黄芩汤多成分药代动力学及肠道菌群作用的相关研究
|
摘要
黄芩汤主要成分体外经肠道菌群的代谢作用研究表明，黄芩汤中的主要成分黄芩苷(BG)、汉黄芩苷(WG)、千层纸素A苷(OG)(来源于黄芩)，芍药苷(PF)(来源于芍药)和甘草苷(LG)、甘草酸(GL)、异甘草苷(ILG)(来源于甘草)经过肠道菌群在体外的代谢，分别转化为相应的代谢产物黄芩素(B)、汉黄芩素(W)、千层纸素A(O)、芍药苷代谢素I(PM-I)、甘草素(L)、甘草次酸(GA)和异甘草素(IL)等。本文进行了黄芩汤主要成分在大鼠体内的药代动力学及肠道菌群作用的相关研究，实验主要围绕以下几个方面进行：
1．黄芩汤主要成分在普通、悉生和无菌动物肠道内的代谢
接种特定菌株后的无菌动物成为悉生动物，将它们与普通动物进行体内代谢作用的比较研究，是考察肠道菌群在体内对药物进行代谢的主要方法之一。乳杆菌和真杆菌是肠道内与黄芩汤多成分代谢关系比较密切的菌株，在本试验中，给无菌小鼠接种这两种菌株，形成感染真杆菌的悉生小鼠和感染乳杆菌的悉生小鼠。给三种小鼠口服黄芩汤后，于不同时间点收集盲肠内容物和粪便，用HPLC方法对黄芩汤中的主要成分及其代谢产物进行分析，并且绘制了普通小鼠盲肠内容物中各成分及代谢产物的浓度-时间曲线。
结果表明：在无菌小鼠盲肠内容物和粪便中，黄芩汤中各主要成分没有发生明显的代谢转化，而普通小鼠、感染真杆菌和感染乳杆菌的悉生小鼠，发生了显著的代谢转化，其代谢规律与体外试验基本相同；与乳杆菌相比，真杆菌是一种代谢能力较强的菌株，而普通小鼠肠道内的混合菌，虽然完全代谢药物的作用时间长于真杆菌，但是其代谢强度高于真杆菌和乳杆菌；从普通小鼠盲肠内容物中各成分和代谢产物的浓度-时间曲线中可以发现，代谢产物的浓度达峰时间比原型化合物的浓度达峰时间要延迟4h左右。
2．黄芩汤及其肠道菌群的代谢产物的药效学比较
给普通小鼠联合使用多种抗生素三天，造成伪无菌小鼠模型，其肠道内的菌群被广泛地抑制。此种动物模型用于黄芩汤及代谢产物的体内药效学的比较试验。
2．1体内保肝降酶作用的比较
使用普通小鼠和伪无菌小鼠，分别给予黄芩汤和经肠道菌群作用的代谢产物，测定肝损伤模型小鼠血清转氨酶的水平，比较黄芩汤和代谢产物对D-半乳糖胺诱导的肝损伤动物的保护作用。结果表明黄芩汤对普通小鼠有保肝降酶的作用，对伪无菌小鼠则没有作用；而代谢产物对伪无菌小鼠有显著的保肝降酶作用。
2．2体外抗菌作用的比较
2 黄岑汤多成分药代动力学及肠道菌群作用的相关研究
试验采用琼脂稀释法。用最小抑菌浓度（MIC）表示试验药物的抑菌强度，
比较黄芍汤和代谢产物体外的抗菌作用。结果为黄岑汤代谢产物对沙门氏菌、痢
疾杆菌和变形杆菌的体外抗菌作用均明显强于黄岑汤。
2．3体内抗菌作用的比较
采用动物死亡保护法进行体内抗菌试验。使用伪无菌小鼠，分另u给予黄岑汤
或肠道菌群的代谢产物，动物的死亡是由感染金葡菌或大肠杆菌（腹腔注入）引
起的，感染后连续观察七天，并记录动物发病及死亡结果，比较黄岑汤和代谢产
物体内的抗菌作用。结果黄苹汤对由金葡菌和大肠杆菌腹腔感染引起的伪无菌小
鼠死亡都没有明显的保护作用，而代谢产物对由以上两种菌分别引起的伪无菌小
鼠死亡均具有明显的保护作用。
3．黄冬汤多成分在大鼠体内的药代动力学
3．1黄苹汤主要成分的胃肠道吸收
采用原位漳技术，对黄岑汤中主要成分在大鼠胃肠道各部位（胃、小肠和大
肠）的吸收情况进行了研究，同时进行了黄苹汤在大鼠胃肠道各部位的生物转化
的研究。
结果发现：黄苹汤中的旮成分BG；WG，OG；PF，LG和GL在胃肠道各
部位都很难吸收；而黄苹汤中的苦元成分B，W，O，L和GA的吸收率明显高
于相应的普成分。大肠是黄苹汤中各成分进行代谢转化的重要部位，盲肠的转化
率最高，其次是直肠和胃，各种成分在小肠都没有发生转化。黄芍汤中的苦成分，
只有很少的量在胃肠道直接吸收，而主要是在大肠（盲肠）部位转化为相应的代
谢产物，进而被吸收进入体内。
3．二黄革汤主要成分的组织分布
对黄芬汤口服后各成分在组织中的分布进行了研究，并对相同成分在黄冬汤
复方和黄苹单味药中的组织分布进行了比较。
结果在小肠、胃、肝和肾中，黄岑中大多数成分（其中包括在肝中的代谢产
物）的分布明显高于单味黄冬水煎剂中，说明复方对黄冬中的成分在组织中的分
布具有促进作用。
3．3黄芍汤主要成分及其代谢产物的血浆药代动力学
在建立的多成分HPLC分析方法学认证的基础上，对单次口服黄苹汤及各单
味药水煎剂（10g／kg）后的大鼠血浆中多种成分及代谢产物的药代动力学进行了
初步的研究，并对血浆中相同成分在复方和单味药中的药代动力学参数进行了比
较。
口服后，黄苹汤中各成分及代谢产物在血浆中的药时曲线均符合一室模型。
在复方和单味药中各成分的药动学参数之问存在差异。在复方中Cmax和AUC
比在单味药中偏高的有：BG，WG，OG，VDJ和LG等成分，其中WG具有显
著性差异；AUC在复方中比在单味药中?
In our previous studies, by using a high-performance liquid chromatographic (HPLC) method which was established in our laboratory, the metabolites in both the compound prescription and all the single herb decoctions were identified and determined both qualitatively and quantitatively. It could be found that the constituents of Huangqin-Tang, induing baicalin (baicalein 