Cytochrome P450 (CYP450) enzymes belong to a superfamily of heme-containing proteins that are involved in the metabolism of structurally diverse endogenous and exogenous compounds. Various proof-of-concept studies indicate that metabolic stability and intrinsic clearance of CYP450 substrates are linked with the respective lipophilicity (log P or log D). This necessitates the normalization of lipophilicity (log P or log D) of a given CYP450 substrate with respect to its metabolic stability (LipMetE) and intrinsic clearance (log10CLint,u). Therefore, in this article, the LipMetE values of already known substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, including some marketed drugs, have been calculated to elucidate the relationship between lipophilicity (log D 7.4) and in vitro clearance. Moreover, various drug efficiency metrics including lipophilic efficiency (LipE) and ligand efficiency (LE) have been evaluated, and the thresholds of these parameters have been defined for the CYP450 substrates exhibiting normalized LipMetE. Our results indicate that for a given range of LipMetE, greater the log D value of the substrate the more avidly it binds to a given CYP450 enzyme and shows more intrinsic clearance (log10CLint,u). Overall, the majority of the model substrates of CYP450 isoforms and already marketed drugs in our datasets exhibit log D 7.4 values of ∼2.5 with LipMetE values in the range of 0-2.5 and LipE values of ≤3. Overall, consideration of these parameters in ADME profiling could aid in reducing the drug failure rate in the later stages of clinical investigations.

中文翻译：

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亲脂性代谢效率（LipMetE）和药物效率指标，以探讨所选细胞色素P450亚型底物的代谢特性。

细胞色素P450（CYP450）酶属于含血红素的蛋白质超家族，其参与结构多样的内源性和外源性化合物的代谢。各种概念验证研究表明，CYP450底物的代谢稳定性和固有清除率与各自的亲脂性有关（log P或log D）。就其代谢稳定性（LipMetE）和固有清除率（log10CLint，u）而言，这需要使给定CYP450底物的亲脂性（log P或log D）标准化。因此，在本文中，已计算出CYP1A2，CYP2C9，CYP2C19，CYP2D6和CYP3A4的已知底物（包括一些市售药物）的LipMetE值，以阐明亲脂性（log D 7.4）与体外清除率之间的关系。此外，已评估了各种药物效率指标，包括亲脂效率（LipE）和配体效率（LE），并且已针对显示归一化LipMetE的CYP450底物定义了这些参数的阈值。我们的结果表明，对于给定的LipMetE范围，底物的log D值越大，它与指定的CYP450酶的结合力就越大，并显示出更大的内在清除率（log10CLint，u）。总体而言，我们数据集中的大多数CYP450亚型和已上市药物的模型底物的log D 7.4值为〜2.5，LipMetE值为0-2.5，LipE值为≤3。总体而言，在ADME分析中考虑这些参数可以帮助减少临床研究后期的药物失败率。