Transformation of biindole marine alkaloid FGFC1 by hepatic microsome system
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R961

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National Natural Science Foundation of China (81502955, 81750110548) Shanghai Science and Technology Innovation Action Plan (17490742500)

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    Abstract:

    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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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.
ZHANG Benshuai, JIANG Shengnan, YANG Jing, QIAN Shiyun, MA Zibin, GUO Ruihua, BAO Bin, WU Wenhui. Transformation of biindole marine alkaloid FGFC1 by hepatic microsome system[J]. Journal of Shanghai Ocean University,2019,28(4):634-642.

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History
  • Received:December 28,2018
  • Revised:March 14,2019
  • Adopted:April 16,2019
  • Online: July 25,2019
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