药学学报, 2019, 54(6): 1108-1114
引用本文:
赵晟宇, 王汝冰, 白洁, 范小庆, 胡民万, 孙燕红, 扈金萍, 李燕. 新型抗脑瘤化合物CAT3的体外代谢研究[J]. 药学学报, 2019, 54(6): 1108-1114.
ZHAO Sheng-yu, WANG Ru-bing, BAI Jie, FAN Xiao-qing, HU Min-wan, SUN Yan-hong, HU Jin-ping, LI Yan. Metabolism of a promising anti-tumor agent CAT3 in vitro[J]. Acta Pharmaceutica Sinica, 2019, 54(6): 1108-1114.

新型抗脑瘤化合物CAT3的体外代谢研究
赵晟宇, 王汝冰, 白洁, 范小庆, 胡民万, 孙燕红, 扈金萍, 李燕
中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 创新药物非临床药物代谢及PK/PD研究北京市重点实验室, 北京 100050
摘要:
CAT3是一种新型抗脑瘤化合物,在Daoy和U87MG裸鼠原位异种移植模型中具有强效抗瘤活性,但其代谢机制尚不清楚。本研究考察了CAT3在小鼠/犬/人全血和肝微粒体、人源化重组酶等温孵体系中的代谢特征,所有动物福利和动物实验遵循中国医学科学院动物伦理委员会规定。研究结果表明CAT3在小鼠/犬/人全血中可水解为活性代谢物PF403,丁酰胆碱酯酶、羧酸酯酶和丝氨酸水解酶参与其生成,代谢速率存在种属差异小鼠>人>犬;应用CYPs同工酶的选择性抑制剂、人源化重组酶研究结果表明,CYP1A2、1A1、2C9和3A4是参与M1(氧化脱水),M2(双氧化脱水),M3(甲基化氧化脱水),M4(氧化),M5(脱甲基)生成的主要同工酶,CYP2B6、2C8、2C19和2D6等亚型也有少量参与;Ⅱ相酶UGT1A1、1A3、1A9可催化PF403生成葡萄糖醛酸化代谢物GLU-PF403。以上结果提示,CAT3代谢是多酶参与的生物转化过程,代谢酶介导的药物相互作用值得临床关注。
关键词:    CAT3      体外代谢      酯酶      细胞色素P450      葡萄糖醛酸转移酶     
Metabolism of a promising anti-tumor agent CAT3 in vitro
ZHAO Sheng-yu, WANG Ru-bing, BAI Jie, FAN Xiao-qing, HU Min-wan, SUN Yan-hong, HU Jin-ping, LI Yan
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
CAT3 is a promising anti-brain tumor agent that has significant anti-tumor activity on Daoy or U87MG orthotopic xenograft in nude mice. This study was carried out to investigate the metabolic profiles of CAT3 in mouse/dog/human blood and microsome as well as in humanized recombinant enzymes. All animal care and experimental procedures were reviewed and approved by the Animal Ethics Committee of Chinese Academy of Medical Sciences. Our findings showed that CAT3 could be hydrolyzed to active metabolite PF403 by carboxylesterase, butyrylcholinesterase and serine hydrolase in mouse/dog/human blood. PF403 could be further metabolized to M1 oxidative dehydration product, M2 double oxidation dehydration product, M3 methylation oxidative dehydration product, M4 oxidation product and M5 demethylation product, which were mainly catalyzed by CYP1A2, 1A1, 2C9 and 3A4, and slightly by CYP2B6, 2C8, 2C19 and 2D6. Besides oxidative metabolism, PF403 also was transformed into glucuronylation metabolites GLU-PF403 by Phase Ⅱ enzymes UGT1A1, 1A3 and 1A9. Taken together, the metabolism of CAT3 was a multiple enzyme catalytic reaction. These results could provide valuable information for potential enzyme-mediated DDI in clinic studies.
Key words:    CAT3    in vitro metabolism    esterase    CYPs    UDP-glucuronosyltransferases   
收稿日期: 2019-03-27
DOI: 10.16438/j.0513-4870.2019-0218
基金项目: 十三五国家科技重大专项(2018ZX09711001-002).
通讯作者: 扈金萍
Email: hujp@imm.ac.cn
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