Metabolizing enzyme toxicology assay chip (MetaChip) for high-throughput microscale toxicity analyses
Metabolizing enzyme toxicology assay chip (MetaChip) for high-throughput microscale toxicity analyses
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DOI：
10.1073/pnas.0406755102
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发表时间：
2005-01-25
影响因子：
11.1
通讯作者：
Clark, DS
中科院分区：
文献类型：
--
作者：
Lee, MY;Park, CB;Clark, DS
毒理学和临床安全性评估方面的技术发展相对缓慢，特别是可用于药物开发的临床前和早期临床阶段的体外方法，阻碍了新化学实体向药物的临床进展。为了缓解这一瓶颈，我们开发了一种代谢酶毒理学分析芯片(MetaChip)，它将高通量P450催化与基于细胞的筛选结合在一个微型平台上。MetaChip的概念是通过使用Sol-Gel包裹的P450来激活前药环磷酰胺，环磷酰胺是抗癌药物环磷酰胺的主要成分，以及通过P450代谢激活的其他化合物。MetaChip提供了一种高通量的微规模替代方法，可替代目前使用的基于肝脏切片、培养的人类肝细胞、纯化的微粒体制剂或分离和纯化的P450进行人体代谢和毒理学筛选的体外方法。这项技术为在药物开发的早期阶段快速和廉价地评估ADME/TOX(吸收、分布、代谢、排泄/毒理学)创造了机会，从而使不合适的候选者能够在药物发现过程中更早地被排除在考虑之外。
The clinical progression of new chemical entities to pharmaceuticals remains hindered by the relatively slow pace of technology development in toxicology and clinical safety evaluation, particularly in vitro approaches, that can be used in the preclinical and early clinical phases of drug development. To alleviate this bottleneck, we have developed a metabolizing enzyme toxicology assay chip (MetaChip) that combines high-throughput P450 catalysis with cell-based screening on a microscale platform. The MetaChip concept is demonstrated by using sol-gel encapsulated P450s to activate the prodrug cyclophosphamide, which is the major constituent of the anticancer drug Cytoxan, as well as other compounds that are activated, by P450 metabolism. The MetaChip provides a high-throughput microscale alternative to currently used in vitro methods for human metabolism and toxicology screening based on liver slices, cultured human hepatocytes, purified microsomal preparations, or isolated and purified P450s. This technology creates opportunities for rapid and inexpensive assessment of ADME/Tox (absorption, distribution, metabolism, excretion/toxicology) at very early phases of drug development, thereby enabling unsuitable candidates to be eliminated from consideration much earlier in the drug discovery process.