7-glucuronide; BG), wogonoside (wogoninoglucuronide; WG), oroxylin-A-glucuronide (OG) from Scutellariae Radix, paeoniflorin (PF) from Paeoniae Radix, liquiritin (liquiritigenin 4'-O-glucoside; LG), isoliquirtin (isoliquiritigenin 4-glucoside; ILG) and glycyrrhizic acid (GL) from Glycyhhizea Radix, were converted to their metabolites baicalein (B), wogonin (W), oroxylin-A (0), paeonimetabolin-I (PM-I), liquiritigenin (L), isoliquiritigenin (IL) and glycyrrhetinic acid (GA) by intestinal bacteria in vitro. And the results suggested that the metabolism of most glycosides was improved in the compound prescription. In the present paper, the pharmacokinetic study of Huangqin-Tang in rats, and the relation between intestinal bacteria and metabolism in vivo of Huangqin-Tang decoction were performanced. The experiments were carried out in the fields as follows:
1. The metabolism of constituents of Huangqin-Tang decoction in conventional, germ-free and gnotobiote mice
Germ-free animals infected certain bacteria to establish the gnotobiote mice, which be used in the study of the metabolism effects of intestinal flora in vivo. In this test, the metabolic fate of the constituents of Huangqin-Tang decoction by intestinal bacteria was investigated using conventional, germ-free and gnotobiote mice (E. aerofaciens-infected and L. fermentum-infected). After oral administration of Huangqin-Tang, the cecal contents and cumulative feces were analyzed by HPLC method.
The constituents of Huangqin-Tang decoction in the cecal contents or feces were not metabolized in germ-free mice through out the experiment. However, the metabolites of the constituents of Huangqin-Tang decoction were detected both in conventional and two kinds of gnotobiote mice, which were similar to those metabolized by human intestinal bacteria in vitro.
2. The comparison of pharmacological effects between Huangqin-Tang decoction and their metabolites by human intestinal bacteria
2.1 The protective activity of liver injury induced by D-galactosamine(GalN)
Using the pseudogerm-free (conventional animals treated with various antibiotics) and conventional animals, the hepatoprotection effects in vivo between Huangqin-Tang decoction and metabolites were compared. The liver injuries in conventional and pseudo-germfree mice were induced by GalN. After oral administration of Huangqin-Tang or their metabolites, the serum transaminase (ALT and AST) activities were detected.
