大黄及牛黄解毒片大鼠给药后血浆中大黄活性成分的药代动力学比较研究

Comparative pharmacokinetics of active anthraquinones ingredients after oral administration of Rhei Radix et Rhizoma and Niuhuang Jiedu Tablets to rats

考察大黄及牛黄解毒片给药后大黄活性成分在大鼠体内药代动力学行为的差异。大鼠分别灌胃给予大黄生药材96 mg/kg(含总蒽醌1.83 mg/kg,相当于大黄酸0.28 mg/kg、大黄素0.30 mg/kg、大黄酚0.81 mg/kg、芦荟大黄素0.23 mg/kg及大黄素甲醚0.20 mg/kg)及牛黄解毒片250 mg/kg(含总蒽醌与大黄生药材等量,相当于大黄酸0.33 mg/kg、大黄素0.38 mg/kg、大黄酚0.71 mg/kg、芦荟大黄素0.24 mg/kg及大黄素甲醚0.17 mg/kg),血浆经甲醇沉淀后,采用LC-MS/MS法测定大黄活性成分血药浓度,Win Nonlin 7.0软件计算药代动力学参数。大鼠灌胃大黄及牛黄解毒片后,大黄酸的c_(max)分别为(121±103)及(474±251)μg/L,AUC_(0-t)分别为(275±176)及(406±194)μg·h/L;大黄酚异构体的c_(max)分别为(2 325±1 390)及(3 580±2 169)μg/L,AUC_(0-t)分别为(8 170±2 661)及(8 856±4 023)μg·h/L;仅在牛黄解毒片给药大鼠血浆中检测出大黄素,且牛黄解毒片给药后大鼠血浆中大黄酸的c_(max)、AUC及t_(1/2),大黄酚异构体的Vd及CL与单味大黄相比显著增加,大黄酚异构体的t_(max)显著下降。实验结果表明,牛黄解毒片复方配伍增强了大黄活性成分在大鼠体内的吸收利用,改变了大黄活性成分的药代动力学行为。

The study aims to investigate different pharmacokinetic profilesof anthraquinones after oral administration of Rhei Radix et Rhizoma and Niuhuang Jiedu Tablets(NHJDT)in rats,respectively.Rats were administrated with 96 mg/kg of Rhei Radix et Rhizoma(1.83 mg/kg of total anthraquinone,equivalent to 0.28 mg/kg of rhein,0.30 mg/kg of emodin,0.81 mg/kg of chrysophanol,0.23 mg/kg of aloe-emodin and 0.20 mg/kg of physcion)or 250 mg/kg of NHJDT(equal dose of total anthraquinone as Rhei Radix et Rhizoma,equivalent to 0.33 mg/kg of rhein,0.38 mg/kg of emodin,0.71 mg/kg of chrysophanol,0.24 mg/kg of aloe-emodin and 0.17 mg/kg of physcion),respectively.Followed by protein precipitation with methanol,the anthraquinones in plasma samples were determined by LC-MS/MS.The pharmacokinetic parameters were calculated by WinNonlin 7.0.The c max of rhein were(121±103)and(474±251)μg/L,and the AUC 0-t were(275±176)and(406±194)μg·h/L for Rhei Radix et Rhizoma and NHJDT,respectively.The c max of chrysophanol isomer were(2 325±1 390)and(3 580±2 169)μg/L,and the AUC 0-t were(8 170±2 661)and(8 856±4 023)μg·h/L,respectively.Emodin in very low levels was only detected in rat plasma samples after oral gavage of NHJDT.The c max,AUC and t 1/2 of rhein,as well as Vd and CL of chrysophanol isomer were observed with a much increased degree in comparison with Rhei Radix et Rhizoma counterparts.However,much shorter t max was found in NHJDT group.Therefore,NHJDT with co-existing components enhanced the absorption and influenced the pharmacokinetic behaviors of active ingredients in Rhei Radix et Rhizoma.