附子干姜组分配伍的胃肠吸收动力学研究
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摘要
目的：
研究附子干姜组分配伍的胃肠吸收动力学特征,初步探索附子干姜组分配伍后附子总生物碱的胃肠吸收机制,建立中药组分配伍胃肠吸收动力学的研究方法
方法：
采用大鼠胃原位在体灌注研究附子与干姜组分配伍后在胃内的单位时间内平均吸收率；采用大鼠肠原位在体灌注模型研究附子干姜组分配伍后肠吸收,建立附子总生物碱中乌头碱、新乌头碱、次乌头碱在肠内的吸收动力学方程,计算吸收动力学参数；采用大鼠离体肠翻转囊法研究附子干姜组分配伍后附子总生物碱在肠不同部位、不同浓度的单位时间内平均吸收率；选用P-gp抑制剂利用大鼠离体肠翻转囊法研究附子干姜组分配伍后附子总生物碱在肠内不同部位的单位时间内的平均吸收率,初步分析其在肠内的吸收机制。
结果：
1、采用大鼠原位胃灌注对附子总生物碱的胃内吸收进行研究,对附子总生物碱单独给药与附子干姜组分配伍给药时,乌头碱、新乌头碱、次乌头碱在胃内单位时间吸收百分率进行统计分析,发现差异无统计学意义(p>0.05)。但发现附子干姜组分配伍按相应比例配伍后有降低附子总生物碱中乌头碱、新乌头碱、次乌头碱单位时间内胃内吸收率的趋势。提示附子总生物碱与干姜挥发油(1∶1)组分配伍、附子总生物碱与干姜提取物(2∶1)组分配伍具有减毒增效的作用,可能与干姜组分(包括挥发油、提取物)有降低附子总生物碱中有毒的无乌头类双酯型生物碱乌头碱、新乌头碱、次乌头碱在胃内的吸收趋势有关。
2、利用大鼠在体小肠原位灌注实验与大鼠离体外翻肠囊实验,分别进行了附子总生物碱组分单独给药、附子总生物碱与干姜挥发油组分配伍给药、附子总生物碱与干姜提取物组分配伍给药的小肠吸收研究,发现附子总生物碱中乌头碱、新乌头碱、次乌头碱在大鼠小肠内的吸收属于一级吸收动力学过程。
对吸收速率常数与半衰期进行分析,发现差异无统计学意义(p>0.05),但附子干姜组分配伍按相应比例配伍后有降低附子总生物碱中乌头碱、新乌头碱、次乌头碱吸收速率常数,延长半衰期的趋势。提示附子总生物碱与干姜挥发油(1∶1)组分配伍、附子总生物碱与干姜提取物(2∶1)组分配伍具有减毒增效的作用,可能与干姜组分(包括挥发油、提取物)有降低附子总生物碱中有毒的乌头类双酯型生物碱乌头碱、新乌头碱、次乌头碱在小肠内吸收的趋势有关。
附子总生物碱中乌头碱、新乌头碱、次乌头碱在空肠、回肠、结肠段的吸收率均与药物浓度浓度无关。乌头碱、新乌头碱、次乌头碱在空肠、回肠、结肠段的吸收机制可能为被动扩散。附子总生物碱中乌头碱、新乌头碱、次乌头碱在空肠、回肠、结肠段中均有吸收,三个肠段相比较,空肠与回肠吸收率相似,结肠吸收率略低。提示附子总生物碱中有毒的乌头类双酯型生物碱乌头碱、新乌头碱、次乌头碱的主要吸收部位应为小肠即空肠、回肠。
3、利用外翻肠囊实验,研究P-gp与乌头碱、新乌头碱、次乌头碱肠吸收的关系时,分别对不同肠段中附子总生物碱中乌头碱、新乌头碱、次乌头碱的吸收率进行统计学分析,结果差异无统计学意义(p>0.05),提示乌头碱、新乌头碱、次乌头碱均不是P-gp的底物。乌头碱、新乌头碱、次乌头碱的吸收机可能与P-gp无关。
结论：
附子总生物碱中乌头碱、新乌头碱、次乌头碱在大鼠小肠内的吸收属于一级吸收动力学过程。附子干姜组分配伍按相应比例配伍后具有降低附子总生物碱中乌头碱、新乌头碱、次乌头碱吸收速率常数、单位时间内胃内吸收率,延长半衰期的趋势。附子总生物碱中乌头碱、新乌头碱、次乌头碱在空肠、回肠、结肠段的吸收率均与药物浓度浓度无关。乌头碱、新乌头碱、次乌头碱在空肠、回肠、结肠段的吸收机制可能为被动扩散。附子总生物碱中乌头碱、新乌头碱、次乌头碱的主要吸收部位应为小肠即空肠、回肠。乌头碱、新乌头碱、次乌头碱均不是P-gp的底物。乌头碱、新乌头碱、次乌头碱的吸收机制可能与P-gp无关。
通过对附子干姜组分配伍胃肠吸收动力学的研究,对中药组分配伍胃肠吸收动力学研究进行了探索,揭示了以下几个问题：(1)提出了中药组分配伍胃肠吸收动力学的假说；(2)总结了中药组分胃肠吸收动力学研究的关键环节；(3)对附子干姜组分配伍的胃肠吸收动力学进行了研究,得到了附子干姜组分配伍后的胃肠吸收动力学参数,初步发现了附子干姜组分配伍减毒的规律。
Aims
To investigate the characteristics of gastrointestinal absorption kinetics of composition compatibilities from Radix Aconiti Lateralis Preparata (RALP) and Rhizoma Zingiberis (RZ), initially explore absorptive mechanism of total alkaloids from RALP (TA) in gastrointestine, and finally set up a method for gastrointestinal absorption kinetics for composition compatibilities of traditional Chinese medicinals (GAKTCM).
Methods
