甘草与大黄配伍主要化学成分在体外及体内相互作用研究
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摘要
大黄是一味常用的重要中药,始载于《神农本草经》,其药用历史悠久,功效独特,有黄良、将军、川军等名。美国学者诺尔曼·泰勒在《改变世界的植物》一书中,将大黄列为有全球影响的十几种传统药物之一。大黄性寒、味苦,具有攻积导滞、泻火、凉血、活血祛瘀、利胆退黄等功效。
甘草是我国的常用中药,自古甘草入药组方较多。南朝医学家陶景弘说:“此草最为众药之王,经方少有不用者”,故有“十方九草”之说,尊称“国老”。东汉张仲景的《伤寒杂病论》中记载了256首处方,其中含有甘草的处方就有154首,占总处方数的60%以上。所以各药与甘草配伍的中药组方相当广泛,可见甘草的重要。
大黄甘草汤出自张仲景的《金匮要略》,该方原治实热积滞胃肠,食已即吐,大便秘结者,沿用至今,并被日本等国广泛采用,主治便秘。大黄通便,甘草润燥缓急,助大黄通滞泻下而不伤正。大黄甘草汤为中药复方中最简单的配伍之一,是研究中药复方化学成分中甘草与大黄配伍时其中主要成分在体内外的相互作用的代表性和理想的模型。
目的通过实验研究大黄甘草汤中大黄与甘草的主要化学成分在体外体内的相互作用,为临床合理应用含大黄与甘草的组方奠定基础。方法测定大黄甘草汤单煎、合煎两种方法中大黄蒽醌和甘草酸的含量。按处方比例准确称取大黄4g,甘草1g待用。于圆底烧瓶中加入药材量20倍的水加热至沸,下甘草,回流提取15min后,下大黄,再回流提取25min后离心,即得大黄甘草汤合煎液。准确称取大黄4g,甘草2g,按上述方法操作,即得大黄甘草汤4︰2合煎液。准确称取大黄4g,甘草4g,按上述方法操作,即得大黄甘草汤4︰4合煎液。准确称取大黄4g,甘草6g,按上述方法操作,即得大黄甘草汤4︰6合煎液。游离蒽醌的提取,精密量取各煎液5mL于圆底烧瓶中,加水10mL,混匀,加氯仿水浴回流3次,分取氯仿层,合并氯仿提取液,水浴蒸干溶剂,残渣用适量甲醇溶解于10mL量瓶中,加甲醇至刻度,摇匀,作为游离蒽醌含量测定供试品溶液。总蒽醌的提取,精密量取大黄提取液5mL于圆底烧瓶中,加水10 mL、盐酸2mL,混匀,加氯仿水浴回流提取3次(使结合蒽醌水解为游离蒽醌),分取氯仿层,合并氯仿提取液,水浴蒸干溶剂,残渣用适量甲醇溶解于10mL量瓶中,加甲醇至刻度,摇匀,作为总蒽醌含量测定供试品溶液。在色谱柱Angilent公司Zorbox SB C18(150 mm×4.6 mm),流动相为甲醇-水-冰乙酸(77︰22︰1),检测波长428 nm,流速1.0 ml/min,柱温室温的条件下测定大黄蒽醌包括游离蒽醌和结合蒽醌的含量。在色谱柱为迪马C18(250mm×416 mm),流动相为甲醇-水-冰乙酸(83.5︰15︰1.5),检测波长254 nm,流速1.0 ml/min,柱温室温的条件下测定甘草酸的含量。
建立高效液相色谱法测定大黄酸血浆样品中大黄酸含量,并进行精密度与回收率的实验。采用SD雄性大鼠50只,随机分成5组,分别大黄酸灌胃组(rh i.g.)、甘草酸灌胃诱导组(GL i.g.)、甘草酸静脉注射诱导组(GL i.v.)、甘草次酸灌胃诱导组(GA i.g.)、甘草次酸静脉注射诱导组(GA i.v.),每组10只,诱导期为7d,甘草酸(GL)及次酸(GA)剂量均为50mg/kg,实验前12h禁食不禁水。灌胃给药后在不同时间点测定各血浆样品中大黄酸浓度,利用3p97药代动力学软件进行房室模型的拟合并计算大黄酸药物代谢动力学参数AUC、Cmax、CL,比较各种处置条件下大黄酸在大鼠体内吸收的差异。结果大黄甘草汤提取20 min与60 min相比,蒽醌含量相当,但都比40 min的少,游离蒽醌少20%~40%,总蒽醌也少在10%以上,可见大黄煎煮5 min或太长(45min),蒽醌含量都很低,只有大黄甘草汤提取40 min,即大黄提取25 min时,游离蒽醌和总蒽醌的含量都是最高的。且甘草酸的量也是提取40 min时是最高的。
