Effect of pregnancy on the pharmacokinetics of phenytoin in rats.

Phenytoin, in single doses of 10 or 30 mg/kg, was administered by i.v. injection to nonpregnant (congruent to 200-300 g) and 20 days pregnant inbred Lewis rats. The plasma protein binding of phenytoin was determined under conditions which minimized in vitro lipolysis and consequent artifactual results. The absolute (milliliters per minute) plasma clearance of total (free plus bound) phenytoin by the pregnant rats was increased (10-mg/kg dose) or not significantly different (30-mg/kg dose) compared to concurrent nonpregnant controls. The relative (milliliters per minute per kilogram) plasma clearance of total phenytoin was not significantly changed (10-mg/kg dose) or was decreased (30-mg/kg dose) in pregnancy. The relative apparent volume of distribution of free drug (but not of total drug) was essentially the same in the pregnant and nonpregnant animals and was independent of dose. The plasma clearance of free (unbound) phenytoin decreased with dose and was decreased during pregnancy, at both doses studied (more so at the larger dose). The elimination kinetics of p- hydroxyphenytoin , the major metabolite of phenytoin which inhibits phenytoin metabolism in rats, were similar in pregnant and nonpregnant rats and so were the plasma concentrations of this metabolite after phenytoin administration. The relatively more pronounced effect of pregnancy on the elimination of the larger dose of phenytoin may reflect a greater inhibitory effect of p- hydroxyphenytoin during pregnancy. This does not occur in humans (due to much lower plasma concentrations of the metabolite) and that may account for possible differences in the effect of pregnancy on phenytoin pharmacokinetics in rats and humans.