Evaluation of the Utility of PXB Chimeric Mice for Predicting Human Liver Partitioning of Hepatic Organic Anion-Transporting Polypeptide Transporter Substrates

Abstract

The ability to predict human liver-to-plasma unbound partition coefficient (K puu ) 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 OATP 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 in 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 severely compromised immune-deficient (SCID) control mice compared with the PXB chimeric mice, which suggest that mouse has a stronger transporter-mediated hepatic uptake than human. In vivo liver-to-plasma K puu from PXB chimeric and SCID control mice were also compared, and rosuvastatin and pravastatin K puu in SCID mice were more than 10-fold higher than that in PXB chimeric mice, whereas pitavastatin, valsartan, and repaglinide K puu in SCID mice were comparable with K puu in PXB chimeric mice. Finally, PXB chimeric mouse liver-to-plasma K puu values were compared with the reported human K puu , and a good correlation was observed as the PXB K puu vales were within 3-fold of human K puu . Our results indicate that PXB mice could be a useful tool to delineate hepatic uptake and enable prediction of human liver-toplasma K puu of hepatic uptake transporter substrates. SIGNIFICANCE STATEMENTWe evaluated PXB mouse with humanized liver for its ability to predict human liver disposition of five organic anion-transporting polypeptide 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 unbound partition coefficient (K puu ) values were compared with the reported human K puu , and a good correlation was observed. PXB mice could be a useful tool to project human liver-to-plasma K puu of hepatic uptake transporter substrates.The work was supported by Vertex Pharmaceutical Company Limited and Chimeric Mouse with Humanized Liver (CMHL) Consortium. Y.M. is an employee of PhoenixBio Co., Ltd., Hiroshima, Japan. He provided PXB mice but did not have any additional role in conducting the experiment, performing the data analysis, or preparing the manuscript. All other authors (B.

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