熊果酸共晶在大鼠体内的药代动力学  

Pharmacokinetics of ursolic acid-ethanol cocrystal in rats

作　　者：刘夕琳[1] 张羽男[1] 杨玉婷[1] 殷和美 张宇[1] 孙长海[1] 

机构地区：[1]佳木斯大学药学院,黑龙江佳木斯154007

出　　处：《沈阳药科大学学报》2017年第11期973-978,993,共7页Journal of Shenyang Pharmaceutical University

基　　金：佳木斯大学抗肿瘤共晶药物科技创新团队(CXTD-2013-05);佳木斯大学研究生创新项目(LM2015_089);中国博士后科学基金资助项目(2014M561382)

摘　　要：目的建立基于高效液相色谱-质谱联用技术(HPLC-MS)的熊果酸血药浓度测定方法,考察熊果酸乙醇共晶在大鼠体内的相对生物利用度。方法采用口服灌胃方式给大鼠服用熊果酸及其乙醇共晶,分别于给药后0、0.25、0.50、1.00、1.50、2.00、3.00、4.00、5.00、6.00、8.00、10.00和12.00 h,大鼠眼眶后静脉丛取血。血浆经乙酸乙酯提取后,采用HPLC-MS测定血浆中熊果酸的浓度并绘制药代动力学曲线。方法的色谱条件为,固定相:Sino Pak-C18色谱柱(250 mm×4.6 mm,5.0μm),流动相:甲醇-纯净水(含体积分数为0.02%的三乙胺)(体积比为90∶10),流速:0.5 m L·min-1,柱温:25℃,进样量:10μL。质谱条件为:采集方式:多反应监测(multiple reaction monitoring,MRM),离子极性:负离子,离子源:电喷雾离子源,检测离子:熊果酸m/z=455.7、甘草次酸m/z=470.6,N2体积流量:35.0 L·min-1,加热温度:350℃。药动学数据处理采用中国药理学会编制的DAS 2.0药动学软件处理。结果熊果酸的线性为10~640μg·L-1,定量下限为10μg·L-1,日内、日间精密度(RSD)均小于10%,提取回收率为80.57%,熊果酸及其乙醇共晶在大鼠体内的血药浓度-时间过程均符合一室模型,其中熊果酸-乙醇共晶和熊果酸原料药经灌胃给药后,AUC0-12 h分别为(279.7±22.9)和(171.1±11.4)h·μg·L-1,AUC0-∞分别为(352.9±45.0)和(297.9±65.9)h·μg·L-1,ρmax分别为(83.5±4.1)和(44.01±2.79)μg·L-1。药动学参数经方差分析后均存在显著性差异(P<0.05)。结论该方法适用于熊果酸及其乙醇共晶在大鼠体内的血药浓度测定及药代动力学研究,熊果酸-乙醇共晶灌胃给药后明显提高其血药浓度,改善生物利用度。Objective To establish a method for the determination of ursolic acid concentration in rat plasma by High Performance Liquid Chromatography-Mass Spectrometric,the relative bioavailability between ursolic acid and ursolic acid-ethanol cocrystal were compared in this paper. Methods The rats were given ursolic acid and its cocrystal by oral gavage administration. Blood was sampled from the posterior orbital venous plexus of rats at 0,0. 25,0. 5,0. 75,1,1. 5,2,3,4,5,6,8,10 and 12 h after oral administration.Plasma was extracted with ethyl acetate and determined by HPLC-MS, then the plasma concentration-time curve of ursolicc acid was drawn. The chromatographic condition： Stationary Phase： SinoPak-C18 chromatographic column（250 mm × 4. 6 mm,5. 0 μm）; The mobile phase was consisted of methanol-water（V∶ V 0∶ 10,0. 02% triethylamine included）; flow rate： 0. 5 mL·min-1; column temperature： 25 ℃;injection volume： 10 μL; collection： MRM（multiple reaction monitoring,MRM）; ion polarity： negative;ionization method： electrospray ionization; detecting objects： m/z 455. 7 for ursolic acid and m/z 470. 6 for IS; N2 volume flow： 35. 0 L·min-1; heating temperature： 350 ℃. Calculation of the pharmacokinetic parameters was performed using the DAS 2. 0 pharmacokinetic software of Chinese pharmacological society.Results The linear over the range of ursolic acid was 10-640 μg·L-1, the lower limit of quantification was10 μg·L-1, intra-day and inter-day precision（RSD） was less than 10%,and extraction recovery rate was80. 57%. The plasma concentration-time curve course of ursolic acid in rats was consistent with one compartment model. After the gavage administration of ursolic acid and ursolic acid-ethanol cocrystal,AUC0-12 h were（171. 0 ± 11. 44） and（279. 7 ± 22. 9） h·μg·L-1,AUC0-∞ were（297. 8 ± 65. 94） and（352. 9 ±45. 0） h·μg·L-1,ρmax were（44. 01 ± 2. 79） and（83. 5 ± 4. 1） μg·L-1,respectively. Pharmacokinetic parameters have significant differe

关 键 词：熊果酸 熊果酸乙醇共晶 药代动力学 血药浓度 高效液相色谱-质谱联用仪 

分 类 号：R318.15[医药卫生—生物医学工程] R587.1[医药卫生—基础医学]