Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457 Riyadh, 11451, Saudi Arabia.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457 Riyadh, 11451, Saudi Arabia.
J Pharm Biomed Anal. 2019 Feb 5;164:659-667. doi: 10.1016/j.jpba.2018.11.033. Epub 2018 Nov 17.
Avitinib (AC0010) is a third generation inhibitor of the EGFR (epidermal growth factor receptor) that was permitted parallel phase I clinical trials in the US and in 2014. It is estimated to enter in market within two years. In the current study, eight in vitro metabolites were detected and their chemical structures were postulated. The main in vitro phase-I metabolic reaction was N-oxidation in piperazine moiety. The generation of reactive metabolites in avitinib metabolism was investigated using rat liver microsomes while adding capturing agents, viz potassium cyanide for reactive iminium intermediates, GSH for iminoquinones and methoxylamine for aldehyde forming stable adducts which are identifiable by LC-MS/MS. Ten reactive intermediates (four iminoquinones, three iminium and three aldehydes) were characterized. The three capturing agents used resulted in proposing four different bioactivation pathways. Upon literature examination, no former articles were found for avitinib metabolism including the produced reactive metabolites.
阿维替尼（AC0010）是第三代表皮生长因子受体（EGFR）抑制剂，已获准在美国和 2014 年进行平行的 I 期临床试验。预计将在两年内进入市场。在本研究中，检测到了 8 种体外代谢物，并推测了它们的化学结构。哌嗪部分的 N-氧化是主要的体外 I 期代谢反应。使用大鼠肝微粒体研究阿维替尼代谢中的反应性代谢物生成，同时加入捕获剂，即氰化钾用于反应性亚氨基中间体，GSH 用于亚氨基醌，甲氧胺用于形成可通过 LC-MS/MS 鉴定的醛稳定加合物。鉴定了十种反应性中间体（四个亚氨基醌，三个亚氨基和三个醛）。三种捕获剂的使用提出了四种不同的生物活化途径。通过文献研究，没有发现以前有关于阿维替尼代谢的文章，包括产生的反应性代谢物。
