A Useful Model Capable of Predicting the Clearance of Cytochrome P450 3A4 (CYP3A4) Substrates in Humans: Validity of CYP3A4 Transgenic Mice Lacking Their Own Cyp3a Enzymes
A Useful Model Capable of Predicting the Clearance of Cytochrome P450 3A4 (CYP3A4) Substrates in Humans: Validity of CYP3A4 Transgenic Mice Lacking Their Own Cyp3a Enzymes
复制标题
能够预测人类细胞色素 P450 3A4 (CYP3A4) 底物清除的有用模型：缺乏自身 Cyp3a 酶的 CYP3A4 转基因小鼠的有效性
DOI：
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发表时间：
2014
影响因子：
3.9
通讯作者：
H. Yamada
中科院分区：
文献类型：
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作者：
Tetsuya Mitsui;Takayuki Nemoto;T. Miyake;Shunsuke Nagao;Kotaro Ogawa;Motohiro Kato;M. Ishigai;H. Yamada
在临床前阶段准确预测人体对一种新型候选药物的清除有助于其成功开发。为了提高人类肝脏清除率的可预测性，我们将重点放在CYP3A4上，它参与了目前所有上市药物中50%以上的代谢。在本研究中，我们使用携带人类CYP3A4基因且缺乏自身Cyp3a基因的转基因小鼠（CYP3A4- tg小鼠）来研究体内模型的有效性。CYP3A4对肝微粒体底物的活性在CYP3A4- tg小鼠和人体内相似。在清除率方面，将6种CYP3A4底物（阿普唑仑、非洛地平、咪达唑仑、硝苯地平、尼群地平、奎尼丁）静脉给予CYP3A4- tg小鼠，评估其肝脏内清除率（CLint,h）。对所得数据进行回归分析发现，CYP3A4-Tg小鼠体内6种底物的CLint，h值与人体内CLint，h值高度相关（R2 = 0.95）。这种相关性可以通过人工表达CYP3A4对小鼠整体代谢的相对贡献来纠正CLint，h值来改善。根据这些发现，我们有理由期望，通过将CYP3A4-Tg小鼠中获得的CLint，h应用于事先制备的回归线，可以预测人类特定药物的CLint，h。对该方法预测的CLint，h的方差进行了评估，发现方差在回归值的2倍范围内。这些结果表明，CYP3A4- tg小鼠模型有可能准确预测CYP3A4底物的人类肝脏清除。
The accurate prediction for the body clearance of a novel drug candidate by humans during the preclinical stage contributes to its successful development. To improve the predictability of human hepatic clearance, we focused on CYP3A4, which is involved in the metabolism of more than 50% of all currently marketed drugs. In this study, we investigated the validity of the in vivo model using transgenic mice carrying the human CYP3A4 gene and lacking their own Cyp3a genes (CYP3A4-Tg mice). The CYP3A4 activity toward its substrates in liver microsomes was similar in CYP3A4-Tg mice and humans. As for the clearance, six CYP3A4 substrates (alprazolam, felodipine, midazolam, nifedipine, nitrendipine, and quinidine) were given intravenously to CYP3A4-Tg mice, and their hepatic intrinsic clearance (CLint,h) was evaluated. A regression analysis of the data obtained indicated that the CLint,h values of six substrates in CYP3A4-Tg mice were highly correlated with those in humans (R2 = 0.95). This correlation could be improved by correcting the CLint,h values by the relative contribution of artificially expressed CYP3A4 to the overall metabolism in the mice. From these findings, it is reasonable to expect that the CLint,h of a particular drug in humans is predictable by applying the CLint,h obtained in CYP3A4-Tg mice to a regression line prepared in advance. The variance of the CLint,h prediction by this method was evaluated and found to be within a range of 2-fold of the regression value. These results suggest that the CYP3A4-Tg mouse model has the potential to accurately predict the human hepatic clearance of CYP3A4 substrates.