In pseudo-germfree mice, the metabolites significantly reduced ALT levels. However, Huangqing-Tang didn't affect the ALT levels in this kind of mice. It indicated that the metabolites had a more potential hepatoprotection effect than Huangqin-Tang decoction in pseudo-germfree mice.
2.2 The antibacterial activity in vitro and in vivo.
The antibacterial tests in vitro and in vivo were performed by agar dilution method and lethal protection of animal respectively.
The antibacterial activity of metabolites of Huangqin-Tang to Salmomella, Dysentery bacillus and Proteus in vitro was stronger than Huangqin-Tang decoction. The metabolites of Huangqin-Tang had lethal protection to the animals, which were infected by Staphylococcus aureus and Escherichia coll respectively, whereas Huangqin-Tang had no lethal protection effect.
All the results from the pharmacological effect tests suggested that intestinal bacteria played an important role in the metabolism of Huangqin-Tang decoction in vivo, and the metabolites of the constituents in Huangqin-Tang decoction by intestinal bacteria were the real active components in vivo. 3. Pharmacokinetics study of Huangqin-Tang decoction in rats
3.1 The gastrointestinal absorption and tran
1．黄芩汤主要成分在普通、悉生和无菌动物肠道内的代谢
接种特定菌株后的无菌动物成为悉生动物，将它们与普通动物进行体内代谢作用的比较研究，是考察肠道菌群在体内对药物进行代谢的主要方法之一。乳杆菌和真杆菌是肠道内与黄芩汤多成分代谢关系比较密切的菌株，在本试验中，给无菌小鼠接种这两种菌株，形成感染真杆菌的悉生小鼠和感染乳杆菌的悉生小鼠。给三种小鼠口服黄芩汤后，于不同时间点收集盲肠内容物和粪便，用HPLC方法对黄芩汤中的主要成分及其代谢产物进行分析，并且绘制了普通小鼠盲肠内容物中各成分及代谢产物的浓度-时间曲线。
结果表明：在无菌小鼠盲肠内容物和粪便中，黄芩汤中各主要成分没有发生明显的代谢转化，而普通小鼠、感染真杆菌和感染乳杆菌的悉生小鼠，发生了显著的代谢转化，其代谢规律与体外试验基本相同；与乳杆菌相比，真杆菌是一种代谢能力较强的菌株，而普通小鼠肠道内的混合菌，虽然完全代谢药物的作用时间长于真杆菌，但是其代谢强度高于真杆菌和乳杆菌；从普通小鼠盲肠内容物中各成分和代谢产物的浓度-时间曲线中可以发现，代谢产物的浓度达峰时间比原型化合物的浓度达峰时间要延迟4h左右。
2．黄芩汤及其肠道菌群的代谢产物的药效学比较
给普通小鼠联合使用多种抗生素三天，造成伪无菌小鼠模型，其肠道内的菌群被广泛地抑制。此种动物模型用于黄芩汤及代谢产物的体内药效学的比较试验。
2．1体内保肝降酶作用的比较
使用普通小鼠和伪无菌小鼠，分别给予黄芩汤和经肠道菌群作用的代谢产物，测定肝损伤模型小鼠血清转氨酶的水平，比较黄芩汤和代谢产物对D-半乳糖胺诱导的肝损伤动物的保护作用。结果表明黄芩汤对普通小鼠有保肝降酶的作用，对伪无菌小鼠则没有作用；而代谢产物对伪无菌小鼠有显著的保肝降酶作用。
2．2体外抗菌作用的比较
2 黄岑汤多成分药代动力学及肠道菌群作用的相关研究
试验采用琼脂稀释法。用最小抑菌浓度（MIC）表示试验药物的抑菌强度，
比较黄芍汤和代谢产物体外的抗菌作用。结果为黄岑汤代谢产物对沙门氏菌、痢
疾杆菌和变形杆菌的体外抗菌作用均明显强于黄岑汤。
2．3体内抗菌作用的比较
采用动物死亡保护法进行体内抗菌试验。使用伪无菌小鼠，分另u给予黄岑汤
或肠道菌群的代谢产物，动物的死亡是由感染金葡菌或大肠杆菌（腹腔注入）引
起的，感染后连续观察七天，并记录动物发病及死亡结果，比较黄岑汤和代谢产
物体内的抗菌作用。结果黄苹汤对由金葡菌和大肠杆菌腹腔感染引起的伪无菌小
鼠死亡都没有明显的保护作用，而代谢产物对由以上两种菌分别引起的伪无菌小
鼠死亡均具有明显的保护作用。
3．黄冬汤多成分在大鼠体内的药代动力学
3．1黄苹汤主要成分的胃肠道吸收
采用原位漳技术，对黄岑汤中主要成分在大鼠胃肠道各部位（胃、小肠和大
肠）的吸收情况进行了研究，同时进行了黄苹汤在大鼠胃肠道各部位的生物转化
的研究。
结果发现：黄苹汤中的旮成分BG；WG，OG；PF，LG和GL在胃肠道各
部位都很难吸收；而黄苹汤中的苦元成分B，W，O，L和GA的吸收率明显高
于相应的普成分。大肠是黄苹汤中各成分进行代谢转化的重要部位，盲肠的转化
率最高，其次是直肠和胃，各种成分在小肠都没有发生转化。黄芍汤中的苦成分，
只有很少的量在胃肠道直接吸收，而主要是在大肠（盲肠）部位转化为相应的代
谢产物，进而被吸收进入体内。
3．二黄革汤主要成分的组织分布
对黄芬汤口服后各成分在组织中的分布进行了研究，并对相同成分在黄冬汤
复方和黄苹单味药中的组织分布进行了比较。
结果在小肠、胃、肝和肾中，黄岑中大多数成分（其中包括在肝中的代谢产
物）的分布明显高于单味黄冬水煎剂中，说明复方对黄冬中的成分在组织中的分
布具有促进作用。
3．3黄芍汤主要成分及其代谢产物的血浆药代动力学
在建立的多成分HPLC分析方法学认证的基础上，对单次口服黄苹汤及各单
味药水煎剂（10g／kg）后的大鼠血浆中多种成分及代谢产物的药代动力学进行了
初步的研究，并对血浆中相同成分在复方和单味药中的药代动力学参数进行了比
较。
口服后，黄苹汤中各成分及代谢产物在血浆中的药时曲线均符合一室模型。
