RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2020-000276
DO 10.1124/dmd.120.000276
A1 Bo Feng
A1 Rachel Pemberton
A1 Wojciech Dworakowski
A1 Zhengqi Ye
A1 Craig Zetterberg
A1 Guanyu Wang
A1 Yoshio Morikawa
A1 Sanjeev Kumar
YR 2020
UL http://dmd.aspetjournals.org/content/early/2020/12/29/dmd.120.000276.abstract
AB 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.