摘要
药物代谢可以导致高度活性代谢产物的形成。这些活性代谢物已知在毒性产生中发挥了重要作用,这使得药物开发和临床使用产生了很大比例的消耗。因此,越早期发现这样的反应越好。本文总结了我们多年的项目,结合相关文献鉴别一系列体外测试方法对于检测活性代谢产物形成的能力。这样的主要前提条件是测试:已知/未知引起组织损伤的和产生活性代谢物的物质激活系统(主要是人);小分子和大分子的靶标(小分子捕捉器、多肽、蛋白质);分析技术(质谱)和细胞毒性生物标志物。体外工具的当前状态检测活性中间体如下:1.小分子捕获剂(如谷胱甘肽或氰化物等)通过高灵敏度的MS技术检测活性物种的产生。然而,似乎公认的“否定物质”也可产生相应的加合物。2.从肽和dG目标(DNA)捕捉器得到的结果通常与小分子捕捉剂相关,虽然也存在主要的差异,这两种捕获平台不重叠。3.体外加合物的研究只能解释结合毒性生物标志物(如Nrf2通路)来自整个细胞或组织的信息。然而,尽管有方法来描述化合物的能力,并且知道个别/整体与毒性之间存在相关性,但是代谢反应和副作用之间的联系机制的理解仍然存在巨大的差距。
关键词: 细胞色素,细胞色素P450,药物代谢酶,谷胱甘肽,寡核苷酸捕捉器,寡肽捕捉器,氰化钾,活性代谢物,氨基脲,捕获剂
Current Medicinal Chemistry
Title:Reactive Metabolites in Early Drug Development: Predictive In vitro Tools
Volume: 22 Issue: 4
Author(s): Olavi Pelkonen, Markku Pasanen, Ari Tolonen, Mikko Koskinen, Jukka Hakkola, Khaled Abass, Jaana Laine, Merja Hakkinen, Risto Juvonen, Seppo Auriola, Markus Storvik, Pasi Huuskonen, Timo Rousu and Maiju Rahikkala
Affiliation:
关键词: 细胞色素,细胞色素P450,药物代谢酶,谷胱甘肽,寡核苷酸捕捉器,寡肽捕捉器,氰化钾,活性代谢物,氨基脲,捕获剂
摘要: Drug metabolism can result in the formation of highly reactive metabolites that are known to play a role in toxicity resulting in a significant proportion of attrition during drug development and clinical use. Thus, the earlier such reactivity was detected, the better. This review summarizes our multi-year project, together with pertinent literature, to examine a battery of in vitro tests capable of detecting the formation of reactive metabolites. Principal prerequisites for such tests were delineated: chemicals known/not known to cause tissue injury and produce reactive metabolites, activation system (mainly human-derived), small- and large-molecular targets (small-molecular trappers, peptides, proteins), analytical techniques (mass spectrometry), and cellular toxicity biomarkers. The current status of in vitro tools to detect reactive intermediates is the following: 1. Small-molecular trapping agents such glutathione or cyanide detect the production of reactive species with high sensitivity by proper MS technique. However, it seems that also putative “negatives” give rise to corresponding adducts. 2. Results from peptide and dG (DNA targeting) trapper studies are generally in line with those of small-molecular trappers, although also important differences exist. These two trapping platforms do not overlap. 3. It is anticipated that the in vitro adduct studies could be fully interpreted only in conjunction with toxicity biomarker (such as the Nrf2 pathway) information from whole cells or tissues. However, while there are tools to characterize the chemical liability and there are correlation between individual/integrated endpoints and toxicity, there are still severe gaps in understanding the mechanisms behind the link between reactive metabolites and adverse effects.
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Olavi Pelkonen , Markku Pasanen , Ari Tolonen , Mikko Koskinen , Jukka Hakkola , Khaled Abass , Jaana Laine , Merja Hakkinen , Risto Juvonen , Seppo Auriola , Markus Storvik , Pasi Huuskonen , Timo Rousu and Maiju Rahikkala , Reactive Metabolites in Early Drug Development: Predictive In vitro Tools, Current Medicinal Chemistry 2015; 22 (4) . https://dx.doi.org/10.2174/0929867321666141012175543
DOI https://dx.doi.org/10.2174/0929867321666141012175543 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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