黄连解毒汤中黄芩苷和汉黄芩苷在糖尿病大鼠体内的药动学

Pharmacokinetic study on baicalin and wogonoside in diabetic rats in vivo after oral administrating Huanglian-Jiedu Decoction

目的研究黄连解毒汤中主要成分黄芩苷、汉黄芩苷在糖尿病大鼠体内的药动学。方法链脲佐菌素ip给药建立糖尿病大鼠模型,ig黄连解毒汤提取物后取血分离血浆,采用HPLC-UV法检测血浆中黄芩苷、汉黄芩苷质量浓度,以矩量法计算药动学参数。采用黄连解毒汤提取物与大鼠粪便温孵,从肠道代谢方面研究黄芩苷和汉黄芩苷动力学改变的初步机制。结果黄芩苷在正常大鼠和糖尿病大鼠中的tmax2分别为(4.50±1.92)、(7.5±1.0)h,Cmax1分别为(2.83±0.25)、(9.54±2.87)μg/mL,Cmax2分别为(2.56±0.63)、(6.58±1.15)μg/mL,AUC(0～24)分别为(37.58±7.57)、(92.75±24.62)μg.h/mL,t1/2分别为(6.6±2.4)、(12.64±3.35)h。汉黄芩苷在正常大鼠和糖尿病大鼠中的tmax2分别为(5.5±1.0)、(8.00±1.63)h,Cmax1分别为(1.36±0.17)、(6.16±1.40)μg/mL,Cmax2分别为(1.58±0.17)、(4.11±0.76)μg/mL,AUC(0～24)分别为(27.02±3.72)、(58.16±16.43)μg.h/mL,t1/2分别为(9.72±2.24)、(7.89±1.63)h。实验结果表明大鼠在糖尿病病理状态下黄芩苷和汉黄芩苷的Cmax1、Cmax2、AUC(0～24)明显增加,黄芩苷的t1/2显著延长。粪便温孵的结果表明,黄芩苷在糖尿病大鼠粪便中降解加快。结论黄芩苷在糖尿病大鼠中的动力学改变的原因可能由于黄芩苷在糖尿病大鼠肠道代谢加快。

Objective To investigate the pharmacokinetic profiles of baicalin and wogonoside in diabetic rats in vivo, which are two major constituents in Huanglian-Jiedu Decoction （HJD）. Methods The diabetic rats were induced by ip administration of streptozotocin （STZ）. After the establishment of the method and the set-up of diabetic rats, the pharmacokinetic profiles of baicalin and wogonoside were investigated. Diabetic and normal rats were ig HJD extract, and then the blood samples were collected at the given time points. Contents of baicalin and wogonoside in diabetic and normal rat plasma were assayed by HPLC-UV method. The pharmacokinetic parameters （except Cmax and tmax） were analyzed by noncompartmental method. The area under the serum concentration-time curve （AUC0-t） was calculated using trapezoidal rule to the last point. Moreover, the presystemic metabolism of baicalin was investigated and compared to explore the pharmacokinetic difference by fermentation of baicalin in feces suspensions of normal and diabetic rats, respectively. Results The pharmacokinetic parameters of baicalin in normal and diabetic rats were： （4. 50±1.92） and （7.5±1.0） h for tmax2; （2.83±0.25） and （9.54±2.87） μg/mL for Cmax1, （2.56±0.63） and （6.58±1.15）μg/mL for Cmax2; （37.58±7.57） and （92.75±24.62）μg · h/mL for AUC（0-24）, （6.6±2.4） and （12.64±3.35） h for tl/2, respectively. And the pharmacokinetic parameters of wogonoside in normal and diabetic rats were： （5.5±1.0） and （8.00±1.63） h for tmax2 （1.36±0.17） and （6. 164±1.40） μg/mL for Cmax1; （1.58±0. 17） and （4.11±0.76）μg/mL for Cmax2; （27. 02±3. 72） and （58.16±16.43）μg·h/mL for AUC（0-24）; （9.72±2.24） and （7.89±1.63） h for t1/2, respectively. The results indicated that Cmax1, Cmax2, AUC（0-24） of baicalin and wogonoside were significantly enhanced and t1/2 of baicalin was remarkably extended when compared with the normal rats. And the results also revealed that baicalin contained in HJD hydrolyzed more rapidly when incubated in the feces suspension of diabetic rats than in that of normal rats. Conclusion The results indicate that the pharmacokinetic difference of baicalin between diabetic and normal rats may result from the presystemic metabolism of baiealin.