川续断皂苷Ⅵ及其活性代谢物在大鼠体内的药代动力学研究

Study on pharmacokinetics of asperosaponin Ⅵ and its active metabolite in rats

研究川续断皂苷Ⅵ(asperosaponin VI,A-VI)及其活性代谢产物常春藤皂苷元(hederagenin,M1)在大鼠体内的药代动力学、排泄特征和A-VI的大鼠血浆蛋白结合率。采用已建立的LC-MS/MS法测定大鼠血浆、胆汁、尿液和粪便中A-VI和M1浓度,计算药代动力学参数,并用平衡透析法测定大鼠血浆中A-VI的血浆蛋白结合率。大鼠以低、中、高(0.03,0.09,0.27g.kg-1)3个剂量分别单次灌胃给予A-VI后,A-VI的血药浓度-时间曲线出现双峰现象,Cmax1和Cmax2分别为(28.88±49.78)和(4.480±1.872)μg.L-1,(35.19±23.53)和(22.11±16.15)μg.L-1,(73.37±37.28)和(132.2±160.7)μg.L-1;AUC0-t分别为(43.21±37.32),(133.9±102.5),(779.6±876.9)μg.h.L-1;t1/2分别为(3.3±0.8),(3.2±2.3),(4.5±1.2)h。代谢产物M1相应的Cmax分别为(16.03±9.336),(26.41±11.95),(28.71±5.874)μg.L-1;AUC0-t分别为(105.6±73.60),(260.0±153.9),(323.1±107.9)μg.h.L-1;t1/2分别为(4.1±3.4),(4.4±2.3),(3.9±0.9)h。A-VI和M1在大鼠体内药动学特征不存在性别差异,按0.09 g.kg-1剂量多次灌胃A-VI后A-VI和M1在体内均无蓄积。灌胃A-VI后,A-Ⅵ的胆汁和尿液排泄速率-时间曲线也出现双峰现象,灌胃A-Ⅵ 6 h以后可以在大鼠粪便中检测到M1。A-Ⅵ在大鼠血浆中的平均血浆蛋白结合率为92.9%。

To study the pharmacokinetics,excretion characteristics and plasma protein binding rate of asperosaponin VI（A-VI） and its active metabolite hederagenin（M1）.A-VI and M1 concentrations in plasma,bile,urine and feces were determined by established LC-MS/MS to calculate the pharmacokinetic parameters.The plasma protein binding rate of A-VI was determined by equilibrium dialysis method.the double peaks was observed in the A-VI plasma concentration-time curve,after rats were orally administered with low,medium and high doses of A-VI（0.03,0.09,0.27 g·kg-1）.The Cmax1 and Cmax2 of A-VI were（28.88±49.78） and（4.480±1.872） μg·L-1,（35.19±23.53） and（22.11±16.15） μg·L-1,（73.37±37.28） and（132.2±160.7） μg·L-1,respectively.The AUC0-tof A-VI were（43.21±37.32）,（133.9±102.5） and（779.6±876.9） μg·h·L-1,respectively.The t1/2of A-VI were（3.3±0.8）,（3.2±2.3） and（4.5±1.2） h,respectively.The Cmax of M1 were（16.03±9.336）,（26.41±11.95） and（28.71±5.874） μg·L-1,respectively.The AUC0-t of M1 were（105.6±73.60）,（260.0±153.9） and（323.1±107.9） μg·h·L-1,respectively.The t1/2 of M1 were（4.1±3.4）,（4.4±2.3）,（3.9±0.9） h,respectively.No significant gender difference was found in the in vivo pharmacokinetics of A-VI and M1.There was no accumulation of A-VI and M1 after multiple administrations of A-VI（0.09 g·kg-1）.After oral administration of A-VI,the double peaks were also observed in biliary and urinary excretion rate-time curves for A-VI.M1 was detected in the feces samples at 6 h after oral administration.The average plasma protein binding rate of A-VI was 92.9% in rats.