大黄单煎及大黄甘草4︰1、4︰2、4︰4和4︰6比例配伍后,总蒽醌类化合物煎出量变化不明显,为1.54、1.44、1.69、1.50和1.86 mg/g,基本保持恒定。但在合煎液中结合型蒽醌的含量0.83、1.09、1.11除4︰4配比外都比单煎的0.75 mg/g要高,而游离型蒽醌的含量0.60、0.58、0.76、0.72 mg/g都比单煎0.78mg/g要低。大黄与不同比例甘草合煎后,甘草酸的煎出量在合煎液中均比单煎液中高,甘草1g单煎(6.88mg/g),合煎4︰1(18.13mg/g);甘草2g单煎(8.34mg/g),合煎4︰2(14.65mg/g);甘草4g单煎(7.22mg/g),合煎4︰4(10.83mg/g);甘草6g单煎(8.99mg/g),合煎4︰6(10.80mg/g)。在经典方剂中大黄与甘草4︰1配伍时,甘草酸的煎出量是单煎时的2.6倍。
GL灌胃诱导组、GL静脉注射诱导组、GA灌胃诱导组、GA静脉注射诱导组与rh灌胃组不论在AUC、Cmax还是CL这些药动学参数上对大黄酸均P<0.01,具有统计学意义,显著降低了大黄酸的生物利用度,清除率明显提高,加快了机体对大黄酸的代谢。
GA灌胃诱导组与GL灌胃诱导组相比,GA灌胃诱导组AUC、Cmax明显降低而CL明显提高,P<0.01说明GA灌胃诱导组比GL灌胃诱导组对大黄酸的代谢作用更强。GA静脉注射诱导组与GL静脉注射诱导组相比,AUC、Cmax明显降低而CL明显提高,P<0.01。说明
GA静脉注射诱导组比GL静脉注射诱导组对大黄酸的代谢作用更强。GA在灌胃诱导和静脉注射诱导条件下,GA静脉注射诱导组对大黄酸的抑制能力更强。除Cmax外,AUC明显减小,而CL明显增大,P<0.01。说明在静脉注射条件下,甘草次酸对大黄酸的抑制更强。
GL在灌胃诱导和静脉注射诱导条件下,GL静脉注射诱导组对大黄酸的抑制能力更强。除Cmax外,AUC明显减小,而CL明显增大,P<0.01。说明在静脉注射条件下,甘草酸对大黄酸的抑制更强。结论甘草与大黄配伍主要化学成分甘草酸和大黄酸在体外及体内均存在相互作用,在体外甘草酸抑制了大黄酸的溶出。在大鼠体内,甘草酸及其代谢产物均加快了大黄酸的代谢,诱导肝药酶P450,而且甘草酸的代谢产物甘草次酸对大黄酸的抑制超过了甘草酸。
Rhubarb is wideiy used as an important traditional Chinese medicine, comes from“Shen Nong Ben Cao Jing”first. It is a long story science rhubarb been used as a very effects medicine, and also byname of Huangliang, Jiangjun and chuanjun. American scholar Norman Taylor defined rhubarb as one of a dozen of traditional medicines which have global implications in "change the world of plants".Rhubarb is cold-natured,bitter in taste,It can purging pathogenic fire, cooling blood and have effects of promoting blood flow and removing stasis and so on.
Licorice is a widely used traditional Chinese medicine, being used as medicine since ancient times. As Taojinghong who is one of Southern physicians said:“Licorice is the king of all the traditional medicine, is rarely not be used as one medicine in prescriptions.”So there is a saying“Shi Yao Jiu Cao”, and be honored as“GuoLao”.There are 256 prescriptions in“Shang Han Za Bing Lun”written by Zhang Zhongjing.There are 154 prescriptions in the 256 prescription, account for 60% in all the prescriptions.So we can see the importance of licorice.
