Abstract
Chimeric mice are immunodeficient mice in which the majority of the hepatic parenchymal cells are replaced with human hepatocytes.
Following intravenous administration of 24 model compounds to control and chimeric mice, human hepatic clearance (CLh) was predicted using the single-species allometric scaling (SSS) method. Predictability of the chimeric mice was better than that of the control mice.
Human CLh was predicted by the physiologically based scaling (PBS) method, wherein observed CLh in chimeric mice was first converted to intrinsic CLh (CLh,int). As the liver of chimeric mice contains remaining mouse hepatocytes, CLh,int was corrected by in vitro CLh ratios of the mouse to human hepatocytes according to their hepatocyte replacement index. Further, predicted human CLh was calculated based on an assumption that CLh,int in chimeric mice normalised for their liver weight was equal to CLh,int per liver weight in humans. Consequently, better prediction performance was observed with the use of the PBS method than the SSS method.
SSS method is an empirical method, and the effects of coexisting mouse metabolism cannot be avoided. However, the PBS method with in vitro CLh correction might be a potential solution and may expand the application of chimeric mice in new drug development.
Acknowledgements
We thank Drs. Hiroshi Suemizu and Shotaro Uehara of the Central Institute for Experimental Animals and Dr. Sayaka Oba and Mr. Yoshiyuki Morikawa of CLEA Japan for supporting this research.
Disclosure statement
HK and MN are employees of CLEA Japan, Inc., the contract research organization and manufacturer of TK-NOG chimeric mice. TY is an employee of In Vivo Science, Inc., the distributor of TK-NOG chimeric mice. The other authors have no interests to declare.