金银花和山银花9种抗炎成分对二甲苯耳肿胀模型小鼠体内的多成分药代动力学比较研究

Comparative polypharmacokinetics of nine anti-inflammatory components of Jinyinhua(Lonicerae Japonicae Flos)and Shanyinhua(Lonicerae Flos)in mice with p-xylene-induced ear edema

目的比较金银花(LJF)和山银花(LF)体内整体多成分药代动力学(PPK)相似性或差异性,为临床用药提供参考。方法运用PPK模型及其总量统计矩相似性(TQSMS)方法比较LJF和LF中具有抗炎作用的9种成分(芦丁、咖啡酸、绿原酸、隐绿原酸、川续断皂苷乙、灰毡毛忍冬皂苷乙、异绿原酸A、异绿原酸B和异绿原酸C)整体PPK特征。54只无特定病原体级(SPF)昆明(KM)小鼠分为2组(n=27),每组根据不同测试时间点分为9个亚组(n=3)。随后口服给予LJF或LF并复制对二甲苯耳肿胀模型小鼠。通过超高效液相色谱/四极杆飞行时间质谱(UPLC-QTOF-MS/MS)测定血浆中9种成分浓度。由药物与统计(DAS)软件分析获得单成分药代动力学(PK)参数,并由自编Excel程序分析获得多成分整体PPK参数[总量统计矩(TQSM)参数和TQSMS]。结果LJF与LF单成分PK参数存在显著差异(P<0.05),而多成分TQSM参数无显著差异,包括总量零阶矩(AUCT0-t,AUCT0-∞)和总量一阶矩(MRTT0-t,MRTT0-∞)(P>0.05)。相应地,单成分TQSMS为0.2204–0.9689,而9种成分整体TQSMS为0.8284,表明LJF和LF生物利用的速度和程度没有显著差异。此外,TQSMS(0.8284)较大,表明LJF和LF 9种抗炎成分整体PPK特征在90%置信区间下相似。结论PPK模型及其TQSMS方法可能是比较多成分中药整体PPK相似性或差异性的一种合适且有效方法。本研究表明金银花和山银花临床治疗炎症时可替代使用。

Objective To reveal the integral in vivo polypharmacokinetics(PPK)similarity or difference between Jinyinhua(Lonicerae Japonicae Flos,LJF)and Shanyinhua(Lonicerae Flos,LF),and provide reference for their clinical application.Methods The PPK model and its total quantum statistical moment similarity(TQSMS)method were used to compare the integral PPK profiles of nine components with anti-inflammatory efficacy(rutin,caffeic acid,chlorogenic acid,cryptochlorogenic acid,dispsacoside B,macranthoidin B,isochlorogenic acid A,isochlorogenic acid B,and isochlorogenic acid C)of LJF and LF.A total of 54 Specific Pathogen Free(SPF)grade Kunming(KM)mice were randomized into LJF group and LF group(n=27),and each group was divided into nine subgroups(n=3)according to different time points.Subsequently,mice model of p-xylene-induced ear edema was constructed by oral administration of LJF and LF.The concentrations of the nine anti-inflammatory components in plasma samples of the mice were determined by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry(UPLC-QTOF-MS/MS).And the pharmacokinetics(PK)parameters of single component and the integral PPK parameters[total quantum statistical moment(TQSM)and TQSMS]of multiple components were calculated by Drug And Statistics(DAS)software and home-brew programs with Excel,respectively.Results There were significant differences in single-component PK parameters between LJF and LF(P<0.05).Whereas,no significant differences were found in multi-component TQSM parameters,including total quantum zero moment(AUCT0-t,AUCT0-∞)and total quantum first moment(MRTT0-t,MRTT0-∞)for the total quanta(P>0.05).Accordingly,single-component TQSMS varied from 0.2204 to 0.9689,and that for the total quanta was 0.8284,suggesting no significant differences in the speed and extent of bioavailability between LJF and LF.Furthermore,in light of high TQSMS(0.8284),the integral PPK profiles of the nine anti-inflammatory components of LJF and LF were similar under 90%confidence intervals.Conclusion The PPK model and its TQSMS method are appropriate and efficient to compare the similarity or difference of integral PPK profiles of multi-component herbal medicines.It is suggested in this research that LJF can be replaced with LF or vice versa for anti-inflammatory treatment.