The prescription named Decoction of Rhubarb and Licorice comes from“Jin Kui Yao Lue”written by Zhang Zhongjing. It originally treats dyspeptic disease、emesis and constipation ,which caused by sthenic fever according to basis of theory of traditional chinese medicine. With following and developing,the prescription,applied extensively in our country and abroad. Rhubarb purge, meantime licorice can relieve the strong reaction. Decoction of Rhubarb and Licorice is one of the most simple prescriptions.It is a representation and the ideal model on study on the main chemical components of Licorice and Rhubarb’s In vitro and In vivo Interaction. Objective study on the main chemical components of Licorice and Rhubarb’s In vitro and In vivo Interaction through experiments, To lay the foundation for the clinical use of prescriptions contain rhubarb and licorice. Methods Determine the contents of anthraquinone of rhubarb and glycyrrhizic acid between individual and combination Decoctions. Accurate weighting rhubarb 4g, licorice 1g according to the proportion of priscription. Round bottom flask at 20 times the amount of added ingredients of water heated to boiling, add glycyrrhiza, reflux extraction 15min, add the rhubarb, then reflux extraction 25min and then centrifugation, which combination decoctions is done. According to the above method prepare the combination decoctions in proportion as 4︰2, 4︰4 and 4︰6. Extraction of anthraquinones, to measure precisely 5mL in each decoction in round bottom flask, add water 10mL, mix,then add chloroform and reflux extraction three times, take the chloroform layer, combined chloroform extract, solvent bath evaporation to dryness, residue dissolved with appropriate methanol in a 10 mL flask, add methanol to the mark, shake, as the sample of nomadic anthraquinones Determination solution. Extraction of total anthraquinone, to measure precisely 5mL of extraction of rhubarb and put in round bottom flask,add water 10 mL , add hydrochloric acid 2 mL, mix, add chloroform and reflux extraction three times, take the chloroform layer, combined chloroform extract, solvent bath evaporation to dryness, residue dissolved with appropriate methanol in a 10 mL flask, add methanol to the mark, shake, as the sample of total anthraquinones Determination solution. Determination the content of nomadic and total anthraquinone with HPLC under Zorbox SB C18(150 mm×4.6 mm ) , methanol-water- glacial acetic acid ( 77︰ 22︰1),428nm,1.0ml/min, room-temperature. Determination the content of glycyrrhizic acid with HPLC under DIKMA C18(250mm×416 mm), methanol-water- glacial acetic acid(83.5︰15︰1.5), 254 nm,1.0ml/min, room-temperature.
Establish the high performance liquid chromatography of plasma samples for Rhein content, and make precision and recovery experiments.With 50 male rats, randomly divided into 5 groups, as rh i.g. , GL i.g. , GL i.v. , GA i.g. , GA i.v.,10 rats in each group, 7d of induction period, dosage of GL and GA are all 50mg/kg, 12h before the experiment can not help but water fasting. After oral administration were measured at different time points of rhein concentration in plasma samples using the 3p97 pharmacokinetic compartment model of the proposed software combined Rhein pharmacokinetic parameters AUC, Cmax, CL, comparing disposal rhein under different absorption in rats.
Result Decoction of Rhubarb and Licorice extract compared to 20 min and 60min, anthraquinone content is about, but less than 40min, nomadic anthraquinones less 20% to 40%,total anthraquinones are less than 10%, that rhubarb decoction 5 min or too long (45min), Anthraquinone content was very low, only Rhubarb Decoction extract 40 min, 25 min when the rhubarb extract, nomadic anthraquinone and total anthraquinones are the highest. And the amount of glycyrrhizin extracted 40 min, also the highest.
Rhubarb decoction and Decoction of Rhubarb and Licorice with 4︰1、4︰2、4︰4 and 4︰6, the total anthraquinone decocted quantity did not change significantly,as 1.54、1.44、1.69、1.50 and 1.86 mg/g,but bound anthraquinones of decoction as 0.83、1.09、1.11 are all higher than rhubarb decoction 0.75 mg/g,except decoction of rhubarb and licorice with 4︰4, while the content of nomadic anthraquinones 0.60、0.58、0.76、0.72 mg/g are lower than rhubarb decoction 0.78mg/g. Rhubarb and licorice decoction by different ratio, the amount of glycyrrhizic acid are higher than licorice decoction . Licorice decoction of 1g (6.88mg/g)compare to decoction of rhubarb and licorice 4︰1 (18.13mg/g ); licorice decoction of 2g( 8.34mg/g ) compare to decoction of rhubarb and licorice 4︰ 2(14.65mg/g); licorice decoction of 4g(7.22mg/g)compare to decoction of rhubarb and licorice 4︰4(10.83mg/g); licorice decoction of 6g ( 8.99mg/g ) compare to decoction of rhubarb and licorice 4︰ 6(10.80mg/g). In the classic decoction of rhubarb and licorice 4︰ 1, the amount of glycyrrhizic acid is 2.6 times higher than licorice decoction.
