八珍汤中主要化学成分在体肠吸收机制研究
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摘要
八珍汤收载于明代薛己的《正体类要》,具有悠久的历史,为补气方四君子汤和补血方四物汤的合方,在现代临床上有广泛的应用。中药复方具有疗效高、毒副作用小等优点且通过多途径、多靶点的整合调节作用发挥治疗作用,并逐渐引起医药工作者的重视。口服药物的肠道吸收作为药物发挥疗效的首要步骤,在医药研究中占有举足轻重的地位。为此,本文对单味药当归、川芎、“当归-川芎”药对及八珍汤中主要有效成分进行小肠吸收动力学研究。主要研究内容及结果如下：
(1)对当归、川芎及二者组成的药对中有效成分阿魏酸的肠吸收机制进行深入研究。阿魏酸的吸收量随浓度变化均呈现线性增长,但其各浓度吸收速率并无显著性变化,表明当归中阿魏酸的吸收符合一级动力学过程,推测其吸收过程为被动扩散,这也符合大多数药物的吸收特点；由于阿魏酸属于弱酸碱类成分,因此其吸收受环境pH值的影响,在酸性条件下易于被吸收；阿魏酸的吸收具有位置特异性,在胃中吸收显著优于其他肠段；实验选择了P-gp的诱导剂利福平和抑制剂维拉帕米分别与实验药品合用来证明阿魏酸是否受到该蛋白影响,结果显示阿魏酸的吸收受该蛋白影响,在今后的临床用药中,可以采用与P-gp抑制剂合用的方式提高当归中阿魏酸的生物利用度。
(2)对八珍汤中主要有效成分芍药苷及阿魏酸的肠吸收机制进行了详尽的分析。分别从浓度、pH值、肠段及P-糖蛋白4个方面对两者的吸收情况进行了研究。结果显示,八珍汤中芍药苷和阿魏酸随浓度变化均呈现良好的线性关系,方程分别为：Y=3.78X+1.1478(r=0.9974),Y=3.3485X+0.1457(r=0.9740),且其各浓度的吸收速率无显著性变化,表明八珍汤中芍药苷和阿魏酸的吸收均为一级动力学过程,推测为被动扩散过程；由于芍药苷属苷类成分,则其吸收不受环境pH值的影响,但阿魏酸的吸收受到环境pH值的影响,在酸性条件下易于被吸收；在吸收的位置选择性上,芍药苷无肠段吸收位置特异性,实现了整肠段的均匀吸收,而阿魏酸在胃中吸收最佳。另外,八珍汤样品液与P-gp的抑制剂和诱导剂合用时,芍药苷、阿魏酸的吸收表现出吸收量、吸收速率常数及累积吸收百分率都有明显的增加或减少,表明其吸收受糖蛋白的影响,因此推断其主要成分芍药苷、阿魏酸可能是P-gp的底物,故可与P-gp抑制剂合用以提高其药用价值。
(3)通过对复方八珍汤、“当归-川芎”药对及单味药当归、川芎中的阿魏酸吸收情况进行比较,发现相同浓度(以阿魏酸浓度为准)、pH值、吸收部位的样品溶液中,复方八珍汤组阿魏酸的Ka、吸收量、A%较其他组显著增大(P<0.05),同时t1/2显著减小(P<0.05)。得出,复方中阿魏酸的吸收在外部环境一致的条件下较药对及单味药中的阿魏酸吸收更佳。
The prescription of Bazhen Decoction originates from"Zheng Ti Lei Yao" written by Xue Ji. It is a Chinese traditional dosage which has a long history. It is the combination of Sijunzi and Siwu Decoction. Nowadays it is used generally in clinic, because it is representative prescription of invigorating vital energy and enriching the blood. Chinese herbal complex is high efficacy, low toxic side effects and by multi-channel and multi-target integration it play a regulating therapeutic role. So more and more specialists have paid attention to it. As a oral drug, the intestinal absorption which occupies an important position in medicine study is the first process to exert therapeutic effects, so my paper aimed at study the absorption mechanism. This paper study the absorption of the main components in Radix Angelica Sinensis, Ligusticum chuanxiong Hort, both of them and Bazhen Decoction in rat's intestines. The predominant content and result as followed:
(1) The experiment analyzed the absorption mechanism of Ferulic acid in Radix Angelica Sinensis、Ligusticum chuanxiong Hort、both of them. Uptake of Ferulic acid depends on concentration and varies linearly, but the absorption rate of different concentration do not changed remarkably It effected the absorption consistented with first order kinetics, infered the process of absorption is passively diffusion. On environmental pH aspect, because Ferulic acid belongs to composition of weak acid and alkalies, the absorption is affected by environmental pH. On the choice of intestinal segments, most of the Ferulic acid is absorbed by the stomach. In order to identify whether the absorption is effected by the P-gp, we corporate Ferulic acid with inducer-rifampicin or inhibitor-verapamil together. The result manifests the absorption is effected by the P-gp. In the future clinic, we can use the Ferulic acid and inducer-rifampicin together to increase the biological effective.
