Wang Dian-lei, Liang Yan, Chen Wei-dong, Xie Lin, Wang Guang-ji, Liu Xiao-dong
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Acta Pharmacol Sin. 2008 Mar;29(3):376-84. doi: 10.1111/j.1745-7254.2008.00758.x.
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.
A liquid chromatography quadrupole mass spectrometer and liquid chromatography ion-trap-time-of-flight 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.
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 micromol/L, while alpha-naphthoflavone, ketoconazole, sulfaphenazole, and diethyldithiocarbamate had no inhibitory effects.
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.
鉴定大鼠尿液中银杏内酯B的代谢产物、银杏内酯B的主要代谢途径以及大鼠肝微粒体中负责银杏内酯B代谢的主要细胞色素（CYP）P450酶。
采用液相色谱四极杆质谱仪和负离子模式电喷雾电离的液相色谱离子阱飞行时间质谱仪对大鼠尿液和肝微粒体孵育中的代谢产物进行结构解析。应用多种选择性CYP450抑制剂研究其对银杏内酯B代谢及大鼠肝微粒体中主要代谢产物形成的影响。
在大鼠尿液中鉴定出3种代谢产物。在大鼠肝微粒体中鉴定出一种银杏内酯B的羟基代谢产物，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）值估计为8 μmol/L，而α-萘黄酮、酮康唑、磺胺苯唑和二乙基二硫代氨基甲酸盐无抑制作用。
银杏内酯B在大鼠体内代谢为其羟基代谢产物，CYP2D6是大鼠肝微粒体中负责银杏内酯B代谢的主要CYP同工酶。
