利用 Secondary Intelligence™ 从脱靶受体相互作用中预测临床结果。

IF 1.3 4区医学 Q4 PHARMACOLOGY & PHARMACY

Journal of pharmacological and toxicological methods Pub Date : 2025-02-01 DOI:10.1016/j.vascn.2024.107570

Will S. Redfern , Chris E. Pollard , Mark Holbrook , Barira Islam , Mitra Abbasi , Joanne Mahmud , Katie Lambert , Augustus Haslam , Heeseung Jo , Hiba Khalidi , Zofia Bielecka , Josh Starkey , Thomas Ellinger , Simon Bryan , Angeli Savas , Steve Andrews , Rob Aspbury , Lyn Rosenbrier Ribeiro , Kim A. Henderson Park , Hugo M. Vargas , Clare R. Gilmer

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引用次数: 0

摘要

通过仔细比较受试化合物的预期血浆浓度和脱靶活性与针对该受体发挥疗效的参考药物的预期血浆浓度和脱靶活性之间的关系，可以预测脱靶活性导致的不良反应。血浆浓度（未结合）与受体 Ki 之间的比值是反映受体占用率的代用指标。在有参考药物数据的情况下，我们对 100 种受体进行了整理和评估，其中 72 种受体可能同时受到药物的负向和正向调节：共计 172 种 "受体调节"。这提供了一个定量框架，在此基础上可对不同受体、不同化合物和不同评估者之间的脱靶相互作用进行一致的风险评估。因此，它实现了二级药理学方法从基于观点到基于证据的重大转变。对其中一种受体相互作用（α1A-肾上腺素受体拮抗作用导致临床应用中的体位性低血压）进行了原则性论证，因为在该受体上有超过 30 种药物的高质量脱靶 Ki 数据。

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Predicting clinical outcomes from off-target receptor interactions using Secondary Intelligence™

Adverse effects due to off-target activity can be predicted by careful comparison of the relationship between expected plasma concentration and off-target activity of the test compound with that of reference drugs targeting that receptor for their therapeutic efficacy. The ratio between plasma concentration (unbound) and the K_i at the receptor is a surrogate measure reflecting receptor occupancy. Where data are available for reference drugs, we have curated and evaluated this at 100 receptors, 72 of which can involve both negative and positive modulations by drugs: a total of 172 ‘receptor modulations’. This provides a quantitative framework upon which to achieve consistent risk assessment of off-target interactions across receptors, across compounds and between assessors. It therefore represents a significant departure from an opinion-based to an evidence-based approach to secondary pharmacology. Demonstration of proof-of-principle was achieved for one of the receptor interactions (α_1A-adrenoceptor antagonism leading to postural hypotension in clinical use) due to the availability of high-quality off-target K_i data for >30 drugs at this receptor.

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来源期刊

Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY

CiteScore

3.60

自引率

10.50%

发文量

审稿时长

26 days

期刊介绍： Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.