TY - JOUR T1 - Evaluation of the Utility of PXB Chimeric Mice for Predicting Human Liver Partitioning of Hepatic Organic Anion-Transporting Peptide Substrates JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.120.000276 SP - DMD-AR-2020-000276 AU - Bo Feng AU - Rachel Pemberton AU - Wojciech Dworakowski AU - Zhengqi Ye AU - Craig Zetterberg AU - Guanyu Wang AU - Yoshio Morikawa AU - Sanjeev Kumar Y1 - 2020/01/01 UR - http://dmd.aspetjournals.org/content/early/2020/12/29/dmd.120.000276.abstract N2 - The ability to predict human liver-to-plasma unbound partition coefficient (Kpuu) is important to estimate unbound liver concentration for drugs that are substrates of hepatic organic anion transporting peptide (OATP) transporters with asymmetric distribution into the liver relative to plasma. Herein, we explored the utility of PXB chimeric mice with humanized liver that are highly repopulated with human hepatocytes to predict human hepatic disposition of OATPs substrates, including rosuvastatin, pravastatin, pitavastatin, valsartan and repaglinide. In vitro total uptake clearance and transporter-mediated active uptake clearance in C57 mouse hepatocytes were greater than PXB chimeric mouse hepatocytes for rosuvastatin, pravastatin, pitavastatin and valsartan. Consistent with in vitro uptake data, enhanced hepatic uptake and resulting total systemic clearance were observed with the above four compounds in control SCID than in PXB chimeric mouse, which suggest that mouse has a stronger transporter-mediated hepatic uptake than human. In vivo liver-to-plasma Kpuu from PXB chimeric and SCID control mice were also compared, and rosuvastatin and pravastatin Kpuu in SCID mouse were more than 10-fold higher than that in PXB chimeric mouse, whereas, pitavastatin, valsartan and repaglinide Kpuu in SCID mouse were comparable with Kpuu in PXB chimeric mouse. Finally, PXB chimeric mouse liver-to-plasma Kpuu values were compared with the reported human Kpuu, and a good correlation was observed as the PXB Kpuu vales were within 3-fold of human Kpuu. Our results indicate that PXB mice could be a useful tool to delineate hepatic uptake and enable prediction of human liver-to-plasma Kpuu of hepatic uptake transporter substrates. Significance Statement We evaluated PXB mouse with humanized liver for its ability to predict human liver disposition of five OATP transporter substrates. Both in vitro and in vivo data suggest that mouse liver has a stronger transporter-mediated hepatic uptake than the humanized liver in PXB mouse. More importantly, PXB liver-to-plasma Kpuu values were compared with the reported human Kpuu, and a good correlation was observed. PXB mice could be a useful tool to project human liver-to-plasma Kpuu of hepatic uptake transporter substrates. ER -