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首页> 外文期刊>Drug Metabolism and Disposition: The Biological Fate of Chemicals >Database Extraction of Metabolite Information of Drug Candidates: Analysis of 27 AstraZeneca Compounds with Human Absorption, Distribution, Metabolism, and Excretion Data
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Database Extraction of Metabolite Information of Drug Candidates: Analysis of 27 AstraZeneca Compounds with Human Absorption, Distribution, Metabolism, and Excretion Data

机译：候选药物代谢物信息的数据库提取：含人体吸收，分布，代谢和排泄数据的27种阿斯利康化合物的分析

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As part of the drug discovery and development process, it is important to understand the human metabolism of a candidate drug prior to clinical studies. Preclinical in vitro and in vivo experiments across species are conducted to build knowledge concerning human circulating metabolites in preparation for clinical studies; therefore, the quality of these experiments is critical. Within AstraZeneca, all metabolite identification (Met-ID) information is stored in a global database using ACDLabs software. In this study, the Met-ID information derived from in vitro and in vivo studies for 27 AstraZeneca drug candidates that underwent human absorption, distribution, metabolism, and excretion studies was extracted from the database. The retrospective analysis showed that 81% of human circulating metabolites were previously observed in preclinical in vitro and/or in vivo experiments. A detailed analysis was carried out to understand which human circulating metabolites were not captured in the preclinical experiments. Metabolites observed in human hepatocytes and rat plasma but not seen in circulation in humans (extraneous metabolites) were also investigated. The majority of human specific circulating metabolites derive from multistep biotransformation reactions that may not be observed in in vitro studies within the limited time frame in which cryopreserved hepatocytes are active. Factors leading to the formation of extraneous metabolites in preclinical studies seemed to be related to species differences with respect to transporter activity, secondary metabolism, and enzyme kinetics. This retrospective analysis assesses the predictive value of Met-ID experiments and improves our ability to discriminate between metabolites expected to circulate in humans and irrelevant metabolites seen in preclinical studies.
机译：作为药物发现和开发过程的一部分，在临床研究之前了解候选药物的人新陈代谢非常重要。进行了跨物种的临床前体外和体内实验，以建立有关人类循环代谢产物的知识，为临床研究做准备。因此，这些实验的质量至关重要。在阿斯利康内部，所有代谢物鉴定（Met-ID）信息都使用ACDLabs软件存储在全局数据库中。在这项研究中，从数据库中提取了对27种阿斯利康候选药物进行了人体吸收，分布，代谢和排泄研究的体外和体内研究的Met-ID信息。回顾性分析表明，以前在临床前的体外和/或体内实验中观察到81％的人循环代谢产物。进行了详细的分析，以了解在临床前实验中未捕获哪些人体循环代谢物。还研究了在人类肝细胞和大鼠血浆中观察到但在人体循环中未观察到的代谢产物（外部代谢产物）。大多数人类特异性循环代谢物均来自多步生物转化反应，在低温保存的肝细胞活跃的有限时间范围内，在体外研究中可能未观察到该反应。临床前研究中导致外来代谢物形成的因素似乎与转运蛋白活性，次级代谢和酶动力学方面的物种差异有关。这项回顾性分析评估了Met-ID实验的预测价值，并提高了我们区分预期在人体中循环的代谢物与临床前研究中发现的无关代谢物的能力。

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