在复方和单味药中各成分的药动学参数之问存在差异。在复方中Cmax和AUC
比在单味药中偏高的有：BG，WG，OG，VDJ和LG等成分，其中WG具有显
著性差异；AUC在复方中比在单味药中?
In our previous studies, by using a high-performance liquid chromatographic (HPLC) method which was established in our laboratory, the metabolites in both the compound prescription and all the single herb decoctions were identified and determined both qualitatively and quantitatively. It could be found that the constituents of Huangqin-Tang, induing baicalin (baicalein 7-glucuronide; BG), wogonoside (wogoninoglucuronide; WG), oroxylin-A-glucuronide (OG) from Scutellariae Radix, paeoniflorin (PF) from Paeoniae Radix, liquiritin (liquiritigenin 4'-O-glucoside; LG), isoliquirtin (isoliquiritigenin 4-glucoside; ILG) and glycyrrhizic acid (GL) from Glycyhhizea Radix, were converted to their metabolites baicalein (B), wogonin (W), oroxylin-A (0), paeonimetabolin-I (PM-I), liquiritigenin (L), isoliquiritigenin (IL) and glycyrrhetinic acid (GA) by intestinal bacteria in vitro. And the results suggested that the metabolism of most glycosides was improved in the compound prescription. In the present paper, the pharmacokinetic study of Huangqin-Tang in rats, and the relation between intestinal bacteria and metabolism in vivo of Huangqin-Tang decoction were performanced. The experiments were carried out in the fields as follows:
1. The metabolism of constituents of Huangqin-Tang decoction in conventional, germ-free and gnotobiote mice
Germ-free animals infected certain bacteria to establish the gnotobiote mice, which be used in the study of the metabolism effects of intestinal flora in vivo. In this test, the metabolic fate of the constituents of Huangqin-Tang decoction by intestinal bacteria was investigated using conventional, germ-free and gnotobiote mice (E. aerofaciens-infected and L. fermentum-infected). After oral administration of Huangqin-Tang, the cecal contents and cumulative feces were analyzed by HPLC method.
The constituents of Huangqin-Tang decoction in the cecal contents or feces were not metabolized in germ-free mice through out the experiment. However, the metabolites of the constituents of Huangqin-Tang decoction were detected both in conventional and two kinds of gnotobiote mice, which were similar to those metabolized by human intestinal bacteria in vitro.
2. The comparison of pharmacological effects between Huangqin-Tang decoction and their metabolites by human intestinal bacteria
2.1 The protective activity of liver injury induced by D-galactosamine(GalN)
Using the pseudogerm-free (conventional animals treated with various antibiotics) and conventional animals, the hepatoprotection effects in vivo between Huangqin-Tang decoction and metabolites were compared. The liver injuries in conventional and pseudo-germfree mice were induced by GalN. After oral administration of Huangqin-Tang or their metabolites, the serum transaminase (ALT and AST) activities were detected.