GL i.g., GL i.v., GA i.g., GA i.v. vs rh i.g. in terms of AUC, Cmax or CL of these on the pharmacokinetic parameters of rhein were P<0.01, statistically significant, significantly reduced the bioavailability of Rhein, clearance rate was significantly increased to speed up the metabolism of the body of the Rhein.
GA i.g. compared with the GL i.g., GA i.g. group AUC, Cmax decreased significantly,the CL increased, P<0.01 Description GA i.g. group than GL i.g .group on the metabolism of rhein more. GA i.v. group compared with the GL i.v., AUC, Cmax decreased significantly and CL increased, P<0.01. GA i.v. group than GL i.v. group on the metabolism of rhein more.
GA induced by oral administration and intravenous injection in inducing conditions, GA intravenous induction group more capable of rhein inhibition. AUC significantly reduced, while the CL increased significantly, P<0.01,except Cmax. Indicate on the condition of intravenous injection, glycyrrhetinic acid on the inhibition of rhein more.
GL induced by oral administration and intravenous induction under inducing conditions, GL intravenous induction group more capable of rhein inhibition. AUC significantly reduced, while the CL increased significantly, P<0.01, except Cmax. Indicate on the condition of intravenous injection, glycyrrhizic acid on the inhibition of rhein more
Conclusion Licorice and rhubarb combined with the main chemical ingredient glycyrrhizin and Rhein both act interaction in vitro and in vivo interaction, in vitro glycyrrhizin inhibited the synthesis of rhein. In rats, glycyrrhizic acid and its metabolites act as inducers of hepatic drug metabolizing enzyme P450, rhein accelerated the metabolism of glycyrrhizin and glycyrrhetinic acid metabolites of rhein inhibition on more than glycyrrhizin.
甘草是我国的常用中药,自古甘草入药组方较多。南朝医学家陶景弘说:“此草最为众药之王,经方少有不用者”,故有“十方九草”之说,尊称“国老”。东汉张仲景的《伤寒杂病论》中记载了256首处方,其中含有甘草的处方就有154首,占总处方数的60%以上。所以各药与甘草配伍的中药组方相当广泛,可见甘草的重要。
大黄甘草汤出自张仲景的《金匮要略》,该方原治实热积滞胃肠,食已即吐,大便秘结者,沿用至今,并被日本等国广泛采用,主治便秘。大黄通便,甘草润燥缓急,助大黄通滞泻下而不伤正。大黄甘草汤为中药复方中最简单的配伍之一,是研究中药复方化学成分中甘草与大黄配伍时其中主要成分在体内外的相互作用的代表性和理想的模型。
目的通过实验研究大黄甘草汤中大黄与甘草的主要化学成分在体外体内的相互作用,为临床合理应用含大黄与甘草的组方奠定基础。方法测定大黄甘草汤单煎、合煎两种方法中大黄蒽醌和甘草酸的含量。按处方比例准确称取大黄4g,甘草1g待用。于圆底烧瓶中加入药材量20倍的水加热至沸,下甘草,回流提取15min后,下大黄,再回流提取25min后离心,即得大黄甘草汤合煎液。准确称取大黄4g,甘草2g,按上述方法操作,即得大黄甘草汤4︰2合煎液。准确称取大黄4g,甘草4g,按上述方法操作,即得大黄甘草汤4︰4合煎液。准确称取大黄4g,甘草6g,按上述方法操作,即得大黄甘草汤4︰6合煎液。游离蒽醌的提取,精密量取各煎液5mL于圆底烧瓶中,加水10mL,混匀,加氯仿水浴回流3次,分取氯仿层,合并氯仿提取液,水浴蒸干溶剂,残渣用适量甲醇溶解于10mL量瓶中,加甲醇至刻度,摇匀,作为游离蒽醌含量测定供试品溶液。总蒽醌的提取,精密量取大黄提取液5mL于圆底烧瓶中,加水10 mL、盐酸2mL,混匀,加氯仿水浴回流提取3次(使结合蒽醌水解为游离蒽醌),分取氯仿层,合并氯仿提取液,水浴蒸干溶剂,残渣用适量甲醇溶解于10mL量瓶中,加甲醇至刻度,摇匀,作为总蒽醌含量测定供试品溶液。在色谱柱Angilent公司Zorbox SB C18(150 mm×4.6 mm),流动相为甲醇-水-冰乙酸(77︰22︰1),检测波长428 nm,流速1.0 ml/min,柱温室温的条件下测定大黄蒽醌包括游离蒽醌和结合蒽醌的含量。在色谱柱为迪马C18(250mm×416 mm),流动相为甲醇-水-冰乙酸(83.5︰15︰1.5),检测波长254 nm,流速1.0 ml/min,柱温室温的条件下测定甘草酸的含量。
