Graduate School of Biomedical Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553 Japan.
Drug Metab Dispos. 2012 Feb;40(2):322-8. doi: 10.1124/dmd.111.040923. Epub 2011 Nov 2.
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 (CL(int,in vitro)) in PXB mice hepatocytes and in vivo intrinsic clearance (CL(int,in vivo)) in humans, calculated based on a well stirred model, showed a moderate correlation (r² = 0.475, p = 0.009). However, when CL(int,in vivo) values in humans and PXB mice were compared similarly, there was a good correlation (r² = 0.754, p = 1.174 × 10⁻⁴). Elimination half-life (t(1/2)) after intravenous administration also showed a good correlation (r² = 0.886, p = 1.506 × 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.
由于各种原因，包括物种差异，准确地从动物数据预测人体药代动力学（PK）参数是困难的。然而，已经开发出具有人源化肝脏的嵌合小鼠（PXB 小鼠；尿激酶型纤溶酶原激活物/严重联合免疫缺陷小鼠，其中约 80%的肝细胞被人源化）。PXB 小鼠肝脏中的细胞色素 P450（P450）和非 P450 酶的表达水平和代谢活性与人相似。在这项研究中，我们检查了从 PXB 小鼠中获得的数据对人体 PK 参数的预测能力。选择的药物的消除涉及多种代谢途径，这些途径不仅由 P450 介导，还由非 P450 酶介导，如 UDP-葡糖醛酸基转移酶、磺基转移酶和醛氧化酶。PXB 小鼠肝细胞中体外内在清除率（CL(int,in vitro)）与基于完全搅拌模型计算的人体内在清除率（CL(int,in vivo)）之间的直接比较显示出中度相关性（r² = 0.475，p = 0.009）。然而，当以类似的方式比较人类和 PXB 小鼠中的 CL(int,in vivo)值时，相关性很好（r² = 0.754，p = 1.174×10⁻⁴）。静脉内给药后的消除半衰期（t(1/2)）也显示出人类和 PXB 小鼠之间的良好相关性（r² = 0.886，p = 1.506×10⁻⁴）。尽管由于预测误差较大，可能无法预测绝对值，但至少可以预测人体中候选药物的 CL 和 t(1/2)的秩序。我们的结果表明，使用 PXB 小鼠进行的体外和体内实验至少对于候选药物在人体中的 PK 特征的半定量预测应该是有用的。
