黄连吴茱萸药对在药物吸收模型上的生物表达研究
摘要
本课题在较全面综述近年来对黄连、吴茱萸配伍的研究进展及药物肠吸收模型的研究基础上,尝试把用于化学药物吸收研究的体外和在体模型,应用于中药复方药对研究,通过建立中药吸收研究的体外和在体模型,采用指纹图谱法分析黄连-吴茱萸药对配伍前、配伍后及代谢后化学成分的变化,试图阐明该药对化学成份在这两种药物吸收模型上的表达,并结合药动学参数,探讨黄连吴茱萸药对的配伍规律。
目的
通过对黄连吴茱萸药对不同配比(黄连：吴茱萸=1：1、2：1、6：1)进行在体肠吸收和Caco-2细胞模型上的吸收表达研究,探讨黄连吴茱萸药对的配伍规律。
方法
1运用指纹图谱技术,采用高效液相色谱法,从整体角度比较黄连单煎液、吴茱萸单煎液、黄连吴茱萸合煎液不同配比中化学成分的差异,综合考察配伍对化学成分的影响。
2采用单向灌流法研究黄连吴茱萸不同配比的大鼠在体肠吸收,麻醉并固定大鼠,沿腹中线于剑突下2cm处打开腹腔,分离待考察肠段,两端切口插管并结扎,每种药物按照0.2mL·min-1的流速灌流30min,收集出口管中灌流液,进行高效液相检测。
3 Caco-2细胞在transwell培养板上形成紧密完整的单细胞层后,将药物用HBSS液稀释至最大细胞无毒浓度。细胞层A面加0.5 mL药物,B面加1.5mL HBSS液,然后把Transwell培养板放在37℃孵箱里孵育,在0,30,60,90,120min从B面收集接受液0.5mL,并立即加等量HBSS液,考察药物中成分在细胞层的吸收情况,并计算能表达的成分和特征的吸收程度。
4取家兔随机分成3组,麻醉后,分离一侧颈总动脉,插管固定,各组动物灌胃给药,均于给药前和给药后在固定时间点自颈总动脉采集1mL血样,肝素抗凝,3000rpm离心10min得血浆样品,各样品进行相应处理后直接注入色谱仪中,得出样品药物浓度。
5取动物随机分组,各给药组灌胃给药每天一次,末次给药1h后分别进行对冰醋酸所致小鼠扭体反应,对内毒素所致大鼠发热及对小鼠小肠推进度的实验。
结果
1黄连与吴茱萸配伍后,黄连中各组分的溶出率明显减少,但其溶出率与黄连及吴茱萸在药对中所占的比例有关,黄连比例越大,吴茱萸比例越小,溶出率越大。而黄连和吴茱萸配伍则有利于吴茱萸中主要生物碱的溶出。
2肠段及浓度对于不同配比的黄连吴茱萸的小肠吸收并无明显影响,但黄连吴茱萸2：1和6：1在相同肠段比黄连吴茱萸1：1的吸收要好,说明随着黄连比例的增加,药物的吸收也呈上升趋势。增加黄连的配伍比例,均有利于黄连和吴茱萸主要化学成份的吸收,且黄连吴茱萸配比为6：1时促进了黄连活性成分与吴茱萸活性成分的小肠吸收。
3黄连吴茱萸主要成分在Caco-2细胞吸收的转运速率,其中黄连吴茱萸6：1的巴马汀Papp比黄连吴茱萸1：1及2：1的要高,差异有显著性
4小檗碱、巴马汀及药根碱血浆动力学参数与黄连吴茱萸配比的比例并不呈现相关性,说明不同的吴茱萸比例配伍黄连在体内吸收利用及消除均不同,但黄连吴茱萸2：1时三个生物碱的CL较小,t1/2β则均较大,说明这个比例的配伍在体内主要往周围组织分布。
5黄连吴茱萸2：1及黄连吴茱萸6：1镇痛效果比较明显,有缩短潜伏期和减少扭体次数的作用；黄连吴茱萸6：1及黄连吴茱萸2：1对降低发热大鼠肛温有一定影响；黄连吴茱萸1：1及6：1有一定的止泻作用。
The topic was based on a more comprehensive overview of progress of Coptis& Evodia in recent years and drug compatibility of intestinal absorption model. And try to use in vitro and in vivo models of chemical drug absorption in the study of Chinese herbal compound medicine.Through establishing the absorption of chemicals in vitro and in vivo models, used fingerprinting method.LC-MS-MS ect. to contrast the changes of chemical composition of Coptis-Evodia on front&after the compatibility and metabolic. Attempt to clarify the expression of the chemical composition of fingerprints, combined with pharmacokinetic parameters, investigate the law of compatibility of bcrbcrine drug.
Objective
Though studying the absorption of expression of the intestinal absorption and Caco-2 cell model of the Coptis-Evodia by different ratios, investigate the law of compatibility of berberine drug.