In pseudo-germfree mice, the metabolites significantly reduced ALT levels. However, Huangqing-Tang didn't affect the ALT levels in this kind of mice. It indicated that the metabolites had a more potential hepatoprotection effect than Huangqin-Tang decoction in pseudo-germfree mice.
2.2 The antibacterial activity in vitro and in vivo.
The antibacterial tests in vitro and in vivo were performed by agar dilution method and lethal protection of animal respectively.
The antibacterial activity of metabolites of Huangqin-Tang to Salmomella, Dysentery bacillus and Proteus in vitro was stronger than Huangqin-Tang decoction. The metabolites of Huangqin-Tang had lethal protection to the animals, which were infected by Staphylococcus aureus and Escherichia coll respectively, whereas Huangqin-Tang had no lethal protection effect.
All the results from the pharmacological effect tests suggested that intestinal bacteria played an important role in the metabolism of Huangqin-Tang decoction in vivo, and the metabolites of the constituents in Huangqin-Tang decoction by intestinal bacteria were the real active components in vivo. 3. Pharmacokinetics study of Huangqin-Tang decoction in rats
3.1 The gastrointestinal absorption and tran
引文
[1] 康白主编：微生态学．大连：大连出版社，1988，95
[2] 韩国柱：药物在肠道的代谢及其对药物作用的影响。药学通报，1985，20(5)：294
[3] 赤尾光昭，他：肠内菌酵素生药成分代谢活化。和汉医药学会志，1992，9(1)：1
[4] Hattori M, Sakamoto T, Kobashi K, et al: Metabolism of Glycyrrhizin by human intestinal flora. Planta Med, 1983, 48:38
[5] Hattori M, Sakamoto T, Yamagishi T, et al: Metabolism of glycyrrhizin by human intestinal flora. Ⅱ Isolation and characterization of human intestinal bacteria capable of metabolizing glycyrrhizin and related compounds. Chem Pharm Bull, 1985, 33: 210
[6] Kim DH, Kim SY, Park SY, et al: Metabolism of quercitrin by human intestinal bacteria and its relation to some biological activities. Biol Pharm Bull, 1999, 22:749
[7] Kim DH, Jang IS, Lee SW, et al: Bacterioides J-37, a human intestinal bacterium, produces α-glucuronidase. Biol Pharm Bull, 1997, 20:834
[8] Akao T, et al: Glycyrrhizin β-glucuronidase of Eubacterium sp. from human intetinal flora. Chem Pharm Bull, 1987, 35:705
[9] Akao T: Localization of enzymes involved in metabolism of glycyrrhizin in contents of rat gastrointestinal tract. Biol Pharm Bull, 1997, 20:122
[10] Akao T: Hydrolysis of glycyrrhetyl mono-glucuronide to glycyrrhrtic acid by glycyrrhetyl mono-glucuronide β-D-glucuronidase of Eubacterium sp. GLH. Biol Pharm Bull, 1997, 20:1245
[11] Akao T: Hasty effect on the metabolism of glycyrrhizin by Eubacterium sp. GLH, with Ruminococcus sp. P01-3 and Clostridium innocuum ES24-06 of human intestinal bacteria. Biol Pharm Bull, 2000, 23:6
[12] Akao T: Effects of glycyrrhizin and glycyrrhetic acid on the growth, glycyrrhizin β-D-glucuronidase and 3β-hydroxysteriod dehydrogenase of human intestinal bacteria. Biol Pharm Bull, 2000, 23:104
[13] Akao T: Competition in the metabolism of glycyrrhizin with glycyrrhetic acidmono-glucuronide by mixed Eubacterium sp. GLH and Ruminococcus sp. P01-3.Biol Pharm Bull, 2000, 23:149
[14] Akao T: Effect of pH on metabolism of glycyrrhizin, glycyrrhetic acid andglycyrrhetic acid monoglucuronide by collected human intestinal flora. Biol PharmBull, 2001, 24:1108-1112
[15] Ishida S, Sakiya Y, Ichikawa T, et al: Pharmacokinetics of glycyrrhetic acid, A mojor metabolite of glycyrrhizin, in rats. Chem Pharm Bull, 1989, 37:2509
