预测人体新陈代谢的镇静催眠药zaleplon使用嵌合小鼠与人类肝细胞移植。

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Tanoue C,苏吉哈拉K, Uramaru N, Tayama Y, Y,渡边崛江T,太年代,Kitamura年代

预测人体新陈代谢的镇静催眠药zaleplon使用嵌合小鼠与人类肝细胞移植。

Xenobiotica。2013年11月,43 (11):956 - 62。doi: 10.3109 / 00498254.2013.788232。2013年5月8日Epub。

PubMed ID

23651075 (在PubMed

]

文摘

1。人类嵌合小鼠(h-PXB老鼠)拥有人性化的肝脏,由人类肝细胞移植,被评价为一个实验模型预测人类药物代谢。新陈代谢的zaleplon h-PXB老鼠在鼠嵌合小鼠相比(r-PXB老鼠)由鼠肝细胞的移植。2。Zaleplon 5-oxo-zaleplon代谢是由醛氧化酶和desethyl-zaleplon细胞色素P450 (CYP3A4)在老鼠和人类肝脏的准备工作。3所示。肝脏S9分数h-PXB小鼠代谢zaleplon 5-oxo-zaleplon和desethyl-zaleplon相似。然而,肝脏S9分数r-PXB和控制(urokinase-type纤溶酶原activator-transgenic物严重联合免疫缺陷)小鼠主要代谢zaleplon desethyl-zaleplon。5-Oxo-zaleplon检测作为一个次要的代谢物。4所示。 Oxidase activity of h-PXB mouse liver cytosol toward zaleplon was about 10-fold higher than that of r-PXB or control mice. In contrast, activities for desethyl-zaleplon formation were similar in liver microsomes from these mice, as well as rat and human liver microsomes. 5. In vivo, the level of 5-oxo-zaleplon in plasma of h-PXB mice was about 7-fold higher than that in r-PXB or control mice, in agreement with the in vitro data. Thus, aldehyde oxidase in h-PXB mice functions as human aldehyde oxidase, both in vivo and in vitro. 6. In contrast, the plasma level of desethyl-zaleplon in r-PXB and control mice was higher than that in h-PXB mice. 7. These results suggest h-PXB mice with humanized liver could be a useful experimental model to predict aldehyde oxidase- and CYP3A4-mediated drug metabolism in humans.

DrugBank数据引用了这篇文章

药物酶

药物	酶	类	生物	药理作用	行动
Zaleplon	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节