Kinetics of drug action in disease states III: Effect of pregnancy on the relationship between phenytoin concentration and antiseizure activity in rats.

The purposes of this investigation were to determine the effect of pregnancy on the susceptibility of female rats to experimentally induced seizures and on the relationship between serum phenytoin concentration and antiseizure activity. Pregnant rats (on the 18th day of gestation) were more susceptible than nonpregnant female rats to seizures produced by maximal electroshock or by a body-weight-based dose of pentylenetetrazol. There was no apparent difference between pregnant (20th day of gestation) and nonpregnant rats in the relationship between seizure protection (percent of animals protected) and the serum concentration of total (free plus protein-bound) phenytoin. The relationship between concentration and effect was essentially the same 20 min after an injection of phenytoin and 2 h after the start of a constant-rate infusion preceded by a loading dose of the drug. Since the protein binding of phenytoin is appreciably decreased in late pregnancy, the serum concentration of free phenytoin required for seizure protection tended to be higher in pregnant than in nonpregnant rats. This may be due to the increased susceptibility of pregnant rats to seizure stimuli.