建立高效液相色谱法测定大黄酸血浆样品中大黄酸含量,并进行精密度与回收率的实验。采用SD雄性大鼠50只,随机分成5组,分别大黄酸灌胃组(rh i.g.)、甘草酸灌胃诱导组(GL i.g.)、甘草酸静脉注射诱导组(GL i.v.)、甘草次酸灌胃诱导组(GA i.g.)、甘草次酸静脉注射诱导组(GA i.v.),每组10只,诱导期为7d,甘草酸(GL)及次酸(GA)剂量均为50mg/kg,实验前12h禁食不禁水。灌胃给药后在不同时间点测定各血浆样品中大黄酸浓度,利用3p97药代动力学软件进行房室模型的拟合并计算大黄酸药物代谢动力学参数AUC、Cmax、CL,比较各种处置条件下大黄酸在大鼠体内吸收的差异。结果大黄甘草汤提取20 min与60 min相比,蒽醌含量相当,但都比40 min的少,游离蒽醌少20%~40%,总蒽醌也少在10%以上,可见大黄煎煮5 min或太长(45min),蒽醌含量都很低,只有大黄甘草汤提取40 min,即大黄提取25 min时,游离蒽醌和总蒽醌的含量都是最高的。且甘草酸的量也是提取40 min时是最高的。
大黄单煎及大黄甘草4︰1、4︰2、4︰4和4︰6比例配伍后,总蒽醌类化合物煎出量变化不明显,为1.54、1.44、1.69、1.50和1.86 mg/g,基本保持恒定。但在合煎液中结合型蒽醌的含量0.83、1.09、1.11除4︰4配比外都比单煎的0.75 mg/g要高,而游离型蒽醌的含量0.60、0.58、0.76、0.72 mg/g都比单煎0.78mg/g要低。大黄与不同比例甘草合煎后,甘草酸的煎出量在合煎液中均比单煎液中高,甘草1g单煎(6.88mg/g),合煎4︰1(18.13mg/g);甘草2g单煎(8.34mg/g),合煎4︰2(14.65mg/g);甘草4g单煎(7.22mg/g),合煎4︰4(10.83mg/g);甘草6g单煎(8.99mg/g),合煎4︰6(10.80mg/g)。在经典方剂中大黄与甘草4︰1配伍时,甘草酸的煎出量是单煎时的2.6倍。
GL灌胃诱导组、GL静脉注射诱导组、GA灌胃诱导组、GA静脉注射诱导组与rh灌胃组不论在AUC、Cmax还是CL这些药动学参数上对大黄酸均P<0.01,具有统计学意义,显著降低了大黄酸的生物利用度,清除率明显提高,加快了机体对大黄酸的代谢。
GA灌胃诱导组与GL灌胃诱导组相比,GA灌胃诱导组AUC、Cmax明显降低而CL明显提高,P<0.01说明GA灌胃诱导组比GL灌胃诱导组对大黄酸的代谢作用更强。GA静脉注射诱导组与GL静脉注射诱导组相比,AUC、Cmax明显降低而CL明显提高,P<0.01。说明
GA静脉注射诱导组比GL静脉注射诱导组对大黄酸的代谢作用更强。GA在灌胃诱导和静脉注射诱导条件下,GA静脉注射诱导组对大黄酸的抑制能力更强。除Cmax外,AUC明显减小,而CL明显增大,P<0.01。说明在静脉注射条件下,甘草次酸对大黄酸的抑制更强。
GL在灌胃诱导和静脉注射诱导条件下,GL静脉注射诱导组对大黄酸的抑制能力更强。除Cmax外,AUC明显减小,而CL明显增大,P<0.01。说明在静脉注射条件下,甘草酸对大黄酸的抑制更强。结论甘草与大黄配伍主要化学成分甘草酸和大黄酸在体外及体内均存在相互作用,在体外甘草酸抑制了大黄酸的溶出。在大鼠体内,甘草酸及其代谢产物均加快了大黄酸的代谢,诱导肝药酶P450,而且甘草酸的代谢产物甘草次酸对大黄酸的抑制超过了甘草酸。
Rhubarb is wideiy used as an important traditional Chinese medicine, comes from“Shen Nong Ben Cao Jing”first. It is a long story science rhubarb been used as a very effects medicine, and also byname of Huangliang, Jiangjun and chuanjun. American scholar Norman Taylor defined rhubarb as one of a dozen of traditional medicines which have global implications in "change the world of plants".Rhubarb is cold-natured,bitter in taste,It can purging pathogenic fire, cooling blood and have effects of promoting blood flow and removing stasis and so on.
Licorice is a widely used traditional Chinese medicine, being used as medicine since ancient times. As Taojinghong who is one of Southern physicians said:“Licorice is the king of all the traditional medicine, is rarely not be used as one medicine in prescriptions.”So there is a saying“Shi Yao Jiu Cao”, and be honored as“GuoLao”.There are 256 prescriptions in“Shang Han Za Bing Lun”written by Zhang Zhongjing.There are 154 prescriptions in the 256 prescription, account for 60% in all the prescriptions.So we can see the importance of licorice.
