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瑞香素给药后在大鼠体内快速代谢消除,但机制仍不清楚。本研究开展瑞香素体外代谢特征分析,鉴定了瑞香素在大鼠肝S9(RLS9)中的代谢产物结构,测定了不同代谢路径的动力学参数。HPLC-DAD-MS检测发现,瑞香素在RLS9中转化为6个代谢产物,包括7-或8-葡糖醛酸和硫酸酯代谢物、8-甲基代谢物及7-硫酸酯-8-甲基代谢物。动力学分析表明,瑞香素在RLS9的葡糖醛酸化和甲基化反应符合米氏动力学,7-O-磺酸化反应和8-O-磺酸化反应分别符合双位点和底物抑制动力学。3条代谢路径中,清除率最大的为磺酸化反应,其次为甲基化和葡糖醛酸化反应。借助体外代谢动力学数据和体外-体内关联方法,预测获得的瑞香素在大鼠体内肝清除率(54.9 m L·min~(-1)·kg~(-1))与文献报道的大鼠体内总清除率(58.5 m L·min~(-1)·kg~(-1))接近。结果表明,肝脏是瑞香素在大鼠体内主要代谢位点。磺酸化、甲基化和葡糖醛酸化反应是瑞香素在大鼠肝脏中主要清除路径。
Daphnetin in rats after administration of rapid metabolic elimination, but the mechanism remains unclear. In this study, the metabolic characteristics of daphnetin in vitro were analyzed, the structure of metabolites of daphnetin in rat liver S9 (RLS9) was identified, and the kinetic parameters of different metabolic pathways were determined. The HPLC-DAD-MS assay found that daphnetin was converted to six metabolites in RLS9, including 7- or 8-glucuronic and sulfate metabolites, 8-methyl metabolites and 7-sulfate- Metabolites. Kinetic analysis showed that glucuronidation and methylation of daphnetin in RLS9 conformed to Mie kinetics, and the 7-O-sulfonation reaction and 8-O-sulfonation reaction were consistent with the dual site and substrate inhibitory learn. Of the three metabolic pathways, the highest clearance rate was sulfonation, followed by methylation and glucuronidation. The liver clearance rate (54.9 m L · min -1 · kg -1) of daphnetin in rats was predicted by in vitro pharmacokinetic data and in vitro-in vivo correlation method The total body clearance rate (58.5 m L · min -1 · kg -1) was close. The results showed that the liver is the main metabolic site of daphnetin in rats. Sulfonation, methylation and glucuronidation reactions are the major clearing routes for daphnetin in rat livers.