenced by large increases in phenytoin clearance, and decreases in elimination half-life and area under the time versus plasma concentration curve. Maternal toxicity, but not embryolethality, correlated with plasma phenytoin levels. Interspecies comparisons of these parameters from published data were evaluated in the mouse, rat, rabbit, rhesus macaque, and human.