Evaluation of transplacental pharmacology and toxicology from bench to bedside.

摘要

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, P < 0.0001). We then utilized the perfusion model to evaluate the placental transfer of 6-mercaptopurine (6-MP), a drug commonly used in pregnancy for the treatment of inflammatory bowel disease as well as the toxic effects of alcohol and formic acid on the placenta. Placental transfer of 6-MP is limited and binding to placental tissue and maternal pharmacokinetic parameters are the main factors that restrict placental transfer. Evaluation of the placental perfusion results together with our meta-analysis of clinical studies supported other evidence that the benefit of 6-MP outweighs any fetal risk when indicated. The placental transfer of folic acid was decreased in pregnancies with heavy alcohol exposure and folic acid supplementation may decrease the toxic effects of formic acid on the placenta. Furthermore, our validation of the ex vivo perfusion model showed that it is effective in predicting fetal exposure to drugs and should have a place in clinical and regulatory pharmacology and toxicology.