中国中药杂志

2017, v.42(03) 580-586

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UPLC-MS/MS测定复方丹参方中丹参酮Ⅱ_A、丹参酚酸B、人参皂苷Rg_1及其在大鼠血浆和脑组织的药代动力学研究
UPLC-MS/MS determination of tanshinone Ⅱ_A,salvianolic acid B and ginsenoside Rg_1 in Fufang Danshen preparation in rat plasma and brain tissues

张杰;刘胜兰;王慧;阳国平;李劲平;刘世坤;唐智;裴奇;黄攀豪;
ZHANG Jie;LIU Sheng-lan;WANG Hui;YANG Guo-ping;LI Jin-ping;LIU Shi-kun;TANG Zhi;PEI Qi;HUANG Pan-hao;The Third Xiangya Hospital,Central South University;School of Pharmaceutical Sciences,Central South University;Taian Central Hospital;

摘要(Abstract):

建立大鼠血浆和脑组织中丹参酮Ⅱ_A(TSⅡ_A)、丹酚酸B(SAB)、人参皂苷Rg_1(GRg_1)的UPLC-MS/MS分析方法,并开展药物动力学研究。选用SD大鼠,单剂量灌胃(ig)复方丹参方,采集血液与脑组织样品,采用UPLC-MS/MS测定血浆和脑组织中TSⅡ_A、SAB和GRg_1的浓度,以Phoenix Win Nolin 6.1药动学程序软件对数据进行非房室模型拟合,采用统计矩法计算药动学参数。经方法学考证,3种成分的峰面积与其在血样及脑组织中的浓度线性关系良好(r>0.992 2);回收率为58.86%~112.1%,日内、日间RSD≤9.7%,准确度及稳定性均符合体内药物分析的要求。大鼠ig给复方丹参方后的血浆药动参数如下:丹参酮Ⅱ_AT_(max)(1.58±0.081)h,C_(max)(725.4±88.20)μg·L~(-1),AUC_(0-t)(2 101.3±124.85)μg·h·L~(-1),MRT_(0-t)(3.66±0.05)h;丹酚酸B T_(max)(1.29±0.21)h,C_(max)(307.9±46.75)μg·L~(-1),AUC_(0-t)(537.4±88.24)μg·h·L~(-1),MRT_(last)(2.08±0.11)h;人参皂苷Rg_1T_(max)(1.42±0.20)h,C_(max)(460.38±154.60)μg·L~(-1),AUC_(0-t)(383.4±88.16)μg·h·L~(-1),MRT_(last)(1.87±0.046)h。脑组织药动参数如下:丹参酮Ⅱ_AT_(max)(0.75±0.22)h,C_(max)(1.41±0.420)ng·g~(-1),AUC_(0-t)(4.34±2.48)ng·h·g~(-1),MRT_(0-t)(4.00±1.90)h;丹酚酸B T_(max)(1.08±0.20)h,C_(max)(21.09±4.850)ng·g~(-1),AUC_(0-t)(14.83±3.160)ng·h·g~(-1),MRT_(0-t)(0.99±0.08)h;人参皂苷Rg_1T_(max)(0.50±0.16)h,C_(max)(130.96±54.220)ng·g~(-1),AUC_(0-t)(136.24±34.350)ng·h·g~(-1),MRT_(0-t)(2.87±0.33)h。该研究所建立的UPLC-MS/MS方法可用于大鼠血浆及脑组织中丹参酮Ⅱ_A、丹酚酸B、人参皂苷Rg_1中的药动学研究。
A sensitive and specific ultra-performance liquid chromatography-mass spectrometry( UPLC-MS/MS) method was developed for analysis of tanshinone Ⅱ_A( TSⅡ_A),salvianolic acid B( SAB) and ginsenoside Rg_1( GRg_1) in rat plasma and brain tissues.Male healthy Sprague-Dawley( SD) rats were orally given single dose of Fufang Danshen preparation( TS Ⅱ_A60 mg·kg~(-1),SAB 300mg·kg~(-1),GRg_1150 mg·kg~(-1),borneol 300 mg·kg~(-1)),and their blood samples and brain tissues were collected at different time points. The drug plasma and brain tissue concentrations of the three analytes were determined by UPLC-MS/MS method. Subsequently,the main pharmacokinetics parameters of plasma and brain tissues were calculated by using Phoenix Win Nolin 6. 