Abstract

1. Chimeric mice are immunodeficient mice in which the majority of the hepatic parenchymal cells are replaced with human hepatocytes.

2. Following intravenous administration of 24 model compounds to control and chimeric mice, human hepatic clearance (CL_h) was predicted using the single-species allometric scaling (SSS) method. Predictability of the chimeric mice was better than that of the control mice.

3. Human CL_h was predicted by the physiologically based scaling (PBS) method, wherein observed CL_h in chimeric mice was first converted to intrinsic CL_h (CL_h,int). As the liver of chimeric mice contains remaining mouse hepatocytes, CL_h,int was corrected by in vitro CL_h ratios of the mouse to human hepatocytes according to their hepatocyte replacement index. Further, predicted human CL_h was calculated based on an assumption that CL_h,int in chimeric mice normalised for their liver weight was equal to CL_h,int per liver weight in humans. Consequently, better prediction performance was observed with the use of the PBS method than the SSS method.

4. SSS method is an empirical method, and the effects of coexisting mouse metabolism cannot be avoided. However, the PBS method with in vitro CL_h correction might be a potential solution and may expand the application of chimeric mice in new drug development.

摘要

1. 嵌合小鼠是免疫缺陷小鼠，其中大部分肝实质细胞被人肝细胞取代。

2. 在向对照和嵌合小鼠静脉内施用 24 种模型化合物后，使用单物种异速生长缩放 (SSS) 方法预测人类肝脏清除率 (CL _h )。嵌合小鼠的可预测性优于对照小鼠。

3. 人类 CL _h是通过基于生理学的缩放 (PBS) 方法预测的，其中在嵌合小鼠中观察到的 CL _h首先转换为内在 CL _h (CL _h,int )。由于嵌合小鼠的肝脏含有剩余的小鼠肝细胞，因此根据肝细胞置换指数，通过小鼠与人肝细胞的体外CL _h比率校正CL _h,int。此外，预测的人类CL _ħ计算基于一个假设，即CL_小时，INT在归一化为其肝脏重量嵌合小鼠等于CL_小时，INT人体每肝脏重量。因此，使用 PBS 方法观察到比 SSS 方法更好的预测性能。

4. SSS方法是一种经验方法，不能避免共存小鼠代谢的影响。然而，具有体外CL _h校正的 PBS 方法可能是一个潜在的解决方案，并可能扩大嵌合小鼠在新药开发中的应用。