甘草次酸差向异构体单独和联合给药后在大鼠体内的药动学研究(英文)

Pharmacokinetic analysis of α and β epimers of glycyrrhetinic acid in rat plasma: differences in singly and combined administrations

本文建立了大鼠血浆中甘草次酸差向异构体的高效液相测定方法,用于研究甘草次酸差向异构体在单独与混合灌胃给药后大鼠的药物代谢动力学过程。本研究分别对大鼠灌胃给予甘草次酸α异构体、β异构体和两者的混合物,于给药后不同时间点采集血样,样品经液液萃取后,用高效液相色谱法测定甘草次酸差向异构体的血药浓度。色谱柱为Kromasil C18(150 mm×4.6 mm,5μm);流动相为乙腈–4 mmol.L-1醋酸铵水溶液(46∶54,v/v);流速为1.0 mL.min-1;检测波长为250 nm;采用DAS 2.0软件计算药动学参数。结果显示,大鼠单独给予单体后,α-甘草次酸的AUC0-t为(11.30±1.53)μg.h.mL-1,Cmax为(2.36±0.58)μg.mL-1;β-甘草次酸的AUC0-t为(9.79±0.98)μg.h.mL-1,Cmax为(2.09±0.41)μg.mL-1。两单体混合给药后,α-甘草次酸的AUC0-t为(13.04±2.63)μg.h.mL-1,Cmax为(2.72±0.50)μg.mL-1;β-甘草次酸的AUC0-t为(7.46±1.77)μg.h.mL-1,Cmax为(1.90±0.31)μg.mL-1。本研究所建立的高效液相色谱法专属性强、灵敏度高,可用于甘草次酸差向异构体的体内药动学研究。α-甘草次酸与β-甘草次酸混合给药时,主要药动学参数存在显著性差异(P<0.05);单独给药时,α-甘草次酸与β-甘草次酸的主要药动学参数无显著性差异。对各差向异构体单独给药与混合给药时的主要药动学参数进一步进行统计分析,α-甘草次酸在两种给药方式时无显著性差异,而β-甘草次酸的AUC0-t与AUC0-∞存在显著性差异。

An HPLC method for the determination of 18α-glycyrrhetinic acid and 18β-glycyrrhetinic acid in rat plasma was established, which was used subsequently to determine the pharmacokinetic profiles of both epimers of glycyrrhetinic acid in rats. α-glycyrrhetinic acid, β-glycyrrhetinic acid, and a mixture of a-glycyrrhetinic and β-glycyrrhetinic acids were administered to rats via gastric infusion. Blood samples were collected at different time intervals and extracted by liquid-liquid extraction. Separation was achieved by using a Kromasil C18 column （150 mm . 4.6 mm, 5 μm） with the mobile phase composed of acetonitrile - 4 mmol.L-1 ammonium acetate solution （46 ： 54, v/v） at a flow rate of 1.0 mL.min-1, and the detection wavelength was set at 250 nm. The pharmacokinetic parameters were calculated using the software DAS 2.0. In a combined administration, the main pharmacokinetic parameters offl-glycyrrhetinic acid are significantly different from that of a-glycyrrhetinic acid （P 〈 0.05）, while no significant difference was obtained when administrated individually. Compared to the single administration, significant differences （P 〈 0.05） on the values of AUC0-1 and AUC0-∞ of β-glycyrrhetinic acid were observed when this chemical was administrated together with α-glycyrrhetinic acid. In contrast, the pharmacokinetic parameters of α-glycyrrhetinic acid were not affected even under the co-administration. Here, α sensitive, specific, rapid and reproducible HPLC method was developed for the pharmacokinetic studies of a-glycyrrhetinic acid and β-glycyrrhetinic acid in rat plasma.