麻黄汤有效组分配伍在发热大鼠体内的药动学研究
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摘要
该研究以注射干酵母制备大鼠发热模型,灌胃给予麻黄汤组方药味主要有效组分(麻黄总生物碱、桂枝挥发油、苦杏仁苷、甘草总黄酮+甘草总皂苷)正交剂量配比不同的9个组方,然后运用LC-MS方法测定麻黄汤7种主要有效成分(盐酸麻黄碱、盐酸伪麻黄碱、盐酸甲基麻黄碱、桂皮酸、苦杏仁苷、甘草苷以及甘草酸)在不同时间点的血药浓度。在非房室模型拟合药动学参数的基础上,计算总量零阶距AUCt和总量一阶距MRTt,探讨配伍对总量统计矩参数的影响。结果显示麻黄汤有效组分正交配伍给药后,7种有效成分在发热大鼠体内的药代动力学特征存在差异。正交分析说明不同配伍组分对总量统计矩参数有不同的影响,麻黄汤各组分对AUCt的贡献率大小依次为:麻黄总生物碱>桂枝挥发油>苦杏仁苷>甘草总黄酮+甘草总皂苷,而对MRTt的贡献率大小依次为:麻黄总生物碱>甘草总黄酮+甘草总皂苷>苦杏仁苷>桂枝挥发油,其中麻黄总生物碱对两者的影响均最为显著。各组分对AUCt的最优组合为A_3B_3C_2D_1,对MRTt的最优配伍为A_1B_1C_1D_1。
In the present paper,after the febrile rat model was prepared by injecting yeast,orthogonally compatible effective components from prescription drugs of Mahuang Decoction( Ephedra sinica total alkaloids,Cinnamomum cassia essential oil,amygdalin,Glycyrrhiza uralensis total flavonoids+G. uralensis total saponins) with nine different dosage ratios were given by gavage administration.The plasma concentrations of main active ingredients including ephedrine hydrochloride,pseudoephedrine hydrochloride,methylephedrine hydrochloride,cinnamic acid,amygdalin,liquritin and glycyrrhizin at different time points were analyzed by liquid chromatograph mass spectrometer( LC-MS). Based on the pharmacokinetic parameters of non-compartmental model,the area under curve of total quantum( AUCt) and the mean chromatographic retention time of total quantum( MRTt) were further calculated,in order to evaluate the effect of compatibility on the total statistical moment parameters. The results showed that the pharmacokinetic characteristics of main active components in febrile rats were significantly different after treatment with orthogonally compatibility of E. sinica total alkaloids,C.cassia essential oil,amygdalin,G. uralensis total flavonoids and G. uralensis total saponins. Orthogonal analysis confirmed that different compatibility components had different effects on the total statistical moment parameters. The contribution of effective components of Mahuang Decoction to AUCtwas as follows in a descending order: E. sinica total alkaloids>C. cassia essential oil>amygdalin>G. uralensis total flavonoids+G. uralensis total saponin,while the contribution to MRTtwas: E. sinica total alkaloids >G. uralensis total flavonoids+G. uralensis total saponin>amygdalin>C. cassia essential oil. The E. sinica total alkaloid had the greatest effects on both of the above parameters,and the optimal combination was A_3B_3C_2D_1 for AUCt,and A_1B_1C_1D_1 for MRTt.
In the present paper,after the febrile rat model was prepared by injecting yeast,orthogonally compatible effective components from prescription drugs of Mahuang Decoction( Ephedra sinica total alkaloids,Cinnamomum cassia essential oil,amygdalin,Glycyrrhiza uralensis total flavonoids+G. uralensis total saponins) with nine different dosage ratios were given by gavage administration.The plasma concentrations of main active ingredients including ephedrine hydrochloride,pseudoephedrine hydrochloride,methylephedrine hydrochloride,cinnamic acid,amygdalin,liquritin and glycyrrhizin at different time points were analyzed by liquid chromatograph mass spectrometer( LC-MS). Based on the pharmacokinetic parameters of non-compartmental model,the area under curve of total quantum( AUCt) and the mean chromatographic retention time of total quantum( MRTt) were further calculated,in order to evaluate the effect of compatibility on the total statistical moment parameters. The results showed that the pharmacokinetic characteristics of main active components in febrile rats were significantly different after treatment with orthogonally compatibility of E. sinica total alkaloids,C.cassia essential oil,amygdalin,G. uralensis total flavonoids and G. uralensis total saponins. Orthogonal analysis confirmed that different compatibility components had different effects on the total statistical moment parameters. The contribution of effective components of Mahuang Decoction to AUCtwas as follows in a descending order: E. sinica total alkaloids>C. cassia essential oil>amygdalin>G. uralensis total flavonoids+G. uralensis total saponin,while the contribution to MRTtwas: E. sinica total alkaloids >G. uralensis total flavonoids+G. uralensis total saponin>amygdalin>C. cassia essential oil. The E. sinica total alkaloid had the greatest effects on both of the above parameters,and the optimal combination was A_3B_3C_2D_1 for AUCt,and A_1B_1C_1D_1 for MRTt.
