TY - JOUR T1 - Development of a pharmacokinetic model of transplacental transfer of metformin to predict in vivo fetal exposure JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.120.000127 SP - DMD-AR-2020-000127 AU - Ken Kurosawa AU - Koji Chiba AU - Saki Noguchi AU - Tomohiro Nishimura AU - Masatoshi Tomi Y1 - 2020/01/01 UR - http://dmd.aspetjournals.org/content/early/2020/10/13/dmd.120.000127.abstract N2 - 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 incorporates bidirectional transport via organic cation transporter 3 (OCT3) at the basal plasma membrane, and simulations indicate that the use of trimethoprim (an OCT3 inhibitor) to prevent microbial growth in the placenta ex vivo has a negligible effect on the overall maternal-to-fetal and fetal-to-maternal clearances. The model could successfully predict in vivo fetal exposure using ex vivo human placental perfusion data from both closed and open systems. This transplacental PK modeling approach is expected to be useful for evaluating human fetal exposures to other poorly permeable compounds, besides metformin. Significance Statement In the present study, we developed a novel human transplacental pharmacokinetics model with transporters for estimating fetal exposure of metformin by utilizing previous reported ex vivo human placental perfusion studies. Since our PK model successfully prove the inconsistency in fetal exposure of metformin between in vivo and ex vivo studies, this modelling approach appears to be useful for estimating the in vivo fetal drug exposure of physiologically ionized drugs like metformin. ER -