Liu Yi-tong, Hao Kun, Liu Xiao-quan, Wang Guang-ji
Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Acta Pharmacol Sin. 2006 Sep;27(9):1253-8. doi: 10.1111/j.1745-7254.2006.00369.x.
To study the metabolism of gambogic acid (GA) and the effects of selective cytochrome P-450 (CYP450) inhibitors on the metabolism of GA in rat liver microsomes in vitro.
Rat liver microsomes were used to perform metabolism studies. Various selective CYP450 inhibitors were used to investigate their effects on the metabolism of GA and the principal CYP450 isoform involved in the formation of major metabolite M(1) in rat liver microsomes. Types of inhibition in an enzyme kinetics model were used to model the interaction.
GA was rapidly metabolized to two phase I metabolites, M(1) and M(2), in rat liver microsomes. M(1) and M(2) were tentatively presumed to be the hydration metabolite and epoxide metabolite of GA, respectively. alpha-Naphthoflavone uncompetitively inhibited the formation of M(1) while ketoconazole, sulfaphenazole, diethyl dithiocarbamate and quinidine had little or no inhibitory effects on the formation of M(1).
GA is rapidly metabolized in rat liver microsomes and M(1) is crucial for the elimination of GA. Cytochrome P-450 1A2 is the major rat CYP involved in the metabolism of GA.
研究藤黄酸（GA）的代谢情况以及选择性细胞色素P-450（CYP450）抑制剂对体外大鼠肝微粒体中GA代谢的影响。
采用大鼠肝微粒体进行代谢研究。使用多种选择性CYP450抑制剂来研究它们对GA代谢的影响以及参与大鼠肝微粒体中主要代谢产物M(1)形成的主要CYP450同工酶。利用酶动力学模型中的抑制类型来模拟相互作用。
在大鼠肝微粒体中，GA迅速代谢为两种I相代谢产物M(1)和M(2)。初步推测M(1)和M(2)分别为GA的水合代谢产物和环氧化代谢产物。α-萘黄酮对M(1)的形成具有非竞争性抑制作用，而酮康唑、磺胺苯唑、二乙基二硫代氨基甲酸盐和奎尼丁对M(1)的形成几乎没有抑制作用。
GA在大鼠肝微粒体中迅速代谢，M(1)对GA的消除至关重要。细胞色素P-450 1A2是参与GA代谢的主要大鼠CYP。
