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In Vivo Mutagenicity Testing of Arylboronic Acids and Esters.
Environmental and Molecular Mutagenesis ( IF 2.8 ) Pub Date : 2019-08-17 , DOI: 10.1002/em.22320
Melisa J Masuda-Herrera 1 , Krista L Dobo 2 , Michelle O Kenyon 2 , Julia D Kenny 3 , Sheila M Galloway 4 , Patricia A Escobar 4 , M Vijayaraj Reddy 4 , Robert A Jolly 5 , Alejandra Trejo-Martin 1 , Caren Brown 6 , Marie Mckeon 6 , Megan Young 6 , Shannon Bruce 6 , Kamala Pant 6 , Aparajita Dutta 6 , Rohan Kulkarni 6 , Joel P Bercu 1
Affiliation  

Arylboronic acids and esters (referred to collectively as arylboronic compounds) are commonly used intermediates in the synthesis of pharmaceuticals but pose a challenge for chemical syntheses because they are often positive for bacterial mutagenicity in vitro. As such, arylboronic compounds are then typically controlled to levels that are acceptable for mutagenic impurities, that is, the threshold of toxicological concern (TTC). This study used ICH M7 guidance to design and conduct a testing strategy to investigate the in vivo relevance of the in vitro positive findings of arylboronic compounds. Eight arylboronic compounds representing a variety of chemical scaffolds were tested in Sprague Dawley and/or Wistar rats in the in vivo Pig-a (peripheral blood reticulocytes and mature red blood cells) and/or comet assays (duodenum and/or liver). Five of the eight compounds were also tested in the micronucleus (peripheral blood) assay. The arylboronic compounds tested orally demonstrated high systemic exposure; thus the blood and bone marrow were adequately exposed to test article. One compound was administered intravenously due to formulation stability issues. This investigation showed that arylboronic compounds that were mutagenic in vitro were not found to be mutagenic in the corresponding in vivo assays. Therefore, arylboronic compounds similar to the scaffolds tested in this article may be considered non-mutagenic and managed in accordance with the ICH Q3A/Q3B guidelines. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.

中文翻译:

芳基硼酸和酯的体内致突变性测试。

芳基硼酸和酯(统称为芳基硼酸酯化合物)是药物合成中常用的中间体,但对化学合成提出了挑战,因为它们通常对体外细菌致突变性呈阳性。因此,通常将芳基硼化合物控制在诱变杂质可接受的水平,即毒理学关注阈值(TTC)。这项研究使用ICH M7指南设计和实施了一项测试策略,以研究芳基硼化合物的体外阳性结果的体内相关性。在体内的Pig-a(外周血网状细胞和成熟的红细胞)和/或彗星试验(十二指肠和/或肝脏)中,在Sprague Dawley和/或Wistar大鼠中测试了代表多种化学支架的八种芳基硼化合物。八种化合物中的五种也在微核(外周血)测定中进行了测试。口服测试的芳基硼化合物表现出很高的全身性暴露。因此,血液和骨髓充分暴露于测试物品。由于制剂稳定性问题,静脉内施用一种化合物。该研究表明,在相应的体内测定中未发现在体外诱变的芳基硼化合物是诱变的。因此,与本文测试的支架相似的芳基硼化合物可以被认为是非诱变的,并可以按照ICH Q3A / Q3B指南进行管理。环境。大声笑 诱变剂。2019.©2019 Wiley Periodicals,Inc. 口服测试的芳基硼化合物表现出很高的全身性暴露。因此血液和骨髓都充分暴露于测试物品。由于制剂稳定性问题,静脉内施用一种化合物。该研究表明,在相应的体内测定中未发现在体外诱变的芳基硼化合物。因此,与本文测试的支架相似的芳基硼化合物可以被认为是非诱变的,并可以按照ICH Q3A / Q3B指南进行管理。环境。大声笑 诱变剂。2019.©2019 Wiley Periodicals,Inc. 口服测试的芳基硼化合物表现出很高的全身性暴露。因此,血液和骨髓充分暴露于测试物品。由于制剂稳定性问题,静脉内施用一种化合物。该研究表明,在相应的体内测定中未发现在体外诱变的芳基硼化合物。因此,与本文测试的支架相似的芳基硼化合物可以被认为是非诱变的,并可以按照ICH Q3A / Q3B指南进行管理。环境。大声笑 诱变剂。2019.©2019 Wiley Periodicals,Inc. 该研究表明,在相应的体内测定中未发现在体外诱变的芳基硼化合物是诱变的。因此,与本文测试的支架相似的芳基硼化合物可以被认为是非诱变的,并可以按照ICH Q3A / Q3B指南进行管理。环境。大声笑 诱变剂。2019.©2019 Wiley Periodicals,Inc. 该研究表明,在相应的体内测定中未发现在体外诱变的芳基硼化合物是诱变的。因此,与本文测试的支架相似的芳基硼化合物可以被认为是非诱变的,并可以按照ICH Q3A / Q3B指南进行管理。环境。大声笑 诱变剂。2019.©2019 Wiley Periodicals,Inc.
更新日期:2019-11-01
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