Average absorption rates (AARs) of composition compatibilities from RALP and RZ in stomach was studied by in situ stomach perfusion in rats in vivo and AAR in small intestine was studied also with rats by the similar method in small intestine in vivo. Based on the results, the kinetic equations of aconitine (AC), mesaconitine (MA), and hypaconitine (HA), which are components of TA, in gastrointestinal absorption were created and related kinetic parameters were calculated. The method of in vitro reversal intestinal sac was applied to study different AARs of TA in different places in small intestine, in different concentrations, or when in combination with P-glucoprotein (P-gp) inhibitor to initially analyze the absorptive mechanism of TA in gastrointestine.
Results
1. AARs of AC, MA, and HA in stomach in vivo had no difference when TA was given alone or in combination with RZ (p>0.05). However, the AARs of AC, MA, and HA in stomach were tend to decrease when TA was combined with the volatile oil of Rhizoma Zingiberis (OVRZ) (1:1) or combined with aqueous extract of Rhizoma Zingiberis (AERZ) (2:1). The results indicated that OVRZ and AERZ had a tendency to restrain absorption of AC, MA, and HA in stomach, which probably contributes to the phenomena that composition compatibilities of TA with OVRZ (1:1) and TA with AERZ (2:1) could successfully reduce the toxicity of TA and strengthen pharmacological effects simultaneously.
2. By applying both techniques of in situ small intestine perfusion in vivo and reversal intestinal sac in vitro, the absorptions of AC, MA, and HA in intestine were studied when TA was given to rats singly, in combination with OVRZ or AERZ. The results showed first-order absorption kinetics of t all of the three main components of TA, exactly AC, MA, and HA.
Both Ka and T1/2 were showed no significantly difference when TA was given to rats singley, or in combination with OVRZ and AERZ in ratio mentioned above (p>0.05) However, there was a tendency that Ka was decreased and simultaneously T1/2 was prolonged for all of AC, MA, and HA by compatibility. The results indicated that OVRZ and AERZ had a tendency to restrain intestinal absorption of AC, MA, and HA, which probably contributes to the phenomena that composition compatibilities of TA with OVRZ (1:1) and TA with AERZ (2:1) could successfully reduce the toxicity of TA and strengthen pharmacological effects simultaneously.