The prescription named Decoction of Rhubarb and Licorice comes from“Jin Kui Yao Lue”written by Zhang Zhongjing. It originally treats dyspeptic disease、emesis and constipation ,which caused by sthenic fever according to basis of theory of traditional chinese medicine. With following and developing,the prescription,applied extensively in our country and abroad. Rhubarb purge, meantime licorice can relieve the strong reaction. Decoction of Rhubarb and Licorice is one of the most simple prescriptions.It is a representation and the ideal model on study on the main chemical components of Licorice and Rhubarb’s In vitro and In vivo Interaction. Objective study on the main chemical components of Licorice and Rhubarb’s In vitro and In vivo Interaction through experiments, To lay the foundation for the clinical use of prescriptions contain rhubarb and licorice. Methods Determine the contents of anthraquinone of rhubarb and glycyrrhizic acid between individual and combination Decoctions. Accurate weighting rhubarb 4g, licorice 1g according to the proportion of priscription. Round bottom flask at 20 times the amount of added ingredients of water heated to boiling, add glycyrrhiza, reflux extraction 15min, add the rhubarb, then reflux extraction 25min and then centrifugation, which combination decoctions is done. According to the above method prepare the combination decoctions in proportion as 4︰2, 4︰4 and 4︰6. Extraction of anthraquinones, to measure precisely 5mL in each decoction in round bottom flask, add water 10mL, mix,then add chloroform and reflux extraction three times, take the chloroform layer, combined chloroform extract, solvent bath evaporation to dryness, residue dissolved with appropriate methanol in a 10 mL flask, add methanol to the mark, shake, as the sample of nomadic anthraquinones Determination solution. Extraction of total anthraquinone, to measure precisely 5mL of extraction of rhubarb and put in round bottom flask,add water 10 mL , add hydrochloric acid 2 mL, mix, add chloroform and reflux extraction three times, take the chloroform layer, combined chloroform extract, solvent bath evaporation to dryness, residue dissolved with appropriate methanol in a 10 mL flask, add methanol to the mark, shake, as the sample of total anthraquinones Determination solution. Determination the content of nomadic and total anthraquinone with HPLC under Zorbox SB C18(150 mm×4.6 mm ) , methanol-water- glacial acetic acid ( 77︰ 22︰1),428nm,1.0ml/min, room-temperature. Determination the content of glycyrrhizic acid with HPLC under DIKMA C18(250mm×416 mm), methanol-water- glacial acetic acid(83.5︰15︰1.5), 254 nm,1.0ml/min, room-temperature.