[16] Akao T, Hayashi T, Kobashi K, et al: Intestinal bacterial hydrolysis is indispensable to absorption of 18 β-glycyrrhetic acid after oral administration of glycyrrhizin in rats. J Pharm Pharmacol, 1994,46: 135
[17] Nose M, Ito M, Kamimura K, et al: A comparison of antihepatotoxic activity between glycyrrhizin and glycyrrhinic acid. Planta Med, 1993,49: 136
[18] Hattori M, Shu YZ, Shimizu M, et al: Metabolism of paeoniflorin and related compounds by human intestinal bacteria. Chem Pharm Bull, 1985, 33: 3838
[19] Shu YZ, et al: Metabolism of paeoniflorin and related compounds by human intestinal bacteria. Ⅱ. Structures of 7S-and 7R-paeonimetabolines Ⅰand Ⅱformed by Bacterides fragilis and Lactobacillus brevis. Chem Pharm Bull, 1987, 35: 3726
[20] Shu YZ, Hattori M, Akao T, et al: Metbolism of paeoniflorin and related compounds by human intestinal bacteria Ⅲ. Metabolic ability of intestinal bacterial strains and fecal from different individuals. J Tradit Med, 1987, 4: 82
[21] Akao T, Shu YZ, Matsuda Y, et al: Metabolism of peaoniflorin and Related compounds by intestinal bacteria.Ⅳ. Formation and structures of adducts of a metabolic intermediate with sulfhydryl compound by Lactobacillus brevis. Chem Pharm Bull, 1988,36:3043
[22] Abdal-Hafez A, Meshlhy MR, Nakamura N, et al: Potent anticonvulsant peaonimetabolin-Ⅰ derivatives obtained by incubation of paeoniflorin and thiol compounds with Lactobacillus brevis. Chem Pharm Bull, 1998, 46: 1486
[23] Takeda S, Wakui Y, Mizuhara Y, et al: Gastrointestinal absorption of paeoniflorin in germ-free rats. J Tradit Med, 1996,13:248
[24] Takeda S, Lsono T, Wakui Y, et al: In-vivo Assessment of extrahepatic metabolism of paeoniflorin in rats: Relevance to intestinal florai metabolism. J Pharm Pharmacol, 1997,49: 35
[25] Heikal OA, Akao T, Takeda S, et al: Pharmacokinetic study of paeonimetabolin-Ⅰ, a major metabolite of paeoniflorin from Paeony Roots. Biol Pharm Bull, 1997, 20: 517
[26] Hasegawa H, sung JH, Matsumiya S, et al: Main ginseng saponin metabolites formed by intestinal bacteria. Plant Med, 1996,62: 453
[27] Wang Y, Wang BX, Liu TH, et al: Metabolism of ginsenoside Rgl by intestinal bacteria. Ⅱ. Immunological activity of ginsenoside Rgl and Rh1． Acta Pharmacol Sin, 2000,21:792
[28] Bae EA, Han MJ, Choo MK, et al: Metabolism of 20(S)-and 20(R)-ginsenoside Rg3 by human intestinal bacteria and its relation to in vitro biological activities. Biol
Pharm Bull, 2002, 25:58
[29] Hasegawa H, Sung JH, Benno Y: Role of human intestinal prevotella oris in Hydrolyzing ginseng saponins. Plant Med, 1997, 63:436
[30] Akao T, Kida H, Kanaoka M, et al: Intestinal bacterial hydrolysis is required for the appearance of compound K in rat plasma after oral administration of Ginsenoside Rb1 from Panax ginseng. J Pharm Pharmacol, 1998, 50:1155
[31] 陈昕，周秋丽，王本祥：人参皂苷Rb1在大鼠肠内菌代谢物吸收入血成分的研究。药学学报，1999，34(7)：481
[32] Hasegawa H, Uchiyama M: Antimetastatic efficacy of orally administered ginsenoside Rbl in dependence on intestinal bacterial hydrolyzing potential and significance of treatment with an active bacterial metabolite. Planta Med, 1998, 64:696
[33] Hasegawa H, Lee KS, Nagaoka T, et al: Pharmacokinetics of ginsenoside deglycosylated by intestinal bacteria and its transformation to biologicaJly active fatty acid esters. Biol Pharm Bull, 2000, 23:298
[34] 小桥恭一：和汉药配糖体天然-踢内细菌役割．汉方研究，1995，279：74
[35] Akao T, Kawabata K, Yanaginsawa E, et al: Balicalin, the predominant flavone glucuronide of Scutellariae Radix, is absorbed from the rat gastrointestinal tract as the aglycone and restored to its original form. J Pharm Pharmacol, 2000, 52:1563