AARs of AC, MA, and HA in jejunum, ileum, and colon were not influenced by drug concentration. The three alkaloids were probably absorbed by passive diffusion. AC, MA, and HA could be absorbed in jejunum, ileum, and colon, in which the AARs in jejunum and ileum were similar and AARs in colon was relatively lower than that in jejunum and ileum. The results indicated that the main absorptive place for AC, MA, and HA, diester alkaloids of aconitum, is small intestine, exactly jejunum and ileum.
3. By applying P-gp in in vitro reversal intestine sac test, it was found that the AARs of AC, MA, and HA in jejunum, ileum, and colon were not significantly different between non-P-gp test and P-gp test (p>0.05), which indicated that none of AC, MA, and HA was the substrate of P-gp and P-gp may not involved in intestinal absorption of AC, MA, and HA.
Conclusions:The absorptions of TA components, exactly AC, MA, and HA, belongs to first order absorption kinetics. When TA is combined with compositions of RZ in corresponding ratios, there is a tendency that both Ka and AARs in stomach can be decreased in contrast to increase of T1/2. AARs of AC, MA, and HA in jejunum, ileum. and colon is not influenced by drug concentration and the absorptive mechanism may refers to passive diffusion. Jejunum and ileum are main places for absorption. None of AC, MA, and HA was the substrate of P-gp and P-gp may not involved in intestinal absorption of AC, MA, and HA.
By study of gastrointestinal absorption kinetics of composition compatibilities from RALP and RZ, we devoted to set up the method and technology for GAKTCM and finally solved several problems as following:(1) We proposed the hypothesis of GAKTCM. (2) The key parts on the study of GAKTCM were concluded. (3) By study of gastrointestinal absorption kinetics of composition compatibilities from RALP and RZ, we got the related kinetic parameters and initially reveal the law of reducing toxicity in compositon compatibility of RALP and RZ.
研究附子干姜组分配伍的胃肠吸收动力学特征,初步探索附子干姜组分配伍后附子总生物碱的胃肠吸收机制,建立中药组分配伍胃肠吸收动力学的研究方法
方法：