(2)The experiment analyzed the absorption mechanism of Peoniflorin and Ferulic acid in Bazhen Decoction. It is the same with Ferulic acid, the absorption of Peoniflorin and Ferulic acid in Bazhen Decoction are studied on four aspects such as concentration, pH, intestinal segments, P-gp. The absorption of Peoniflorin and Ferulic acid changed depend on concentration by linear relationship, the linear equations:Y=3.78X+1.1478(r=0.9974), Y=3.3485X+0.1457(r=0.9740). The absorption rate of different concentration do not changed remarkably, it reflected the absorption of Peoniflorin and Ferulic acid consistented with first order kinetics. It infered the process of absorption of Peoniflorin and Ferulic acid are passively diffusion. On pH aspects, the absorption of Peoniflorin is not affected by pH. On the absorption position, Ferulic acid in Bazhen Decoction the same as that in Radix Angelica Sinensis、Ligusticum chuanxiong Hort and both of them, the Ferulic acid absorption position in Bazhen Decoction is stomach too. Furthermore, we corporate Bazhen Decoction extact with inducer-rifampicin or inhibitor-verapamil together. The absorbed dose, Ka, absorption fraction and t1/2 of Peoniflorin and Ferulic acid have increased or decreased obviously. So we can include that Peoniflorin and Ferulic acid in Bazhen Decoction is affected by the P-gp, and in future clinic we can use with catastaltic of P-gp to increase its effective in Bazhen Decoction.
(3) By compare absorption of Ferulic acid in Radix Angelica Sinensis, Ligusticum chuanxiong Hort, both of them and Bazhen Decoction compound, we can gain the result that Ferulic acid in Bazhen Decoction compound are absorbed more on the aspects concentration, pH, intestinal segments than in others. So Bazhen Decoction compound exploitation is valuable.
(1)对当归、川芎及二者组成的药对中有效成分阿魏酸的肠吸收机制进行深入研究。阿魏酸的吸收量随浓度变化均呈现线性增长,但其各浓度吸收速率并无显著性变化,表明当归中阿魏酸的吸收符合一级动力学过程,推测其吸收过程为被动扩散,这也符合大多数药物的吸收特点；由于阿魏酸属于弱酸碱类成分,因此其吸收受环境pH值的影响,在酸性条件下易于被吸收；阿魏酸的吸收具有位置特异性,在胃中吸收显著优于其他肠段；实验选择了P-gp的诱导剂利福平和抑制剂维拉帕米分别与实验药品合用来证明阿魏酸是否受到该蛋白影响,结果显示阿魏酸的吸收受该蛋白影响,在今后的临床用药中,可以采用与P-gp抑制剂合用的方式提高当归中阿魏酸的生物利用度。
(2)对八珍汤中主要有效成分芍药苷及阿魏酸的肠吸收机制进行了详尽的分析。分别从浓度、pH值、肠段及P-糖蛋白4个方面对两者的吸收情况进行了研究。结果显示,八珍汤中芍药苷和阿魏酸随浓度变化均呈现良好的线性关系,方程分别为：Y=3.78X+1.1478(r=0.9974),Y=3.3485X+0.1457(r=0.9740),且其各浓度的吸收速率无显著性变化,表明八珍汤中芍药苷和阿魏酸的吸收均为一级动力学过程,推测为被动扩散过程；由于芍药苷属苷类成分,则其吸收不受环境pH值的影响,但阿魏酸的吸收受到环境pH值的影响,在酸性条件下易于被吸收；在吸收的位置选择性上,芍药苷无肠段吸收位置特异性,实现了整肠段的均匀吸收,而阿魏酸在胃中吸收最佳。另外,八珍汤样品液与P-gp的抑制剂和诱导剂合用时,芍药苷、阿魏酸的吸收表现出吸收量、吸收速率常数及累积吸收百分率都有明显的增加或减少,表明其吸收受糖蛋白的影响,因此推断其主要成分芍药苷、阿魏酸可能是P-gp的底物,故可与P-gp抑制剂合用以提高其药用价值。
(3)通过对复方八珍汤、“当归-川芎”药对及单味药当归、川芎中的阿魏酸吸收情况进行比较,发现相同浓度(以阿魏酸浓度为准)、pH值、吸收部位的样品溶液中,复方八珍汤组阿魏酸的Ka、吸收量、A%较其他组显著增大(P<0.05),同时t1/2显著减小(P<0.05)。得出,复方中阿魏酸的吸收在外部环境一致的条件下较药对及单味药中的阿魏酸吸收更佳。
The prescription of Bazhen Decoction originates from"Zheng Ti Lei Yao" written by Xue Ji. It is a Chinese traditional dosage which has a long history. It is the combination of Sijunzi and Siwu Decoction. Nowadays it is used generally in clinic, because it is representative prescription of invigorating vital energy and enriching the blood. Chinese herbal complex is high efficacy, low toxic side effects and by multi-channel and multi-target integration it play a regulating therapeutic role. So more and more specialists have paid attention to it. As a oral drug, the intestinal absorption which occupies an important position in medicine study is the first process to exert therapeutic effects, so my paper aimed at study the absorption mechanism. This paper study the absorption of the main components in Radix Angelica Sinensis, Ligusticum chuanxiong Hort, both of them and Bazhen Decoction in rat's intestines. The predominant content and result as followed:
(1) The experiment analyzed the absorption mechanism of Ferulic acid in Radix Angelica Sinensis、Ligusticum chuanxiong Hort、both of them. Uptake of Ferulic acid depends on concentration and varies linearly, but the absorption rate of different concentration do not changed remarkably It effected the absorption consistented with first order kinetics, infered the process of absorption is passively diffusion. On environmental pH aspect, because Ferulic acid belongs to composition of weak acid and alkalies, the absorption is affected by environmental pH. On the choice of intestinal segments, most of the Ferulic acid is absorbed by the stomach. In order to identify whether the absorption is effected by the P-gp, we corporate Ferulic acid with inducer-rifampicin or inhibitor-verapamil together. The result manifests the absorption is effected by the P-gp. In the future clinic, we can use the Ferulic acid and inducer-rifampicin together to increase the biological effective.
(2)The experiment analyzed the absorption mechanism of Peoniflorin and Ferulic acid in Bazhen Decoction. It is the same with Ferulic acid, the absorption of Peoniflorin and Ferulic acid in Bazhen Decoction are studied on four aspects such as concentration, pH, intestinal segments, P-gp. The absorption of Peoniflorin and Ferulic acid changed depend on concentration by linear relationship, the linear equations:Y=3.78X+1.1478(r=0.9974), Y=3.3485X+0.1457(r=0.9740). The absorption rate of different concentration do not changed remarkably, it reflected the absorption of Peoniflorin and Ferulic acid consistented with first order kinetics. It infered the process of absorption of Peoniflorin and Ferulic acid are passively diffusion. On pH aspects, the absorption of Peoniflorin is not affected by pH. On the absorption position, Ferulic acid in Bazhen Decoction the same as that in Radix Angelica Sinensis、Ligusticum chuanxiong Hort and both of them, the Ferulic acid absorption position in Bazhen Decoction is stomach too. Furthermore, we corporate Bazhen Decoction extact with inducer-rifampicin or inhibitor-verapamil together. The absorbed dose, Ka, absorption fraction and t1/2 of Peoniflorin and Ferulic acid have increased or decreased obviously. So we can include that Peoniflorin and Ferulic acid in Bazhen Decoction is affected by the P-gp, and in future clinic we can use with catastaltic of P-gp to increase its effective in Bazhen Decoction.
(3) By compare absorption of Ferulic acid in Radix Angelica Sinensis, Ligusticum chuanxiong Hort, both of them and Bazhen Decoction compound, we can gain the result that Ferulic acid in Bazhen Decoction compound are absorbed more on the aspects concentration, pH, intestinal segments than in others. So Bazhen Decoction compound exploitation is valuable.
引文
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