基于女贞子和酒女贞子中主要差异性成分的体内药代动力学研究  

Pharmacokinetics of the main components differing between Ligustri Lucidi Fructus and its wine-steamed product

作　　者：纪鑫 刘晓谦[1] 高陆 肖苏萍 梁曜华[1] 李春[1] 王智民[1] JI Xin;LIU Xiao-qian;GAO Lu;XIAO Su-ping;LIANG Yao-hua;LI Chun;WANG Zhi-min(Institute of Chinese Materia Medica,National Engineering Laboratory for Quality Control Technology of Chinese Herbal Medicines,China Academy of Chinese Medical Sciences,Beijing 100700,China;Xiuzheng Pharmaceutical Group Co.,Ltd.,Changchun 130012,China;China National of Traditional&Herbal Medicine Co.,Ltd.,Beijing 102600,China)

机构地区：[1]中国中医科学院中药研究所,中药质量控制技术国家工程实验室,北京100700 [2]修正药业集团股份有限公司,吉林长春130012 [3]中国中药有限公司,北京102600

出　　处：《药学学报》2021年第12期3518-3525,共8页Acta Pharmaceutica Sinica

基　　金：国家中药标准化项目(ZYBZH-C-JL-26);国家科技重大专项_重大新药创制项目(2018ZX09721004-001)。

摘　　要：针对女贞子和酒女贞子中的10个主要差异性成分建立定量分析方法,研究女贞子和酒女贞子分别给药后大鼠体内这10个成分(苯乙醇类、环烯醚萜类和三萜类)的药代动力学行为。本研究利用LC-QQQ-MS技术建立了10个成分的定量分析方法,方法学考察结果均符合生物样本分析要求。之后利用该方法检测了大鼠单次给药(同批次女贞子和酒女贞子水提物)后不同时间点血浆中的各成分浓度,计算了药物的药代动力学参数,构建了各成分的药-时曲线。分析药代动力学参数发现,苯乙醇类成分(红景天苷、酪醇、羟基酪醇)在两种样本中的AUC0-24 h和C_(max)均较大,说明该类成分为女贞子类样本的主要药效物质。此外,其中8种体外主要差异性成分的t_(max)值在酒女贞子给药条件时更小,说明这些成分在酒女贞子给药后起效更快;而另外2种成分-特女贞苷和齐墩果酸的t_(max)值则在酒女贞子给药时更大,说明这两类成分在酒女贞子给药环境下有缓释、长效的特征。观察各成分药-时曲线发现,酪醇和羟基酪醇在两组样本中均有二次达峰现象,但红景天苷只在酒女贞子中有二次达峰,该现象进一步提示酒女贞子给药后发挥作用更持久。另外,通过计算发现,酒女贞子给药条件下特女贞苷和齐墩果酸的相对生物利用度都大于100%,进一步验证了"女贞子酒制增效"的中医理论。本文不仅明确了体外有差异的10种成分在不同给药组的药代参数及相对生物利用度的差异,而且揭示了各类成分在体内外的变化规律及其关联性,为女贞子和酒女贞子质控指标的选择以及炮制机制、体内代谢规律的深入研究提供了实验依据。本实验获得中国中医科学院中医基础理论研究所伦理委员会批准。A quantitative analysis method for ten principal components(phenylethanol,iridoids and triterpenes)of raw Ligustri Lucidi Fructus and its wine-steamed product was developed using liquid chromatography tandem triple quadrupole mass spectrometry(LC-QQQ-MS)to study their pharmacokinetic behavior in vivo.The results of methodological investigation were in accord with the criteria of biological analysis.After a single administration to rats of the water extracts of Ligustri Lucidi Fructus and its wine-steamed product,the plasma concentration of each component at different time points was measured and the pharmacokinetic parameters were determined.The AUC0-24 h and C_(max)of the phenylethanol components(salidroside,tyrosol,hydroxytyrosol)were the greatest,suggesting that these components are the main pharmacological substances of Ligustri Lucidi Fructus.In addition,the t_(max)values of the eight major components were even lower with administration of the wine-steamed product,suggesting that these components are rapidly absorbed.However,the t_(max)values of specnuezhenide and oleanolic acid were greater with administration of the wine-steamed product,indicating that these two components were more slowly absorbed.A secondary peak phenomenon of tyrosol and hydroxytyrosol were observed in two sample groups,whereas the secondary peak phenomenon of salidroside occurred only with the wine-steamed product.This result suggests that the effect of wine-steamed product could persist for a long period.Meanwhile,the relative bioavailability of specnuezhenide and oleanolic acid was greater than 100%with administration of the wine-steamed product,consistent with the Traditional Chinese Medicine theory of the wine-steamed product being more effective than the raw material.The results reveal the different pharmacokinetic parameters and relative bioavailability of each component of Ligustri Lucidi Fructus and its wine-steamed product,and also demonstrate the variation and correlation of various components in vivo and in vitro,providing a

关 键 词：女贞子 酒女贞子 差异性成分 药代动力学 液相色谱串联三重四极杆质谱 

分 类 号：R917[医药卫生—药物分析学]