Prediction of In Vivo Hepatic Clearance and Half-Life of Drug Candidates in Human Using Chimeric Mice with Humanized Liver
Prediction of In Vivo Hepatic Clearance and Half-Life of Drug Candidates in Human Using Chimeric Mice with Humanized Liver
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DOI：
10.1124/dmd.111.040923
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发表时间：
2012-02-01
影响因子：
3.9
通讯作者：
Ohta, Shigeru
中科院分区：
文献类型：
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作者：
Sanoh, Seigo;Horiguchi, Aya;Ohta, Shigeru
由于各种原因，包括物种差异，很难从动物数据准确预测人体药代动力学（PK）参数。然而，已经开发了具有人源化肝脏的嵌合小鼠（PXB小鼠;用约80%的人肝细胞重新填充的尿激酶型纤溶酶原激活物/严重联合免疫缺陷小鼠）。PXB小鼠肝脏中细胞色素P450（P450）和非P450酶的表达水平和代谢活性与人类相似。在本研究中，我们从PXB小鼠中获得的数据中检查了人体PK参数的可预测性。所选药物的消除涉及多种代谢途径，不仅由P450介导，而且由非P450酶介导，如UDP-葡萄糖醛酸转移酶、磺基转移酶和肝脏中的醛氧化酶。PXB小鼠肝细胞的体外固有清除率（克林特，in vitro）与基于充分搅拌模型计算的人体内固有清除率（克林特，in vivo）之间的直接比较显示出中度相关性（r（2）= 0.475，p = 0.009）。然而，当类似地比较人类和PXB小鼠中的克林特、体内值时，存在良好的相关性（r（2）= 0.754，p = 1.174 x 10（-4））。静脉给药后的消除半衰期（t（1/2））也显示出人类和PXB小鼠之间良好的相关性（r（2）= 0.886，p = 1.506 x 10（-4））。尽管由于预测误差较大，可能无法预测绝对值，但至少可以预测人类CL和t（1/2）的等级顺序。我们的研究结果表明，在体外和体内实验与PXB小鼠应该是有用的，至少半定量预测候选药物在人体内的PK特征。
Accurate prediction of pharmacokinetics (PK) parameters in humans from animal data is difficult for various reasons, including species differences. However, chimeric mice with humanized liver (PXB mice; urokinase-type plasminogen activator/severe combined immunodeficiency mice repopulated with approximately 80% human hepatocytes) have been developed. The expression levels and metabolic activities of cytochrome P450 (P450) and non-P450 enzymes in the livers of PXB mice are similar to those in humans. In this study, we examined the predictability for human PK parameters from data obtained in PXB mice. Elimination of selected drugs involves multiple metabolic pathways mediated not only by P450 but also by non-P450 enzymes, such as UDP-glucuronosyltransferase, sulfotransferase, and aldehyde oxidase in liver. Direct comparison between in vitro intrinsic clearance (CLint, in vitro) in PXB mice hepatocytes and in vivo intrinsic clearance (CLint, in vivo) in humans, calculated based on a well stirred model, showed a moderate correlation (r(2) = 0.475, p = 0.009). However, when CLint, in vivo values in humans and PXB mice were compared similarly, there was a good correlation (r(2) = 0.754, p = 1.174 x 10(-4)). Elimination half-life (t(1/2)) after intravenous administration also showed a good correlation (r(2) = 0.886, p = 1.506 x 10(-4)) between humans and PXB mice. The rank order of CL and t(1/2) in human could be predicted at least, although it may not be possible to predict absolute values due to rather large prediction errors. Our results indicate that in vitro and in vivo experiments with PXB mice should be useful at least for semiquantitative prediction of the PK characteristics of candidate drugs in humans.