采用大鼠胃原位在体灌注研究附子与干姜组分配伍后在胃内的单位时间内平均吸收率；采用大鼠肠原位在体灌注模型研究附子干姜组分配伍后肠吸收,建立附子总生物碱中乌头碱、新乌头碱、次乌头碱在肠内的吸收动力学方程,计算吸收动力学参数；采用大鼠离体肠翻转囊法研究附子干姜组分配伍后附子总生物碱在肠不同部位、不同浓度的单位时间内平均吸收率；选用P-gp抑制剂利用大鼠离体肠翻转囊法研究附子干姜组分配伍后附子总生物碱在肠内不同部位的单位时间内的平均吸收率,初步分析其在肠内的吸收机制。
结果：
1、采用大鼠原位胃灌注对附子总生物碱的胃内吸收进行研究,对附子总生物碱单独给药与附子干姜组分配伍给药时,乌头碱、新乌头碱、次乌头碱在胃内单位时间吸收百分率进行统计分析,发现差异无统计学意义(p>0.05)。但发现附子干姜组分配伍按相应比例配伍后有降低附子总生物碱中乌头碱、新乌头碱、次乌头碱单位时间内胃内吸收率的趋势。提示附子总生物碱与干姜挥发油(1∶1)组分配伍、附子总生物碱与干姜提取物(2∶1)组分配伍具有减毒增效的作用,可能与干姜组分(包括挥发油、提取物)有降低附子总生物碱中有毒的无乌头类双酯型生物碱乌头碱、新乌头碱、次乌头碱在胃内的吸收趋势有关。
2、利用大鼠在体小肠原位灌注实验与大鼠离体外翻肠囊实验,分别进行了附子总生物碱组分单独给药、附子总生物碱与干姜挥发油组分配伍给药、附子总生物碱与干姜提取物组分配伍给药的小肠吸收研究,发现附子总生物碱中乌头碱、新乌头碱、次乌头碱在大鼠小肠内的吸收属于一级吸收动力学过程。
对吸收速率常数与半衰期进行分析,发现差异无统计学意义(p>0.05),但附子干姜组分配伍按相应比例配伍后有降低附子总生物碱中乌头碱、新乌头碱、次乌头碱吸收速率常数,延长半衰期的趋势。提示附子总生物碱与干姜挥发油(1∶1)组分配伍、附子总生物碱与干姜提取物(2∶1)组分配伍具有减毒增效的作用,可能与干姜组分(包括挥发油、提取物)有降低附子总生物碱中有毒的乌头类双酯型生物碱乌头碱、新乌头碱、次乌头碱在小肠内吸收的趋势有关。
附子总生物碱中乌头碱、新乌头碱、次乌头碱在空肠、回肠、结肠段的吸收率均与药物浓度浓度无关。乌头碱、新乌头碱、次乌头碱在空肠、回肠、结肠段的吸收机制可能为被动扩散。附子总生物碱中乌头碱、新乌头碱、次乌头碱在空肠、回肠、结肠段中均有吸收,三个肠段相比较,空肠与回肠吸收率相似,结肠吸收率略低。提示附子总生物碱中有毒的乌头类双酯型生物碱乌头碱、新乌头碱、次乌头碱的主要吸收部位应为小肠即空肠、回肠。
3、利用外翻肠囊实验,研究P-gp与乌头碱、新乌头碱、次乌头碱肠吸收的关系时,分别对不同肠段中附子总生物碱中乌头碱、新乌头碱、次乌头碱的吸收率进行统计学分析,结果差异无统计学意义(p>0.05),提示乌头碱、新乌头碱、次乌头碱均不是P-gp的底物。乌头碱、新乌头碱、次乌头碱的吸收机可能与P-gp无关。
结论：
附子总生物碱中乌头碱、新乌头碱、次乌头碱在大鼠小肠内的吸收属于一级吸收动力学过程。附子干姜组分配伍按相应比例配伍后具有降低附子总生物碱中乌头碱、新乌头碱、次乌头碱吸收速率常数、单位时间内胃内吸收率,延长半衰期的趋势。附子总生物碱中乌头碱、新乌头碱、次乌头碱在空肠、回肠、结肠段的吸收率均与药物浓度浓度无关。乌头碱、新乌头碱、次乌头碱在空肠、回肠、结肠段的吸收机制可能为被动扩散。附子总生物碱中乌头碱、新乌头碱、次乌头碱的主要吸收部位应为小肠即空肠、回肠。乌头碱、新乌头碱、次乌头碱均不是P-gp的底物。乌头碱、新乌头碱、次乌头碱的吸收机制可能与P-gp无关。
通过对附子干姜组分配伍胃肠吸收动力学的研究,对中药组分配伍胃肠吸收动力学研究进行了探索,揭示了以下几个问题：(1)提出了中药组分配伍胃肠吸收动力学的假说；(2)总结了中药组分胃肠吸收动力学研究的关键环节；(3)对附子干姜组分配伍的胃肠吸收动力学进行了研究,得到了附子干姜组分配伍后的胃肠吸收动力学参数,初步发现了附子干姜组分配伍减毒的规律。
Aims
To investigate the characteristics of gastrointestinal absorption kinetics of composition compatibilities from Radix Aconiti Lateralis Preparata (RALP) and Rhizoma Zingiberis (RZ), initially explore absorptive mechanism of total alkaloids from RALP (TA) in gastrointestine, and finally set up a method for gastrointestinal absorption kinetics for composition compatibilities of traditional Chinese medicinals (GAKTCM).