引文
[1]林祝山,刘宇聪,林晓春,等.麻黄汤超微饮片与传统饮片药效学剂量对比研究[J].时珍国医国药,2013,24(11):2667.
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[6]郑孟凯,何昱,万海同,等.响应面法优化大孔树脂纯化麻黄总生物碱的工艺研究[J].中华中医药杂志,2015,30(6):2079.
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[10]刘蓉,何婷,曾南,等.桂枝挥发油及桂皮醛抗流感病毒的机制研究[J].中草药,2013,44(11):1460.
[11]王彬辉,章文红,张晓芬,等.苦杏仁苷提取工艺及药理作用研究新进展[J].中华中医药学刊,2014,32(2):381.
[12]周开放,黄刚,肖雄,等.麻黄-苦杏仁药对减轻大鼠气道损伤的物质基础及作用机制分析[J].中国实验方剂学杂志,2018,24(19):172.
[13]冯月,吴文夫,魏建华,等.甘草酸及甘草苷的提取纯化方法和药理作用研究进展[J].人参研究,2012(3):46.
[14]邓康颖,谭晓梅,罗佳波.一种苦杏仁苷提取物的制备方法[J].中华中医药学刊,2010,28(10):2172.
[15]田彦芳,万海同,朱紫烨,等.基于熵权法的多目标筛选甘草黄酮类成分纯化工艺[J].中草药,2016,47(7):1118.
[16] Tang Y H,Zheng M K,Chen Y L,et al. Pharmacokinetic effects of cinnamic acid,amygdalin,glycyrrhizic acid and liquiritin on Ephedra alkaloids in rats[J]. Eur J Drug Metab Pharmacokinet,2017,42(3):527.
[17] Wang J W,Chiang M H,Lu C M,et al. Determination the active compounds of herbal preparation by UHPLC-MS/MS and its application on the preclinical pharmacokinetics of pure ephedrine,single herbal extract of Ephedra,and a multiple herbal preparation in rats[J]. J Chromatogr B,2016,1026(7):152.
[18] Wei P,Huo H L,Ma Q H,et al. Pharmacokinetic comparisons of five ephedrine alkaloids following oral administration of four different Mahuang-Guizhi herb-pair aqueous extracts ratios in rats[J]. J Ethnopharmacol,2014,155(1):642.
[19]苏春萌,唐嘉熙,罗阳,等.柴胡注射液解热作用的谱-效关系研究[J].中国药房,2016,27(10):1340.
[20]吴永丽.加减白虎汤对酵母引起大鼠发热的解热作用研究[D].长春:吉林大学,2016.
[21]彭珑.基于清开灵注射液解热作用的PK-PD结合模型研究[D].北京:北京中医药大学,2014.
[22]徐文杰,方芳,余林中,等.麻黄桂枝药对解热作用及其机制的实验研究[J].时珍国医国药,2013,24(7):1547.
[23]郭莹,杨洁红,张恒义,等.统计矩法评价养阴通脑颗粒各有效部位配伍在脑缺血再灌大鼠中的药动学变化[J].中国中药杂志,2010,35(4):493.
[24]周惠芬,何昱,艾进超,等.丹红注射液主要有效成分配伍在脑缺血再灌注大鼠体内的药动学研究[J].中草药,2016,47(20):3656.
[25]邓常清.中药复方有效组分研究的思路与实践[J].中西医结合学报,2010,8(12):1107.
[26]柯敏,李居怡,刘新国,等.中药复方有效部位群与创新药物的研究[J].时珍国医国药,2013,24(4):920.
[27]肖美凤,段晓鹏,邓凯文,等.动态中药成分群的谱动学数学模型创立及对补阳还五汤验证研究[J].中国中药杂志,2019,44(3):574.
