Identification of ginkgolide B metabolites in urine and rat liver cytochrome P450 enzymes responsible for their formation in vitro
Identification of ginkgolide B metabolites in urine and rat liver cytochrome P450 enzymes responsible for their formation in vitro
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DOI：
10.1111/j.1745-7254.2008.00758.x
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发表时间：
2008-03
影响因子：
8.2
通讯作者：
Dian-lei Wang;Yan Liang;Wei-dong Chen;Lin Xie;Guang-Ji Wang;Xiao-dong Liu
中科院分区：
文献类型：
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作者：
Dian-lei Wang;Yan Liang;Wei-dong Chen;Lin Xie;Guang-Ji Wang;Xiao-dong Liu
目的：确定银杏内酯B在大鼠尿液中的主要代谢产物，以及银杏内酯B在大鼠肝微粒体中代谢的主要细胞色素(CYP)P450酶。方法：采用高效液相四极质谱仪和负离子电喷雾电离-离子捕获时间质谱仪对大鼠尿和肝微粒体中的代谢物进行结构鉴定。研究了不同选择性细胞色素P450抑制剂对银杏内酯B代谢及大鼠肝微粒体主要代谢产物形成的影响。结果：在大鼠尿中检测到3种代谢产物。结论：银杏内酯B在大鼠肝微粒体中可代谢为羟基代谢物，奎尼丁对该代谢产物的形成具有非竞争性抑制作用，其抑制羟基代谢产物的抑制常数(Ki)为8μ/L，而α-萘黄酮、酮康唑、磺苯唑和二乙基二硫代氨基甲酸酯对银杏内酯B无抑制作用。
AbstractAim:To identify metabolites of ginkgolide B in rat urine, the predominant metabolism of ginkgolide B and the major cytochrome (CYP) P450 enzymes responsible for the metabolism of ginkgolide B in rat liver microsomes.Methods:A liquid chromatography quadrupole mass spectrometer and liquid chromatography ion-trap-time-of-fight mass spectrometer with electrospray ionization in negative-ion mode were used for the structure elucidation of metabolites in rat urine and liver microsome incubation. Various selective CYP450 inhibitors were applied to investigate their effects on the metabolism of ginkgolide B and the formation of the major metabolite in rat liver microsomes.Results:Three metabolites were identified in rat urine. One hydroxyl metabolite of ginkgolide B were identified in rat liver microsomes, and quinidine uncompetitively inhibited the formation of the metabolite; its inhibitor constant (Ki) value for the inhibition of hydroxyl metabolite was estimated to be 8 μmol/L, while α-naphthoflavone, ketoconazole, sulfaphenazole, and diethyldithiocarbamate had no inhibitory effects.Conclusion:Ginkgolide B was metabolized to its hydroxyl metabolite in rats, and CYP2D6 was the major rat CYP isoform responsible for the ginkgolide B metabolism in rat liver microsomes.