Establish the high performance liquid chromatography of plasma samples for Rhein content, and make precision and recovery experiments.With 50 male rats, randomly divided into 5 groups, as rh i.g. , GL i.g. , GL i.v. , GA i.g. , GA i.v.,10 rats in each group, 7d of induction period, dosage of GL and GA are all 50mg/kg, 12h before the experiment can not help but water fasting. After oral administration were measured at different time points of rhein concentration in plasma samples using the 3p97 pharmacokinetic compartment model of the proposed software combined Rhein pharmacokinetic parameters AUC, Cmax, CL, comparing disposal rhein under different absorption in rats.
Result Decoction of Rhubarb and Licorice extract compared to 20 min and 60min, anthraquinone content is about, but less than 40min, nomadic anthraquinones less 20% to 40%,total anthraquinones are less than 10%, that rhubarb decoction 5 min or too long (45min), Anthraquinone content was very low, only Rhubarb Decoction extract 40 min, 25 min when the rhubarb extract, nomadic anthraquinone and total anthraquinones are the highest. And the amount of glycyrrhizin extracted 40 min, also the highest.
Rhubarb decoction and Decoction of Rhubarb and Licorice with 4︰1、4︰2、4︰4 and 4︰6, the total anthraquinone decocted quantity did not change significantly,as 1.54、1.44、1.69、1.50 and 1.86 mg/g,but bound anthraquinones of decoction as 0.83、1.09、1.11 are all higher than rhubarb decoction 0.75 mg/g,except decoction of rhubarb and licorice with 4︰4, while the content of nomadic anthraquinones 0.60、0.58、0.76、0.72 mg/g are lower than rhubarb decoction 0.78mg/g. Rhubarb and licorice decoction by different ratio, the amount of glycyrrhizic acid are higher than licorice decoction . Licorice decoction of 1g (6.88mg/g)compare to decoction of rhubarb and licorice 4︰1 (18.13mg/g ); licorice decoction of 2g( 8.34mg/g ) compare to decoction of rhubarb and licorice 4︰ 2(14.65mg/g); licorice decoction of 4g(7.22mg/g)compare to decoction of rhubarb and licorice 4︰4(10.83mg/g); licorice decoction of 6g ( 8.99mg/g ) compare to decoction of rhubarb and licorice 4︰ 6(10.80mg/g). In the classic decoction of rhubarb and licorice 4︰ 1, the amount of glycyrrhizic acid is 2.6 times higher than licorice decoction.
GL i.g., GL i.v., GA i.g., GA i.v. vs rh i.g. in terms of AUC, Cmax or CL of these on the pharmacokinetic parameters of rhein were P<0.01, statistically significant, significantly reduced the bioavailability of Rhein, clearance rate was significantly increased to speed up the metabolism of the body of the Rhein.
GA i.g. compared with the GL i.g., GA i.g. group AUC, Cmax decreased significantly,the CL increased, P<0.01 Description GA i.g. group than GL i.g .group on the metabolism of rhein more. GA i.v. group compared with the GL i.v., AUC, Cmax decreased significantly and CL increased, P<0.01. GA i.v. group than GL i.v. group on the metabolism of rhein more.
GA induced by oral administration and intravenous injection in inducing conditions, GA intravenous induction group more capable of rhein inhibition. AUC significantly reduced, while the CL increased significantly, P<0.01,except Cmax. Indicate on the condition of intravenous injection, glycyrrhetinic acid on the inhibition of rhein more.
GL induced by oral administration and intravenous induction under inducing conditions, GL intravenous induction group more capable of rhein inhibition. AUC significantly reduced, while the CL increased significantly, P<0.01, except Cmax. Indicate on the condition of intravenous injection, glycyrrhizic acid on the inhibition of rhein more
Conclusion Licorice and rhubarb combined with the main chemical ingredient glycyrrhizin and Rhein both act interaction in vitro and in vivo interaction, in vitro glycyrrhizin inhibited the synthesis of rhein. In rats, glycyrrhizic acid and its metabolites act as inducers of hepatic drug metabolizing enzyme P450, rhein accelerated the metabolism of glycyrrhizin and glycyrrhetinic acid metabolites of rhein inhibition on more than glycyrrhizin.
引文
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