Katoh Miki, Yokoi Tsuyoshi
Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Japan.
Drug Metab Rev. 2007;39(1):145-57. doi: 10.1080/03602530601021340.
Much effort to extrapolate the in vivo pharmacokinetics of drugs in human from experimental animals or in vitro studies has been made by many researchers. A urokinase-type plasminogen activator+/+/severe combined immunodeficient transgenic mouse line, in which the liver could be replaced by more than 80% with human hepatocytes, was established recently in Japan. This chimeric mouse line is remarkable because the replacement is higher than any other chimeric mouse reported previously. Since the liver is the critical organ involved in the pharmacokinetics of drugs, human liver is essential for the development of new drugs. To predict the human drug metabolism and pharmacokinetics, human hepatocytes and liver microsomes are recognized as better tools and are frequently used. Thus, chimeric mice with humanized liver would have great advantages in studies on drug metabolism and pharmacokinetics. We have evaluated chimeric mice for studies on absorption, distribution, metabolism, and excretion (ADME). In the liver of the chimeric mice, human phase I and phase II enzymes were clarified to be expressed and to have a similar drug metabolizing capacity as the donor. Human specific metabolites could be detected in the serum, suggesting that the chimeric mice might be used as a human ADME model for both in vitro and in vivo studies. For predicting human drug interactions, enzyme induction and inhibition are serious problems. By the treatment with typical inducers, human CYP1A2 and CYP3A4 expressed in the liver of the chimeric mice had induction potencies. After the treatment with quinidine, a specific inhibitor of human CYP2D6, the area under the curve (AUC) of a CYP2D6 metabolite, 4'-hydroxydebrisoquin, was significantly decreased in the chimeric mice but not in the control mice. Therefore, it was indicated that the chimeric mice could be used for assessing the drug interactions via enzyme induction and inhibition. As well as drug metabolism, the drug excretion was demonstrated to be humanized because cefmetazole was mainly excreted in urine both in the chimeric mice and human but in feces in control uPA-/-/SCID mice. In this review, basic researches on ADME in the chimeric mice with humanized liver are summarized and the application of the chimeric mice for predictive ADME is proposed.
许多研究人员付出了巨大努力，试图从实验动物或体外研究中推断药物在人体中的体内药代动力学。最近在日本建立了一种尿激酶型纤溶酶原激活剂+/+/重度联合免疫缺陷转基因小鼠品系，其肝脏可被超过80%的人肝细胞替代。这种嵌合小鼠品系很引人注目，因为其替代率高于此前报道的任何其他嵌合小鼠。由于肝脏是参与药物药代动力学的关键器官，人肝脏对于新药开发至关重要。为了预测人体药物代谢和药代动力学，人肝细胞和肝微粒体被认为是更好的工具并被频繁使用。因此，具有人源化肝脏的嵌合小鼠在药物代谢和药代动力学研究中将具有巨大优势。我们已经对嵌合小鼠进行了吸收、分布、代谢和排泄（ADME）研究的评估。在嵌合小鼠的肝脏中，已明确人I相和II相酶能够表达，并且具有与供体相似的药物代谢能力。在血清中能够检测到人类特有的代谢产物，这表明嵌合小鼠可作为用于体外和体内研究的人体ADME模型。对于预测人体药物相互作用而言，酶诱导和抑制是严重问题。通过用典型诱导剂进行处理，在嵌合小鼠肝脏中表达的人CYP1A2和CYP3A4具有诱导能力。在用奎尼丁（一种人CYP2D6的特异性抑制剂）处理后，嵌合小鼠体内CYP2D6代谢产物4'-羟基去甲丙咪嗪的曲线下面积（AUC）显著降低，而对照小鼠则未出现这种情况。因此，表明嵌合小鼠可用于通过酶诱导和抑制来评估药物相互作用。与药物代谢一样，药物排泄也被证明是人源化的，因为头孢美唑在嵌合小鼠和人体中主要经尿液排泄，而在对照uPA-/-/SCID小鼠中则经粪便排泄。在本综述中，总结了具有人源化肝脏的嵌合小鼠在ADME方面的基础研究，并提出了嵌合小鼠在预测性ADME中的应用。