[2]陈燕.麻黄汤中麻黄生物碱体内代谢排泄的研究[D].广州:第一军医大学,2007.
[3]王晶波,李竹英,王雪慧.麻黄汤的临床应用[J].中国民族民间医药,2011,23(10):57.
[4]张保国,刘庆芳.麻黄汤现代药效学研究与临床运用[J].中成药,2007,29(3):415.
[5]贺丰,罗佳波.麻黄汤中臣佐使药对君药中伪麻黄碱的人体药代学的影响[J].中国中药杂志,2005,30(18):1454.
[6]郑孟凯,何昱,万海同,等.响应面法优化大孔树脂纯化麻黄总生物碱的工艺研究[J].中华中医药杂志,2015,30(6):2079.
[7]丁丽丽,施松善,崔健,等.麻黄化学成分与药理作用研究进展[J].中国中药杂志,2006,31(20):1661.
[8]杨学,彭文博,岳小强.《伤寒论》太阳病篇证治规律研究[J].中西医结合学报,2009,7(2):171.
[9]沈映君.中药药理学[M].北京:人民卫生出版社,2011.
[10]刘蓉,何婷,曾南,等.桂枝挥发油及桂皮醛抗流感病毒的机制研究[J].中草药,2013,44(11):1460.
[11]王彬辉,章文红,张晓芬,等.苦杏仁苷提取工艺及药理作用研究新进展[J].中华中医药学刊,2014,32(2):381.
[12]周开放,黄刚,肖雄,等.麻黄-苦杏仁药对减轻大鼠气道损伤的物质基础及作用机制分析[J].中国实验方剂学杂志,2018,24(19):172.
[13]冯月,吴文夫,魏建华,等.甘草酸及甘草苷的提取纯化方法和药理作用研究进展[J].人参研究,2012(3):46.
[14]邓康颖,谭晓梅,罗佳波.一种苦杏仁苷提取物的制备方法[J].中华中医药学刊,2010,28(10):2172.
[15]田彦芳,万海同,朱紫烨,等.基于熵权法的多目标筛选甘草黄酮类成分纯化工艺[J].中草药,2016,47(7):1118.
[16] Tang Y H,Zheng M K,Chen Y L,et al. Pharmacokinetic effects of cinnamic acid,amygdalin,glycyrrhizic acid and liquiritin on Ephedra alkaloids in rats[J]. Eur J Drug Metab Pharmacokinet,2017,42(3):527.
[17] Wang J W,Chiang M H,Lu C M,et al. Determination the active compounds of herbal preparation by UHPLC-MS/MS and its application on the preclinical pharmacokinetics of pure ephedrine,single herbal extract of Ephedra,and a multiple herbal preparation in rats[J]. J Chromatogr B,2016,1026(7):152.
[18] Wei P,Huo H L,Ma Q H,et al. Pharmacokinetic comparisons of five ephedrine alkaloids following oral administration of four different Mahuang-Guizhi herb-pair aqueous extracts ratios in rats[J]. J Ethnopharmacol,2014,155(1):642.
[19]苏春萌,唐嘉熙,罗阳,等.柴胡注射液解热作用的谱-效关系研究[J].中国药房,2016,27(10):1340.
[20]吴永丽.加减白虎汤对酵母引起大鼠发热的解热作用研究[D].长春:吉林大学,2016.
[21]彭珑.基于清开灵注射液解热作用的PK-PD结合模型研究[D].北京:北京中医药大学,2014.
[22]徐文杰,方芳,余林中,等.麻黄桂枝药对解热作用及其机制的实验研究[J].时珍国医国药,2013,24(7):1547.
[23]郭莹,杨洁红,张恒义,等.统计矩法评价养阴通脑颗粒各有效部位配伍在脑缺血再灌大鼠中的药动学变化[J].中国中药杂志,2010,35(4):493.
[24]周惠芬,何昱,艾进超,等.丹红注射液主要有效成分配伍在脑缺血再灌注大鼠体内的药动学研究[J].中草药,2016,47(20):3656.
[25]邓常清.中药复方有效组分研究的思路与实践[J].中西医结合学报,2010,8(12):1107.
[26]柯敏,李居怡,刘新国,等.中药复方有效部位群与创新药物的研究[J].时珍国医国药,2013,24(4):920.
[27]肖美凤,段晓鹏,邓凯文,等.动态中药成分群的谱动学数学模型创立及对补阳还五汤验证研究[J].中国中药杂志,2019,44(3):574.