Pharmacokinetic characteristics in rats of the active components in Erzhi Formula
WANG Hua-jun1, JIANG Jun2, YIN Jiang-ning3
（1. Department of Pharmacy, the Affiliated Hospital of Jiangsu University, Zhenjiang Jiangsu 212001; 2. School of Pharmacy, Jiangsu University, Zhenjiang Jiangsu 212013; 3. Department of Emergency, the Affiliated Hospital of Jiangsu University, Zhenjiang Jiangsu 212001, China)
Abstract：Objective: To elucidate the pharmacokinetic characteristics of terpenoids in Erzhi Formula in rats. Methods: The analytic technique combined with HPLC was carried out to determine the content of Oleanolic acid and Ursolic acid in rats′ plasma and tissue after being fed Erzhi Formula. Then the DAS 2.0 program was used to calculate their corresponding pharmacokinetic parameters and drew the plasma concentrationtime curve. Results: The regression equation of Oleanolic acid and Ursolic acid were as Y=6.510 975 36X+2.180 605 9(R2=0.999 78) and Y=5.412 280 24X-1.627 312 6(R2=0.999 18)， respectively. Linear range was 0.5-50.0 μg/mL; LOD were as 1.24 and 1.26 μg/mL, respectively. The recovery rates of the Erzhi Formula were 99.8% and 102.1%; the extraction recoveries from plasma samples were as 82.15% and 83.73%, respectively. The content range of Oleanolic acid and Ursolic acid in 7 batches of Erzhi Formulas were 0.67%-4.26% and 0.21%-1.19%, respectively; the concentrations of Oleanolic acid in the liver, heart, spleen, lung and kidney tissues were sequentially 197.60,11.70,1.10,43.70 and 40.10 mg/L. The concentrations of Ursolic acid in the liver, heart, spleen, lung and kidney tissues were 92.90, 61.80, 37.90, 307.50 and 301.30 mg/L. Tmax of both Oleanolic acid and Ursolic acid were 0.5 h; Cmax of Oleanolic acid and Ursolic acid were as (111.33±10.50) mg/L and (153.72±3.35) mg/L, respectively. AUC (0-∞) of Oleanolic acid and Ursolic acid were as (342.44±10.15) mg/(L·h) and (589.79±9.49) mg/(L·h), respectively. T1/2z of Oleanolic acid and Ursolic acid were as (2.93±0.03) h and (3.19±0.02) h, respectively. Conclusion: The method can be used to detect the contents of terpenoids in Erzhi Formula, plasma and tissue.
汪华君1， 蒋俊2， 尹江宁3. 二至方中三萜类成分的含量测定及在大鼠体内的药动学特征[J]. 江苏大学学报:医学版, 2018, 28(04): 328-332.
WANG Hua-jun1, JIANG Jun2, YIN Jiang-ning3. Pharmacokinetic characteristics in rats of the active components in Erzhi Formula. Journal of Jiangsu University(Medicine Edition), 2018, 28(04): 328-332.
