Development and application of high throughput plasma stability assay for drug discovery
Development and application of high throughput plasma stability assay for drug discovery
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DOI：
10.1016/j.ijpharm.2005.03.022
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发表时间：
2005-06-13
影响因子：
5.8
通讯作者：
Chen, H
中科院分区：
文献类型：
--
作者：
Di, L;Kerns, EH;Chen, H
血浆稳定性在药物发现和开发中起着重要作用。不稳定的化合物往往具有快速清除和短半衰期，导致体内性能较差。本文研究了影响血浆稳定性测定结果的变量，包括底物浓度、%DMSO、血浆浓度、孵育时的酶活性和批次变化。结果表明等离子体稳定性可以适应广泛的实验条件。条件的较大差异会产生相对较小的结果差异。观察到大鼠血浆存在显着的批次间差异。我们选择以下条件：1 μM 底物浓度、2.5% DMSO 和 pH 7.4 缓冲液中血浆的 50% 稀释度。当化合物意外地快速清除时，血浆稳定性可用作诊断测定；当结构类别包含可能对血浆酶水解敏感的基团时，可用作特殊测定；或者如果资源可用，可用作化合物的一般筛选。血浆稳定性测定在药物发现中有许多应用：提醒团队注意不稳定的结构基序、确定体内研究化合物的优先顺序以及筛选前药和前药。 (c) 2005 Elsevier B.V. 保留所有权利。
Plasma stability plays an important role in drug discovery and development. Unstable compounds tend to have rapid clearance and short half-life, resulting in poor in vivo performance. This paper examines the variables that affect the plasma stability assay results, including substrate concentration, %DMSO, plasma concentration, enzyme activity upon incubation and batch variation. The results show that plasma stability can accommodate a wide range of experimental conditions. Relatively minor differences in results are produced with major differences in conditions. Significant batch-to-batch variations were observed for rat plasma. We selected the following conditions: 1 mu M substrate concentration, 2.5% DMSO, and 50% dilution of plasma in pH 7.4 buffer. Plasma stability can be used as a diagnostic assay when compounds are unexpectedly rapidly cleared, as a special assay when structural classes contain groups that may be susceptible to plasma enzyme hydrolysis, or as general screen for compounds if resources are available. Plasma stability assay has many applications in drug discovery: to alert teams to labile structural motifs, to prioritize compounds for in vivo studies and to screen prodrugs and antedrugs. (c) 2005 Elsevier B.V. All rights reserved.