Methods
Average absorption rates (AARs) of composition compatibilities from RALP and RZ in stomach was studied by in situ stomach perfusion in rats in vivo and AAR in small intestine was studied also with rats by the similar method in small intestine in vivo. Based on the results, the kinetic equations of aconitine (AC), mesaconitine (MA), and hypaconitine (HA), which are components of TA, in gastrointestinal absorption were created and related kinetic parameters were calculated. The method of in vitro reversal intestinal sac was applied to study different AARs of TA in different places in small intestine, in different concentrations, or when in combination with P-glucoprotein (P-gp) inhibitor to initially analyze the absorptive mechanism of TA in gastrointestine.
Results
1. AARs of AC, MA, and HA in stomach in vivo had no difference when TA was given alone or in combination with RZ (p>0.05). However, the AARs of AC, MA, and HA in stomach were tend to decrease when TA was combined with the volatile oil of Rhizoma Zingiberis (OVRZ) (1:1) or combined with aqueous extract of Rhizoma Zingiberis (AERZ) (2:1). The results indicated that OVRZ and AERZ had a tendency to restrain absorption of AC, MA, and HA in stomach, which probably contributes to the phenomena that composition compatibilities of TA with OVRZ (1:1) and TA with AERZ (2:1) could successfully reduce the toxicity of TA and strengthen pharmacological effects simultaneously.
2. By applying both techniques of in situ small intestine perfusion in vivo and reversal intestinal sac in vitro, the absorptions of AC, MA, and HA in intestine were studied when TA was given to rats singly, in combination with OVRZ or AERZ. The results showed first-order absorption kinetics of t all of the three main components of TA, exactly AC, MA, and HA.
Both Ka and T1/2 were showed no significantly difference when TA was given to rats singley, or in combination with OVRZ and AERZ in ratio mentioned above (p>0.05) However, there was a tendency that Ka was decreased and simultaneously T1/2 was prolonged for all of AC, MA, and HA by compatibility. The results indicated that OVRZ and AERZ had a tendency to restrain intestinal absorption of AC, MA, and HA, which probably contributes to the phenomena that composition compatibilities of TA with OVRZ (1:1) and TA with AERZ (2:1) could successfully reduce the toxicity of TA and strengthen pharmacological effects simultaneously.
AARs of AC, MA, and HA in jejunum, ileum, and colon were not influenced by drug concentration. The three alkaloids were probably absorbed by passive diffusion. AC, MA, and HA could be absorbed in jejunum, ileum, and colon, in which the AARs in jejunum and ileum were similar and AARs in colon was relatively lower than that in jejunum and ileum. The results indicated that the main absorptive place for AC, MA, and HA, diester alkaloids of aconitum, is small intestine, exactly jejunum and ileum.
3. By applying P-gp in in vitro reversal intestine sac test, it was found that the AARs of AC, MA, and HA in jejunum, ileum, and colon were not significantly different between non-P-gp test and P-gp test (p>0.05), which indicated that none of AC, MA, and HA was the substrate of P-gp and P-gp may not involved in intestinal absorption of AC, MA, and HA.
Conclusions:The absorptions of TA components, exactly AC, MA, and HA, belongs to first order absorption kinetics. When TA is combined with compositions of RZ in corresponding ratios, there is a tendency that both Ka and AARs in stomach can be decreased in contrast to increase of T1/2. AARs of AC, MA, and HA in jejunum, ileum. and colon is not influenced by drug concentration and the absorptive mechanism may refers to passive diffusion. Jejunum and ileum are main places for absorption. None of AC, MA, and HA was the substrate of P-gp and P-gp may not involved in intestinal absorption of AC, MA, and HA.
By study of gastrointestinal absorption kinetics of composition compatibilities from RALP and RZ, we devoted to set up the method and technology for GAKTCM and finally solved several problems as following:(1) We proposed the hypothesis of GAKTCM. (2) The key parts on the study of GAKTCM were concluded. (3) By study of gastrointestinal absorption kinetics of composition compatibilities from RALP and RZ, we got the related kinetic parameters and initially reveal the law of reducing toxicity in compositon compatibility of RALP and RZ.
引文
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