Methods
1 By using HPLC&fingerprinting technology, of comparethe the differences in chemical composition of single Coptis decoction. Evodia single decoction, and different ratio of Coptis-Evodia decoction from the overall perspective, comprehensive study on the chemical composition of compatibility.
2 Used one-way perfusion to study intestinal absorption in rats of different ratio of coptis-Evodia. anesthetized and fixed the rats, open the abdominal cavity along the midline at the xiphoid under 2cm. isolated intestines to be investigated, intubatedand ligated both ends of the incision, perfused each drug in accordance with 0.2mL·min-1 of 30min. collected perfusate to determined by HPLC
'3 Plus 0.5 mL of drug in the side-A of Caco-2 cell layer.and plus 1.5mL HBSS solution in side- B.and then placed the transwell plates in the culture box at 37℃. Collect 0.5mL accept liquid from the side-B at 0.30，60.90.120 min，and immediately add equal amount of HBSS solution.calculate the absorption characteristics which composition can express and extent.
4 Oral administrating in rabbits after anesthesia, collected lmL blood from the carotid artery at fixed time points, centrifuge 3000rpm×l0min and get plasma samples, that were injected into the chromatography after treatment and get sample concentration.
5 Animals were assigned randomly and take each dose once a day,1 h after the last administration, advancing studies of glacial in mice induced by acetic acid, fever in rats induced by endotoxin and texting intestinal propulsion rate in the small intestine of mice.
Results
1 After Combinating of Coptis and Evodia, the dissolution of each component of Coptis were significantly reduced, but the dissolution rate is related to the proportion of Coptis and Evodia,the greater proportion of Coptis，or the smaller proportion of Evodia, the greater the dissolution rate was. The compatibility of Coptis and Evodia is conducive to the dissolution of the main alkaloids of Evodia.
2 Different Intestines and concentration had no significant effect on the intestinal absorption of different ratios of Coptis- Evodia，but with the increasing in the proportion of Coptis, the drug absorption rised.6:1 of Coptis and Evodia is most ratio that promoted the intestinal absorption of active ingredients in Coptis and Evodia.
3 Papp(transport rate) in Caco-2 cell main of ingredient Coptis and Evodia. which Papp of palmatine in 6:1 of Coptis-Evodia was higher than 1:1 and 2:1, the difference was significant.
4 The kinetic parameters of Berberine. palmatine and jatrorrhizine was not significantly correlated to the ratio of Coptis & Evodia. but CL of three alkaloids in 2:1 of Coptis-Evodia were smaller. t1/2βwere higher, indicating that this compatibility was mainly distributing to the surrounding tissue in the body.52:1&6:1 of Coptis - Evodia had obvious analgesic effect, could shorter the incubation period and reduce the role of writhing:6:1 and 2:1 of Coptis-Evodia had a certain influence in reducing fever in rats rectal temperature:1:1 and 6:1 of Coptis-Evodia had some antidiarrheal effect.
目的
通过对黄连吴茱萸药对不同配比(黄连：吴茱萸=1：1、2：1、6：1)进行在体肠吸收和Caco-2细胞模型上的吸收表达研究,探讨黄连吴茱萸药对的配伍规律。
方法
1运用指纹图谱技术,采用高效液相色谱法,从整体角度比较黄连单煎液、吴茱萸单煎液、黄连吴茱萸合煎液不同配比中化学成分的差异,综合考察配伍对化学成分的影响。
2采用单向灌流法研究黄连吴茱萸不同配比的大鼠在体肠吸收,麻醉并固定大鼠,沿腹中线于剑突下2cm处打开腹腔,分离待考察肠段,两端切口插管并结扎,每种药物按照0.2mL·min-1的流速灌流30min,收集出口管中灌流液,进行高效液相检测。
3 Caco-2细胞在transwell培养板上形成紧密完整的单细胞层后,将药物用HBSS液稀释至最大细胞无毒浓度。细胞层A面加0.5 mL药物,B面加1.5mL HBSS液,然后把Transwell培养板放在37℃孵箱里孵育,在0,30,60,90,120min从B面收集接受液0.5mL,并立即加等量HBSS液,考察药物中成分在细胞层的吸收情况,并计算能表达的成分和特征的吸收程度。
4取家兔随机分成3组,麻醉后,分离一侧颈总动脉,插管固定,各组动物灌胃给药,均于给药前和给药后在固定时间点自颈总动脉采集1mL血样,肝素抗凝,3000rpm离心10min得血浆样品,各样品进行相应处理后直接注入色谱仪中,得出样品药物浓度。
5取动物随机分组,各给药组灌胃给药每天一次,末次给药1h后分别进行对冰醋酸所致小鼠扭体反应,对内毒素所致大鼠发热及对小鼠小肠推进度的实验。
结果
1黄连与吴茱萸配伍后,黄连中各组分的溶出率明显减少,但其溶出率与黄连及吴茱萸在药对中所占的比例有关,黄连比例越大,吴茱萸比例越小,溶出率越大。而黄连和吴茱萸配伍则有利于吴茱萸中主要生物碱的溶出。
2肠段及浓度对于不同配比的黄连吴茱萸的小肠吸收并无明显影响,但黄连吴茱萸2：1和6：1在相同肠段比黄连吴茱萸1：1的吸收要好,说明随着黄连比例的增加,药物的吸收也呈上升趋势。增加黄连的配伍比例,均有利于黄连和吴茱萸主要化学成份的吸收,且黄连吴茱萸配比为6：1时促进了黄连活性成分与吴茱萸活性成分的小肠吸收。
3黄连吴茱萸主要成分在Caco-2细胞吸收的转运速率,其中黄连吴茱萸6：1的巴马汀Papp比黄连吴茱萸1：1及2：1的要高,差异有显著性
4小檗碱、巴马汀及药根碱血浆动力学参数与黄连吴茱萸配比的比例并不呈现相关性,说明不同的吴茱萸比例配伍黄连在体内吸收利用及消除均不同,但黄连吴茱萸2：1时三个生物碱的CL较小,t1/2β则均较大,说明这个比例的配伍在体内主要往周围组织分布。
