Consideration of vendor-related differences in hepatic metabolic stability data to optimize early ADME screening in drug discovery

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

SLAS Discovery Pub Date : 2024-01-01 DOI:10.1016/j.slasd.2023.08.002

Pranav Shah , Elias C. Padilha , Rintaro Kato , Vishal B. Siramshetty , Wenwei Huang , Xin Xu

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引用次数: 0

Abstract

Hepatic metabolic stability is a crucial determinant of oral bioavailability and plasma concentrations of a compound, and its measurement is important in early drug discovery. Preliminary metabolic stability estimations are commonly performed in liver microsomal fractions. At the National Center for Advancing Translational Sciences, a single-point assay in rat liver microsomes (RLM) is employed for initial stability assessment (Tier I) and a multi-point detailed stability assay is employed as a Tier II assay for promising compounds. Although the in vitro and in vivo metabolic stability of compounds typically exhibit good correlation, conflicting results may arise in certain cases. While investigating one such instance, we serendipitously found vendor-related RLM differences in metabolic stability and metabolite formation, which had implications for in vitro and in vivo correlations. In this study, we highlight the importance of considering vendor differences in hepatic metabolic stability data and discuss strategies to avoid these pitfalls.

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考虑肝脏代谢稳定性数据中与供应商有关的差异，优化药物发现中的早期 ADME 筛选。

肝脏代谢稳定性是决定化合物口服生物利用度和血浆浓度的关键因素，其测量在早期药物发现中非常重要。初步代谢稳定性评估通常在肝脏微粒体部分进行。国家转化科学促进中心采用大鼠肝微粒体（RLM）单点测定法进行初步稳定性评估（一级），并采用多点详细稳定性测定法作为二级测定法，对有前途的化合物进行评估。虽然化合物的体外和体内代谢稳定性通常具有良好的相关性，但在某些情况下也会出现相互矛盾的结果。在调查这样一个实例时，我们偶然发现了与供应商有关的代谢稳定性和代谢物形成的 RLM 差异，这对体外和体内相关性产生了影响。在本研究中，我们强调了在肝脏代谢稳定性数据中考虑供应商差异的重要性，并讨论了避免这些陷阱的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

SLAS Discovery Chemistry-Analytical Chemistry

CiteScore

7.00

自引率

3.20%

发文量

审稿时长

39 days

期刊介绍： Advancing Life Sciences R&D: SLAS Discovery reports how scientists develop and utilize novel technologies and/or approaches to provide and characterize chemical and biological tools to understand and treat human disease. SLAS Discovery is a peer-reviewed journal that publishes scientific reports that enable and improve target validation, evaluate current drug discovery technologies, provide novel research tools, and incorporate research approaches that enhance depth of knowledge and drug discovery success. SLAS Discovery emphasizes scientific and technical advances in target identification/validation (including chemical probes, RNA silencing, gene editing technologies); biomarker discovery; assay development; virtual, medium- or high-throughput screening (biochemical and biological, biophysical, phenotypic, toxicological, ADME); lead generation/optimization; chemical biology; and informatics (data analysis, image analysis, statistics, bio- and chemo-informatics). Review articles on target biology, new paradigms in drug discovery and advances in drug discovery technologies. SLAS Discovery is of particular interest to those involved in analytical chemistry, applied microbiology, automation, biochemistry, bioengineering, biomedical optics, biotechnology, bioinformatics, cell biology, DNA science and technology, genetics, information technology, medicinal chemistry, molecular biology, natural products chemistry, organic chemistry, pharmacology, spectroscopy, and toxicology. SLAS Discovery is a member of the Committee on Publication Ethics (COPE) and was published previously (1996-2016) as the Journal of Biomolecular Screening (JBS).