丹红注射液7种药效物质基础的人血浆蛋白结合率  

Determination of binding rates of human plasma protein with seven bioactive components in Danhong injection

作　　者：张倩[1,2] 戴国梁[1] 居文政[1] 郭建明[2] 孙冰婷 宗阳[1] 何书芬[1] 段金廒[2] ZHANG Qian DAI Guo-liang JU Wen-zheng GUO Jian-ming SUN Bing-ting ZONG Yang HE Shu-fen DUAN Jin-ao(Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029,China Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Traditional Chinese Medicine, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing 210046,China)

机构地区：[1]南京中医药大学附属医院,江苏南京210029 [2]南京中医药大学江苏省中药资源产业化过程协同创新中心,江苏省方剂高技术研究重点实验室,中药资源产业化与方剂创新药物国家地方联合工程研究中心,江苏南京210046

出　　处：《中国药理学通报》2017年第5期712-718,共7页Chinese Pharmacological Bulletin

基　　金：国家科技部“重大新药创制”科技重大专项资助项目(No2015ZX09501004001006);江苏省中药资源产业化过程协同创新中心重点项目(No ZDXM-2-2);江苏省高等学校大学生创新创业训练计划省级项目(No 201510315064Y)

摘　　要：目的建立同时测定丹红注射液中7种主要药效物质基础丹参素、原儿茶醛等体外人血浆蛋白结合率的方法,并将结果与同等浓度条件下每个单体化合物的人血浆蛋白结合率进行比较,以考察两者是否存在显著性差异,由此推测多组分之间是否存在血浆蛋白竞争性结合。为丹红注射液主要药效物质基础的体内药动学,及其在临床联合用药时的体内药动学相互作用研究提供参考依据。方法采用平衡透析法测定血浆蛋白结合率,HPLC测定丹红注射液中7种成分,及每种成分单独透析平衡时的血药浓度及游离药物浓度。结果在3种浓度的丹红注射液中,丹参素、原儿茶醛、p-香豆酸、丹酚酸D、迷迭香酸、紫草酸和丹酚酸B的人血浆蛋白结合率分别为(11.88±0.58)%、(78.35±1.72)%、(63.48±2.17)%、(87.72±0.78)%、(82.77±2.83)%、(71.59±0.81)%和(70.55±1.34)%;而同等浓度条件下,这7种单体化合物的人血浆蛋白结合率分别为(23.34±1.06)%、(79.32±1.41)%、(78.97±0.08)%、(92.37±0.66)%、(84.95±0.38)%、(79.15±5.47)%和(75.49±0.75)%。与单体化合物的血浆蛋白结合率相比,丹参素、p-香豆酸和紫草酸在丹红注射液样品中的人血浆蛋白结合率差异有显著性;在本实验的药物浓度范围内,只有紫草酸的人血浆蛋白结合率与浓度呈线性;原儿茶醛、丹酚酸D、迷迭香酸和丹酚酸B的人血浆蛋白结合率差异没有显著性。结论该测定方法简便易行,准确度、稳定性均较好。实验条件下,原儿茶醛、p-香豆酸、丹酚酸D、迷迭香酸、紫草酸和丹酚酸B的人血浆蛋白结合率均>60%,且在样品体系中这7种成分的血浆蛋白结合率均比单独给药的血浆蛋白结合率低,组分之间可能存在竞争性结合,但竞争影响可能较弱。考察血浆蛋白竞争性结合对该药的药物相互作用影响时,其组分间的相互竞争影响较小。Aim To establish the method of simultaneous determination of the human plasma protein binding rates in vitro of seven major pharmacodynamic substances in Danhong injection with HPLC.And to confirm whether the competitive effects of the multi-components exist or not through the comparasion of the plasma protein binding rates in the same concentration in or out of the Danhong injection, so as to provide the reference for the pharmacokinetics of the main bioactive substances of Danhong injection and its pharmacokinetics combined with other drugs in vivo.Methods Equilibrium dialysis method was carried out to calculate the protein binding rates in human plasma of tanshinol, protocatechuic aldehyde, p-coumaric acid, salvianolic acid D, rosmarinic acid, lithospermic acid and salvianolic acid B in Danhong injection or alone.A simple HPLC method for the determination of the concentrations of seven compounds both in inner and outer dialysis was established.Results Linear relationship, precision and accuracy, extraction recovery and stability of the seven compounds all complied with the methodology requirements.Within the low, middle and high concentration（5, 10, 25 mL·L-1）of Danhong injection, the human plasma protein binding rates of tanshinol, protocatechuic aldehyde, p-coumaric acid,salvianolic acid D, rosmarinic acid, lithospermic acid and salvianolic acid B were（11.88±0.58）%,（78.35±1.72）%,（63.48±2.17）%,（87.72±0.78）%,（82.77±2.83）%,（71.59±0.81）% and（70.55±1.34）%, respectively.While in the same concentration, the protein binding rates of the seven components were（23.34±1.06）%,（79.32±1.41）%,（78.97±0.08）%,（92.37±0.66）%,（84.95±0.38）%,（79.15±5.47）% and（75.49±0.75）%,respectively in the groups of dosed alone.There exist significant differences between the two groups of tanshinol,p-coumaric acid and lithospermic acid through the t-test, in which only the lithospermic acid depended on the concentration in this investigation.While the rest had no significa

关 键 词：丹红注射液 酚酸类化合物 人血浆蛋白结合率 多组分竞争性结合 药物相互作用 平衡透析法 

分 类 号：R282.71[医药卫生—中药学] R284.1[医药卫生—中医学]