［1］中华医学会糖尿病学分会.中国2型糖尿病防治指南(2013年版)\[J\].中国医学前沿杂志(电子版)，2015，6(3)：26-89.［2］Bramham K. Diabetic nephropathy and pregnancy\[J\]. Semin Nephrol，2017, 37(4): 362-369.［3］Mir M, Rostami A, Hormozi M. Comparison of serum levels of IL18 in peripheral blood of patients with type Ⅱ diabetes with nephropathy clinical protests and patients with type Ⅱ diabetes without nephropathy clinical protests \[J\]. Diabetes Metab Syndr，2016, pii: S1871-4021(16)30171-0.［4］刘端勇，赵海梅.从滋阴入手，以二至丸调治亚健康的理论解析\[J\].时珍国医国药，2012，23(1)：217-219.［5］殷越，赵雪莹，李胜志.二至丸对D半乳糖致衰老模型大鼠血脂含量影响的实验研究\[J\].中医药信息，2009，26(1)：75-77.［6］Hager MR, Narla AD, Tannock LR. Dyslipidemia in patients with chronic kidney disease\[J\]. Rev Endocr Metab Disord，2017, 18(1): 29-40.［7］Sacks FM, Hermans MP, Fioreto P, et al. Association betwen plasma triglycerides and highdensity lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diadetes melitus:a global casecontrol study in 13 countries \[J\]. Circulation, 2014, 129(9): 999-1008.［8］Kaysen GA, Eiserich JP. The role of oxidative stresaltered lioprotein structure and function and microinflammation on cardiovascular risk in patients with minor renal dysfunction\[J\].J Am Soc Nephrol, 2004, 15(3):538-548.［9］Newman JW, Kaysen GA, Hammock BD, et al. Proteinuria increases oxylipid concentrations in VLDL and HDL but not LDL particles in the rat \[J\]. J Lipid Res, 2007, 48(8):1792-1800.［10］吴疆，侯文彬，张铁军，等.墨旱莲的化学成分研究\[J\].中草药，2008，39(6)：814-816.［11］赵越平，汤海峰，蒋永培，等.中药墨旱莲中的三萜皂苷\[J\].药学学报，2001，36(9)：660-663.［12］Milne JC, Lambert PD, Schenk S, et al. Small molecule activatiors of SIRT1 as therapeutics for the treatment of type 2 diabetes\[J\]. Nature, 2007, 450(7170): 712-716.［13］Wan XM, Zhang M, Zhang P, et al. Jiawei Erzhiwan improves menopausal metabolic syndrome by enhancing insulin secretion in pancreatic β cells\[J\]. Chin J Nat Med，2016, 14(11): 823-834.［14］任爽，李铮，王京辉，等. 中药女贞子饮片中8个成分的含量比较研究\[J\]. 药物分析杂志，2015，35(8)：1393-1401.［15］杨晓静，陈丽娜，秦瑶，等. UPLCMS/MS法测定中药材中齐墩果酸与熊果酸的含量\[J\]. 分析测试学报，2016，35(6)：753-757.［16］裴丹，欧阳臻，赵明，等. 龙柴方总萜部位中熊果酸、齐墩果酸在大鼠体内的药动学研究\[J\]. 中药新药与临床药理，2013，24(3)：267-271.［17］原红霞. 墨旱莲质量控制方法和相关成分药动学研究\[D\]. 沈阳：沈阳药科大学，2007.［18］Lee ES, Kim HM, Kang JS, et al. Oleanolic acid and Nacetylcysteine ameliorate diabetic nephropathy through reduction of oxidative stress and endoplasmic reticulum stress in a type 2 diabetic rat model\[J\]. Nephrol Dial Transplant，2016, 31(3):391-400.［19］Dubey VK, Patil CR, Kamble SM, et al. Oleanolic acid prevents progression of streptozotocin induced diabetic nephropathy and protects renal microstructures in Sprague Dawley rats\[J\]. J Pharmacol Pharmacother，2013, 4(1):47-52.［20］Zeng XY, Wang YP, Cantley J, et al. Oleanolic acid reduces hyperglycemia beyond treatment period with Akt/FoxO1induced suppression of hepatic gluconeogenesis in type 2 diabetic mice\[J\]. PLoS One，2012, 7(7): e42115.［21］Baig MA, Gawali VB, Patil RR, et al. Protective effect of herbomineral formulation (Dolabi) on early diabetic nephropathy in streptozotocininduced diabetic rats\[J\]. J Nat Med，2012, 66(3):500-509.［22］齐敏友，杨钧杰，周斌，等.熊果酸对糖尿病小鼠肾病的保护作用及机制研究\[J\].中国应用生理学杂志，2014, 30(5):445-448.［23］Ling C, Jinping L, Xia L, et al. Ursolic acid provides kidney protection in diabetic rats\[J\].Curr Ther Res Clin Exp，2013, 75:59-63.［24］Zhou Y, Li JS, Zhang X, et al. Ursolic acid inhibits early lesions of diabetic nephropathy\[J\].Int J Mol Med，2010, 26(4):565-570.［收稿日期］2017-08-31［编辑］何承志
2018, Vol. 28 