1 software. The methodological test showed that all of analytes in both plasma and brain homogenate exhibited a good linearity within the concentration range( r > 0. 992 2). Their mean recoveries were between 58. 86% and 112. 1%. Intra-day and inter-day precisions of the investigated components exhibited RSD≤9. 7%,and the accuracy( RE) ranged from-9. 68% to 8. 20% at all quality control levels. The results of accuracy and stability meet the requirements for biopharmaceutical analysis. For TSⅡ_A,the pharmacokinetics parameters T_(max),C_(max),AUC_(0-t),MRT_(last)in the plasma were( 1. 58 ± 0. 081) h,( 725. 4 ± 88. 20) μg·L~(-1),( 2 101. 3 ± 124. 85) μg·h·L~(-1)and( 3. 66 ±0. 05) h,respectively. For SAB,the pharmacokinetics parameters T_(max),C_(max),AUC_(0-t),MRT_(last)in the plasma were( 1. 29 ± 0. 21) h,( 307. 9 ± 46. 75) μg·L~(-1),( 537. 4 ± 88. 24) μg·h·L~(-1)and( 2. 08 ± 0. 11) h,respectively. For GRg_1,the pharmacokinetics parameters T_(max),C_(max),AUC_(0-t),MRT_(last)in the plasma were( 1. 42 ± 0. 20) h,( 460. 38 ± 154. 60) μg·L~(-1),( 383. 4 ± 88. 16) μg·h·L~(-1)and( 1. 87 ± 0. 046) h,respectively. For TSⅡ_A,the pharmacokinetics parameters T_(max),C_(max),AUC_(0-t),MRT_(last)in the brain tissue were( 0. 75 ± 0. 22) h,( 1. 41 ± 0. 42) ng·g~(-1),( 4. 34 ± 2. 48) ng·h·g~(-1)and( 4. 00 ± 1. 90) h,respectively. For SAB,the pharmacokinetics parameters T_(max),C_(max),AUC_(0-t),MRT_(last)in the plasma were( 1. 08 ± 0. 20) h,( 21. 09 ± 4. 850) ng · g~(-1),( 14. 83 ± 3. 160) ng·h·g~(-1)and( 0. 99 ± 0. 08) h,respectively. For GRg_1,the pharmacokinetics parameters T_(max),C_(max),AUC_(0-t),MRT_(last)in the plasma were( 0. 50 ± 0. 16) h,( 130. 96 ± 54. 220) ng·g~(-1),( 136. 24 ± 34. 350) ng·h·g~(-1)and( 2. 87 ± 0. 33) h,respectively. The developed method was successfully applied in pharmacokinetic studies on content of TS Ⅱ_A,SAB and GRg_1 in rat plasma and brain tissues.

关键词(KeyWords): UPLC-MS/MS;丹参酮ⅡA;丹酚酸B;人参皂苷Rg1;药动学
UPLC-MS/MS;tanshinone ⅡA;salvianolic acid B;ginsenoside Rg1;pharmacokinetic

Abstract:

Keywords:

基金项目(Foundation): 湖南省自然科学基金项目(2010JJ4082);; 国家临床药学重点专科建设项目

作者(Author): 张杰;刘胜兰;王慧;阳国平;李劲平;刘世坤;唐智;裴奇;黄攀豪;
ZHANG Jie;LIU Sheng-lan;WANG Hui;YANG Guo-ping;LI Jin-ping;LIU Shi-kun;TANG Zhi;PEI Qi;HUANG Pan-hao;The Third Xiangya Hospital,Central South University;School of Pharmaceutical Sciences,Central South University;Taian Central Hospital;

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DOI: 10.19540/j.cnki.cjcmm.2017.0014

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