[36] Dreessen M, Eyssen H, Lemli J: The metabolism of sennosides A and B by the intestinal microflora: in vitro and in vivo studies on the rat and the mouse. J Pharm Pharmacol, 1981, 33:679
[37] Yang L, Akao T, Kobashi K, et al: Purification and characterization of a novel sennoside-hydrolyzing beta-glucoside from Bifidobacterium sp. Strain SEN, a human intestinal anaerobe. Biol Pharm Bull, 1996, 19:705
[38] Akao T, Che QM, Kobashi K, et al: A purgative action of Barbaloin is induced by Eubacterium sp. Strain BAR, a human intestinal Anaerobe, capable of transforming Barbaloin to Aloe-Emoin Anthron. Biol Pharm Bull, 1996, 19:136
[39] Kida H, Akao T, Meselhy MR, et al: Enzymea responsible for the metabolism of saikosaponins from Eubacterium sp. A-44, a human intestinal anaerobe. Biol Pharm Bull, 1997, 20:1274
[40] Kida H, Akao T, Meselhy MR, et al: Metabolism and pharmacokinetic of oral administration saikosaponin B1 in conventional, germ-free and Eubacterium sp. A-44-infected gnoyobiote rats. Biol Pharm Bull, 1998, 21:588
[41] Akao T, Kobashi K, Aburada M: Enzymic studies on the animal and intestinal bacterial metabolism of geniposide. Biol Pharm Bull, 1994, 17:1573
[42] Kim DH, Yu KU, Bae EA, et al: Metablolism of Puerarin and Daidzin by human intestinal bacteria and their relation to in vitro cytotoxicity. Biol Phaxm Bull, 1998, 21:628
[43] Kim DH, Park EK, Bae EA, et al: Metabolism of Rhaponticin and chrysophanol 8-O-β-D-glucopyranoside from the rhizome of Rheum undulatum by human intestinal bacteria and their anti-allergic actions. Biol Pharm Bull, 2000, 23:830
[44] 谷黎红，李铣，陈英杰，等：大丁草中抗菌活性成分的研究：人肠道微生物对大丁苷及其类似物的代谢产物．药学学报，1988，23(7)：511
[45] DH Kim, et al: Metabolism of quercitrin by human intestinal bacteria and its relation to some biological activities. Biol Phann Bull, 1999, 22:749
[46] Kim DH, Bae EA, Han MJ, et al: Metabolism of kalopanaxsaponin K by human intestinal bacteria and antirheumatoid arthritis activity of their metabolites. Biol Pharm Bull, 2002, 25:68
[47] Bae EA, Took CS, Oh OJ, et al: Metabolism of chiisanoside from Acanthopanax divaricatus var. albeofructus by human intestinal bacteria and its relation to some biological activities. Biol Pharm Bull, 2001, 24:582
[48] 雷厉，宋志宏，李寅增，等：管花肉苁蓉苯乙醇总苷在狗胃肠道内的生物转化。药学学报，2001，36(6)：432
[49] 王金辉，李铣：拟人参皂苷F11在大鼠体内的代谢研究。药学学报，2001，36(6)：427
[50] 杨秀伟，邢增涛，崔景荣，等：华蟾毒精和羟基华蟾毒精的人肠内细菌代谢研究。北京大学学报：医学版，2001，33(3)：199
[51] Kawata Y, Ma CM, Meselhy MR, et al: Conversion of aconitine to lipoaconitine by human intestinal bacteria and their antinociceptive effects in mice. J Tradit Med, 1999, 16:15
[52] Carter JH, Mclafferty MA, Goldman P: Role of the gastrointestinal microflora in amygdalin-induced toxicity. Biochem Phannacol, 1980, 29:301
[53] Kansmuller S, Mohn GR: On the distribution of genotoxic factors in various organs of mice treated with cycasin. Chem Biol Interact, 1986, 58:109
[54] 沈燕，吴立军，王本祥，等：参附汤体内代谢化学成分的初步研究。沈阳药科大学学报，2001，18(1)：23
[2] 韩国柱：药物在肠道的代谢及其对药物作用的影响。药学通报，1985，20(5)：294
[3] 赤尾光昭，他：肠内菌酵素生药成分代谢活化。和汉医药学会志，1992，9(1)：1
[4] Hattori M, Sakamoto T, Kobashi K, et al: Metabolism of Glycyrrhizin by human intestinal flora. Planta Med, 1983, 48:38
[5] Hattori M, Sakamoto T, Yamagishi T, et al: Metabolism of glycyrrhizin by human intestinal flora. Ⅱ Isolation and characterization of human intestinal bacteria capable of metabolizing glycyrrhizin and related compounds. Chem Pharm Bull, 1985, 33: 210
