文章摘要
张本帅,姜胜男,杨晶,钱士云,马子宾,郭锐华,包斌,吴文惠.溶栓候选药物双吲哚海洋生物碱FGFC1的转化特性[J].上海海洋大学学报,2019,28(4):634-642
溶栓候选药物双吲哚海洋生物碱FGFC1的转化特性
Transformation of biindole marine alkaloid FGFC1 by hepatic microsome system
投稿时间:2018-12-28  修订日期:2019-03-14
DOI:10.12024/jsou.20181202492
中文关键词: 肝微粒体  FGFC1  生物转化  半衰期  PIO
英文关键词: liver microsome  FGFC1  biotransformation  half-life  PIO
基金项目:国家自然科学基金(81502955,81750110548);上海市科技创新行动计划(17490742500)
作者单位E-mail
张本帅 上海海洋大学 食品学院, 上海 201306  
姜胜男 上海水产品加工及贮藏工程技术研究中心, 上海 201306  
杨晶 上海水产品加工及贮藏工程技术研究中心, 上海 201306  
钱士云 上海水产品加工及贮藏工程技术研究中心, 上海 201306  
马子宾 国家淡水水产品加工技术研发分中心, 上海 201306  
郭锐华 上海海洋大学 食品学院, 上海 201306  
包斌 上海海洋大学 食品学院, 上海 201306  
吴文惠 上海海洋大学 食品学院, 上海 201306 whwu@shou.edu.cn 
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中文摘要:
      研究新型海洋纤溶化合物FGFC1体外药物代谢动力学特征及其转化产物。从Wistar大鼠获得肝微粒体,lowry法检测肝微粒体蛋白浓度,HPLC方法检测FGFC1及其转化产物的增减,LC-MS/MS方法分析和鉴定FGFC1的转化产物,4-苯基-1,2,3-噻二唑、去乙酰环丙氯地孕酮、苯妥英钠和酮康唑为CYP450酶系亚型的选择性抑制剂。结果显示,FGFC1的体外代谢半衰期T1/2=(96.25±2.3)min,固有清除率CLint=(0.072 0±0.001 4)mL/(min·mg)。FGFC1的唯一转化产物是((2S,3S)-2-((E)-7,8-dihydroxy-4-methylnon-3-en-1-yl)-3,5,8-trihydroxy-2-methyl-3,4,8,9-tetrahydropyrano[2,3-e]isoindol-7(2H)-one)(PIO),其分子质谱和片段峰(m/z)分别为463.20[M+C2H3N+H]+和m/z 110.90[C7H8O+H+H]+、215.70[C13H26O2+H]+、337.00[C18H27NO5]+、337.00[C25H31NO2]+。苯妥英钠显著抑制肝微粒体酶系CYP3A4亚型,FGFC1的转化产物PIO被减少49.11%。研究表明,肝微粒体CYP3A4亚型酶系通过N-脱烷基反应、N-氧化反应和水解反应转化FGFC1为PIO。
英文摘要:
      In vitro pharmacokinetics and transformation products of novel marine fibrinolytic compound FGFC1 were studied. Liver microsomes were prepared by Wistar rats. The liver microsome protein concentration was detected by lowry method. The changes of FGFC1 and its transformation products were detected by HPLC method. The conversion products were analyzed by LC-MS/MS method and 4-phenyl-1,2,3-thiadiazole, deacetylcyclopropionate, phenytoin and ketoconazole are selective inhibitors of different subtypes of the CYP450 enzyme system.The in vitro metabolic half-life of FGFC1 was T1/2=(96.25±2.3) min, and the intrinsic clearance rate CLint=(0.072 0±0.001 4) mL/(min·mg).The conversion product of FGFC1 is((2S,3S)-2-((E)-7,8-dihydroxy-4-methylnon-3-en-1-yl)-3,5,8-trihydroxy-2-methyl-3,4,8,9-tetrahydropyrano[2,3-e]isoindol- 7 (2H)-one)(PIO)with a molecular weight of 421.2.The fragments of the FGFC1 conversion product was detected by LC-MS/MS at 463.30[M+C2H3N+H]+ and m/z 110.90[C7H8O+H+H]+, 215.70[C13H26O2+H]+, 337.00[C18H27NO5]+, 337.00[C25H31NO2]+. Phenytoin significantly inhibited the liver microsomal enzyme system CYP3A4 subtype, and the PIO was reduced with 49.11%. FGFC1 is converted by N-dealkylation reaction, N-oxidation reaction and hydrolysis reaction under the catalysis of CYO450 subtype CYP3A4.
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