5黄连吴茱萸2：1及黄连吴茱萸6：1镇痛效果比较明显,有缩短潜伏期和减少扭体次数的作用；黄连吴茱萸6：1及黄连吴茱萸2：1对降低发热大鼠肛温有一定影响；黄连吴茱萸1：1及6：1有一定的止泻作用。
The topic was based on a more comprehensive overview of progress of Coptis& Evodia in recent years and drug compatibility of intestinal absorption model. And try to use in vitro and in vivo models of chemical drug absorption in the study of Chinese herbal compound medicine.Through establishing the absorption of chemicals in vitro and in vivo models, used fingerprinting method.LC-MS-MS ect. to contrast the changes of chemical composition of Coptis-Evodia on front&after the compatibility and metabolic. Attempt to clarify the expression of the chemical composition of fingerprints, combined with pharmacokinetic parameters, investigate the law of compatibility of bcrbcrine drug.
Objective
Though studying the absorption of expression of the intestinal absorption and Caco-2 cell model of the Coptis-Evodia by different ratios, investigate the law of compatibility of berberine drug.
Methods
1 By using HPLC&fingerprinting technology, of comparethe the differences in chemical composition of single Coptis decoction. Evodia single decoction, and different ratio of Coptis-Evodia decoction from the overall perspective, comprehensive study on the chemical composition of compatibility.
2 Used one-way perfusion to study intestinal absorption in rats of different ratio of coptis-Evodia. anesthetized and fixed the rats, open the abdominal cavity along the midline at the xiphoid under 2cm. isolated intestines to be investigated, intubatedand ligated both ends of the incision, perfused each drug in accordance with 0.2mL·min-1 of 30min. collected perfusate to determined by HPLC
'3 Plus 0.5 mL of drug in the side-A of Caco-2 cell layer.and plus 1.5mL HBSS solution in side- B.and then placed the transwell plates in the culture box at 37℃. Collect 0.5mL accept liquid from the side-B at 0.30，60.90.120 min，and immediately add equal amount of HBSS solution.calculate the absorption characteristics which composition can express and extent.
4 Oral administrating in rabbits after anesthesia, collected lmL blood from the carotid artery at fixed time points, centrifuge 3000rpm×l0min and get plasma samples, that were injected into the chromatography after treatment and get sample concentration.
5 Animals were assigned randomly and take each dose once a day,1 h after the last administration, advancing studies of glacial in mice induced by acetic acid, fever in rats induced by endotoxin and texting intestinal propulsion rate in the small intestine of mice.
Results
1 After Combinating of Coptis and Evodia, the dissolution of each component of Coptis were significantly reduced, but the dissolution rate is related to the proportion of Coptis and Evodia,the greater proportion of Coptis，or the smaller proportion of Evodia, the greater the dissolution rate was. The compatibility of Coptis and Evodia is conducive to the dissolution of the main alkaloids of Evodia.
2 Different Intestines and concentration had no significant effect on the intestinal absorption of different ratios of Coptis- Evodia，but with the increasing in the proportion of Coptis, the drug absorption rised.6:1 of Coptis and Evodia is most ratio that promoted the intestinal absorption of active ingredients in Coptis and Evodia.
3 Papp(transport rate) in Caco-2 cell main of ingredient Coptis and Evodia. which Papp of palmatine in 6:1 of Coptis-Evodia was higher than 1:1 and 2:1, the difference was significant.
4 The kinetic parameters of Berberine. palmatine and jatrorrhizine was not significantly correlated to the ratio of Coptis & Evodia. but CL of three alkaloids in 2:1 of Coptis-Evodia were smaller. t1/2βwere higher, indicating that this compatibility was mainly distributing to the surrounding tissue in the body.52:1&6:1 of Coptis - Evodia had obvious analgesic effect, could shorter the incubation period and reduce the role of writhing:6:1 and 2:1 of Coptis-Evodia had a certain influence in reducing fever in rats rectal temperature:1:1 and 6:1 of Coptis-Evodia had some antidiarrheal effect.
引文
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