The pharmacokinetics of phenytoin in perfused human placenta.

In vivo phenytoin (PHT) and its metabolites are present in the fetal plasma. In order to determine the transfer kinetics and biotransformation characteristics for phenytoin in the human placenta, a dual recirculating perfused human placental lobule preparation was utilized. A single bolus of 14C-PHT with or without tritiated water (3H2O) was injected into the maternal reservoir. Peak concentrations of 3H2O and PHT appeared simultaneously in the maternal artery at 4 minutes and in the maternal vein at 9 minutes, whereas the peak concentrations of 14C-PHT and 3H2O in the fetal vein were at 9 and 7 minutes, respectively. After 4 hours of perfusion, the total phenytoin concentration in the fetal perfusate was only 73% of the maternal perfusate level. Protein-bound PHT was 37 +/- 8% and 7 +/- 3% of the total phenytoin in the maternal and fetal perfusate. The concentrations of free phenytoin in the maternal and fetal compartments were identical by 60 minutes and were maintained for the remainder of the experiment. The concentration of total PHT in perfused placenta was more than 3.5 times greater than the total maternal perfusate levels. In the placenta, PHT concentration was highest in the cytosolic fraction, and 57% of the placental PHT was in the free form. There was no evidence of parahydroxylation, oxidation, or conjugation of PHT. Phenytoin was also concentrated in nonperfused placental tissue. Thus the transfer of PHT by the human placenta is rapid and dependent upon protein binding and flow in both maternal and fetal circulations. Even though the human placenta does concentrate PHT, it does not metabolize PHT under these conditions.