The suitability of a pregnant rat model for the study of transplacental pharmacokinetics was assessed by two test agents, antipyrine, which freely equilibrates in the maternal and fetal blood, and aminoisobutyric acid, which is actively transported from mother to fetus. In accordance with an ideal protocol for a two-compartment model solved for bolus injections, unlabeled antipyrine was injected into the mother (day 20 of gestation), and labeled antipyrine was injected into its fetuses following exteriorization under ether anesthesia. Maternal and fetal blood samples (2-3 fetuses removed at each time period) were collected sequentially under brief periods (2-3 min) of ether anesthesia up to 9-12 hr. In separate studies it was found that sequential removal of fetuses did not significantly alter maternal or fetal serum drug concentrations. As expected, placental clearances (ml/h-1/kg-1) of antipyrine from mother to fetus (392 +/- 86) and from fetus to mother (448 +/- 107) did not significantly differ. As an alternate approach, (3H)aminoisobutyric acid was either injected into the mother or into the fetuses, and maternal and fetal blood samples were sequentially collected in each case; the clearance of this agent from fetus to mother was 53 ml/h-1/kg-1, and, as expected, was much lower than that from mother to fetus (168 ml/h-1/kg-1). It is suggested that the pregnant rat model can be used as a substitute for the chronically catheterized pregnant sheep model for the study of pharmacokinetics in the maternal-fetal unit.