Evaluation of Transplacental Pharmacology and Toxicology from Bench to Bedside

Many women require pharmacologic treatment during pregnancy. Clinical studies of drug safety in human pregnancy are often limited because of ethical considerations and thus a theoretical framework to evaluate drug safety in pregnancy is needed. Dual perfusion of a single placental lobule is the only experimental model to study human placental transfer of substances in organized placental tissue. The objectives of this thesis were to systematically evaluate the perfusion model in predicting placental drug transfer and to develop a model to account for non-placental pharmacokinetic parameters in the perfusion results. In general, the fetal-to-maternal drug concentration ratios matched well between placental perfusion experiments and in vivo samples taken at the time of delivery. After modeling for differences in maternal and fetal/neonatal protein binding and blood pH, the perfusion results were able to accurately predict in vivo transfer at steady state (R2 = 0.85, PPh.D