Multiple exposures to AZT (Zidovudine) for 14 hr were examined in the dually perfused human term placental lobule in order to determine the pharmacokinetics of transfer, as well as several viability parameters of toxicity. In each experiment, three separate additions of AZT at a concentration of 3.8 mM was added to the maternal reservoir, and perfusate samples were obtained from both the maternal and the fetal compartments for determinations of AZT, glucose, lactate, oxygen, and human chorionic gonadotropin (hCG) concentrations. During 14 hr of continuous exposure to this high concentration of AZT, the production of hCG was significantly reduced by 75% when compared to the 2-hr control period before the administration of AZT. In addition, lactate production was reduced by 45% after AZT administration. Such changes in hCG and lactate production were not observed in separate experiments conducted over the same time interval, but with no AZT added. Based upon a lack of total perfusion fluid loss, changes in fetal arterial pressure, and histopathology, placental lobule integrity was maintained throughout the perfusion period. Further, AZT readily crossed the placenta into the fetal compartment reaching equilibrium with maternal levels within 60-90 min after addition of each administration of AZT. Based upon AZT levels in the fetal perfusate, AZT does not accumulate against a concentration gradient and therefore appears to be diffusion limited. Placental tissues obtained from perfused, partially perfused, and nonperfused regions at the conclusion of the experiment were analyzed for AZT levels. Substantial AZT levels in the nonperfused tissues indicated that AZT is a freely diffusible compound. The results of the current study demonstrate that high concentrations of AZT alter placental function resulting in reduced production of hCG and lactate.