Applications of high throughput microsomal stability assay in drug discovery
Applications of high throughput microsomal stability assay in drug discovery
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DOI：
10.2174/138620708784911429
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发表时间：
2008-07-01
影响因子：
1.8
通讯作者：
Carter, Guy T.
中科院分区：
文献类型：
--
作者：
Di, Li;Kerns, Edward H.;Carter, Guy T.
高通量体外微粒体稳定性分析被广泛应用于药物开发中，作为体内稳定性的指标，它影响药物动力学。这是基于对有限数量的模型类药物化合物的深入研究，这些化合物主要是通过细胞色素P450代谢来清除的。然而，药物发现化合物往往不是类药物，通过高通量分析进行评估，并具有许多潜在的未表征的体内清除机制。因此，确定一组药物发现化合物的高通量体外微粒体稳定性数据和简化的体内发现药代动力学研究数据之间的相关性是重要的，以便为发现团队如何可靠地应用体外分析做出关键决策提供证据。本研究以306个实际药物发现化合物为研究对象，考察了简化药物发现药代动力学研究中的体外单个时间点高通量微粒体稳定性与体内清除量之间的关系。结果表明，微球体外I相稳定性t(1/2)与体内清除量显著相关，相关系数为0.001。对于体外大鼠微粒体稳定性较低的化合物(t(1/2)和lt；15min)，87%的化合物在体内具有较高的清除率(CL>；25mL/min/kg)。这表明高通量微粒体稳定性数据在识别体内具有显著清除责任的化合物方面非常有效。对于体外大鼠微粒体稳定性高的化合物(t(1/2)>；15min)，高清除度和低清除度的化合物之间没有明显的差异。这可能是由于除了细胞色素P450代谢提高体内清除外，还有其他清除途径。这一发现支持了药物化学家和药物发现团队使用的策略，即将体外数据应用于对化合物进行体内PK和有效性研究，并指导结构修改以提高代谢稳定性。当一种化合物的体外和体内数据都可用时，可以诊断潜在的体内清除途径，以指导进一步的发现研究。
High throughput in vitro microsomal stability assays are widely used in drug discovery as an indicator for in vivo stability, which affects pharmacokinetics. This is based on in-depth research involving a limited number of model drug-like compounds that are cleared predominantly by cytochrome P450 metabolism. However, drug discovery compounds are often not drug-like, are assessed with high throughput assays, and have many potential uncharacterized in vivo clearance mechanisms. Therefore, it is important to determine the correlation between high throughput in vitro microsomal stability data and abbreviated discovery in vivo pharmacokinetics study data for a set of drug discovery compounds in order to have evidence for how the in vitro assay can be reliably applied by discovery teams for making critical decisions. In this study the relationship between in vitro single time point high throughput microsomal stability and in vivo clearance from abbreviated drug discovery pharmacokinetics studies was examined using 306 real world drug discovery compounds. The results showed that in vitro Phase I microsomal stability t(1/2) is significantly correlated to in vivo clearance with a p-value < 0.001. For compounds with low in vitro rat microsomal stability (t(1/2) < 15 min), 87% showed high clearance in vivo (CL > 25 mL/min/kg). This demonstrates that high throughput microsomal stability data are very effective in identifying compounds with significant clearance liabilities in vivo. For compounds with high in vitro rat microsomal stability (t(1/2) > 15 min), no significant differentiation was observed between high and low clearance compounds. This is likely owing to other clearance pathways, in addition to cytochrome P450 metabolism that enhances in vivo clearance. This finding supports the strategy used by medicinal chemists and drug discovery teams of applying the in vitro data to triage compounds for in vivo PK and efficacy studies and guide structural modification to improve metabolic stability. When in vitro and in vivo data are both available for a compound, potential in vivo clearance pathways can be diagnosed to guide further discovery studies.