常用体外系统预测循环代谢物的实用性。

IF 4.4 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Elyse C Freiberger, Michael P Thompson, Xiaomei Zhang, Essence B Underwood, Thomas L Lynch, Gary J Jenkins, David S Wagner
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引用次数: 0

摘要

体外系统(如培养的肝细胞)在药物开发的早期被用作体内数据的替代物,以预测人体和潜在临床前物种中的代谢物。这些数据支持临床前毒理学研究的物种选择,并为可在人体内产生的潜在活性和反应性代谢物提供早期证据。虽然体内数据是为特定化合物选择临床前物种的最佳方法,但在选择毒物物种时只能使用体外系统。然而,与任何体外系统一样,与实际体内结果的相关性可能会有变化。了解特定体外检测对体内代谢的预测性有助于药物研发团队认识到早期跨物种代谢物图谱对最终临床结果的重要性。使用已知代谢的商业化合物对五种常见体外系统进行直接比较,结果显示悬浮肝细胞和共培养肝细胞在成功生成主要人体循环代谢物方面略优于其他系统。当体内研究不可行时,目前的体外系统在开发早期具有价值,并且是监管部门申请支持临床前毒理学物种选择的必要条件,但不应被视为完全代表特定药物的体内代谢。意义说明 这是对历史代谢数据的全面评估,量化了从体外到体内预测的成功率。用于代谢物分析的体外系统的可靠性对于早期药物开发非常重要,了解预测性有助于为数据提供适当的背景。我们还生成了新的数据,用于比较常见的体外肝脏模型,以确定是否有任何模型可以明确地确定比其他模型更能预测人体循环代谢物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Utility of common in vitro systems for predicting circulating metabolites.

In vitro systems such as cultured hepatocytes are used early in drug development as a proxy for in vivo data to predict metabolites in human and the potential pre-clinical species. These data support preclinical species selection for toxicology studies as well as provide early evidence for potential active and reactive metabolites that can be generated in human. While in vivo data would be best to select preclinical species for a given compound, only in vitro systems are available when selecting tox species. However, as with any in vitro system, the correlation to actual in vivo results can be variable. Understanding the predictivity of a given in vitro assay for in vivo metabolism would help drug development teams appreciate the significance of early cross-species metabolite profiles relative to the eventual clinical outcomes. In a retrospective analysis of historic metabolite profiling data from Abbott/AbbVie, in vitro systems predicted ~50% of circulating metabolites present in vivo, across preclinical species and human, with no correlation between apparent exposures in vitro vs in vivo A direct comparison of five common in vitro systems using commercial compounds with known metabolism resulted in suspension hepatocytes and co-cultured hepatocytes slightly outperforming the other systems in successfully generating major human circulating metabolites. Current in vitro systems have value early in development when in vivo studies are not feasible and are required for regulatory filings to support pre-clinical toxicology species selection but should not be treated as wholly representative of a given drug's in vivo metabolism. Significance Statement This is a comprehensive assessment of historic metabolism data quantitating the success rate of in vitro to in vivo predictivity. Reliability of in vitro systems for metabolite profiling is important for early drug development, and understanding predictivity will help give appropriate context to the data. New data were also generated to compare common in vitro liver models to determine whether any could be definitively identified as more predictive of human circulating metabolites than others.

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来源期刊
CiteScore
6.50
自引率
12.80%
发文量
128
审稿时长
3 months
期刊介绍: An important reference for all pharmacology and toxicology departments, DMD is also a valuable resource for medicinal chemists involved in drug design and biochemists with an interest in drug metabolism, expression of drug metabolizing enzymes, and regulation of drug metabolizing enzyme gene expression. Articles provide experimental results from in vitro and in vivo systems that bring you significant and original information on metabolism and disposition of endogenous and exogenous compounds, including pharmacologic agents and environmental chemicals.
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