ADME evaluation in drug discovery. 6. Can oral bioavailability in humans be effectively predicted by simple molecular property-based rules?
ADME evaluation in drug discovery. 6. Can oral bioavailability in humans be effectively predicted by simple molecular property-based rules?
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DOI：
10.1021/ci6003515
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发表时间：
2007-03-01
影响因子：
5.6
通讯作者：
Xu, Xiaojie
中科院分区：
文献类型：
--
作者：
Hou, Tingjun;Wang, Junmei;Xu, Xiaojie
本研究描述了一个包含768种化合物的经严格评估的人体口服生物利用度数据库（http://modem.ucsd.edu/adme），它为科学界提供了一个开发人体口服生物利用度预测模型的公开且可靠的资源。通过分析大鼠口服生物利用度数据（《药物化学杂志》2002年，45卷，2615页），对几种重要的分子特性与人体口服生物利用度之间的相关性进行了研究，并与早期的一份报告进行了比较。我们发现，基于分子特性符合标准的化合物百分比并不能区分口服生物利用度差的化合物和具有可接受值的化合物，这可能表明基于分子特性的简单规则不能用作高可信度预测口服生物利用度的通用筛选器。还对一组肠道吸收数据进行了检测，并与口服生物利用度数据进行了比较。就假阳性率而言，这些基于分子特性的规则在预测肠道吸收方面的表现明显优于在预测口服生物利用度方面的表现，因此，在应用“基于规则”的方法预测人体生物利用度时应非常谨慎。
A critically evaluated database of human oral bioavailability for 768 chemical compounds is described in this study (http://modem.ucsd.edu/adme), which provides the scientific community a publicly available and reliable source for developing predictive models of human oral bioavailability. The correlations between several important molecular properties and human oral bioavailability were investigated and compared with an earlier report by analyzing the rat oral bioavailability data (J. Med. Chem. 2002, 45, 2615). We showed that the percentages of compounds meeting the criteria based on molecular properties does not distinguish compounds with poor oral bioavailability from those with acceptable values, which may suggest that no simple rule based on molecular properties can be used as general filters to predict oral bioavailability with high confidence. A data set of intestinal absorption was also examined and compared with that of oral bioavailability. The performance of these rules based on molecular properties in the prediction of intestinal absorption is obviously much better than that of oral bioavailability in term of false positive rate, and, therefore, the applications of the "rule-based" approaches on the prediction of human bioavailability should be very cautious.