Drug Metabolism and Disposition

Two types of systems are used in ex vivo human placental perfusion studies to predict fetal drug exposures, i.e. closed systems with recirculation of the maternal and fetal buffer, and open systems using a single-pass mode without recirculation. The in vivo fetal/maternal (F:M) ratio of metformin, a cationic drug that crosses the placenta, is consistent with that reported in an open system ex vivo , but not with that in a closed system. In the present study, we aimed to develop a pharmacokinetic (PK) model of transplacental transfer of metformin in order to predict in vivo fetal exposure to metformin and to resolve the apparent inconsistency between open and closed ex vivo systems. The developed model shows that the difference between open and closed systems is due to the difference in the time required to achieve the steady state. The model-predicted F:M ratio (approx. 0.88) is consistent with reported in vivo values (mean (95% confidence interval): 1.10 (0.69-1.51)). The model incorp