[6] Kim DH, Kim SY, Park SY, et al: Metabolism of quercitrin by human intestinal bacteria and its relation to some biological activities. Biol Pharm Bull, 1999, 22:749
[7] Kim DH, Jang IS, Lee SW, et al: Bacterioides J-37, a human intestinal bacterium, produces α-glucuronidase. Biol Pharm Bull, 1997, 20:834
[8] Akao T, et al: Glycyrrhizin β-glucuronidase of Eubacterium sp. from human intetinal flora. Chem Pharm Bull, 1987, 35:705
[9] Akao T: Localization of enzymes involved in metabolism of glycyrrhizin in contents of rat gastrointestinal tract. Biol Pharm Bull, 1997, 20:122
[10] Akao T: Hydrolysis of glycyrrhetyl mono-glucuronide to glycyrrhrtic acid by glycyrrhetyl mono-glucuronide β-D-glucuronidase of Eubacterium sp. GLH. Biol Pharm Bull, 1997, 20:1245
[11] Akao T: Hasty effect on the metabolism of glycyrrhizin by Eubacterium sp. GLH, with Ruminococcus sp. P01-3 and Clostridium innocuum ES24-06 of human intestinal bacteria. Biol Pharm Bull, 2000, 23:6
[12] Akao T: Effects of glycyrrhizin and glycyrrhetic acid on the growth, glycyrrhizin β-D-glucuronidase and 3β-hydroxysteriod dehydrogenase of human intestinal bacteria. Biol Pharm Bull, 2000, 23:104
[13] Akao T: Competition in the metabolism of glycyrrhizin with glycyrrhetic acidmono-glucuronide by mixed Eubacterium sp. GLH and Ruminococcus sp. P01-3.Biol Pharm Bull, 2000, 23:149
[14] Akao T: Effect of pH on metabolism of glycyrrhizin, glycyrrhetic acid andglycyrrhetic acid monoglucuronide by collected human intestinal flora. Biol PharmBull, 2001, 24:1108-1112
[15] Ishida S, Sakiya Y, Ichikawa T, et al: Pharmacokinetics of glycyrrhetic acid, A mojor metabolite of glycyrrhizin, in rats. Chem Pharm Bull, 1989, 37:2509
[16] Akao T, Hayashi T, Kobashi K, et al: Intestinal bacterial hydrolysis is indispensable to absorption of 18 β-glycyrrhetic acid after oral administration of glycyrrhizin in rats. J Pharm Pharmacol, 1994,46: 135
[17] Nose M, Ito M, Kamimura K, et al: A comparison of antihepatotoxic activity between glycyrrhizin and glycyrrhinic acid. Planta Med, 1993,49: 136
[18] Hattori M, Shu YZ, Shimizu M, et al: Metabolism of paeoniflorin and related compounds by human intestinal bacteria. Chem Pharm Bull, 1985, 33: 3838
[19] Shu YZ, et al: Metabolism of paeoniflorin and related compounds by human intestinal bacteria. Ⅱ. Structures of 7S-and 7R-paeonimetabolines Ⅰand Ⅱformed by Bacterides fragilis and Lactobacillus brevis. Chem Pharm Bull, 1987, 35: 3726
[20] Shu YZ, Hattori M, Akao T, et al: Metbolism of paeoniflorin and related compounds by human intestinal bacteria Ⅲ. Metabolic ability of intestinal bacterial strains and fecal from different individuals. J Tradit Med, 1987, 4: 82
[21] Akao T, Shu YZ, Matsuda Y, et al: Metabolism of peaoniflorin and Related compounds by intestinal bacteria.Ⅳ. Formation and structures of adducts of a metabolic intermediate with sulfhydryl compound by Lactobacillus brevis. Chem Pharm Bull, 1988,36:3043
[22] Abdal-Hafez A, Meshlhy MR, Nakamura N, et al: Potent anticonvulsant peaonimetabolin-Ⅰ derivatives obtained by incubation of paeoniflorin and thiol compounds with Lactobacillus brevis. Chem Pharm Bull, 1998, 46: 1486
[23] Takeda S, Wakui Y, Mizuhara Y, et al: Gastrointestinal absorption of paeoniflorin in germ-free rats. J Tradit Med, 1996,13:248
[24] Takeda S, Lsono T, Wakui Y, et al: In-vivo Assessment of extrahepatic metabolism of paeoniflorin in rats: Relevance to intestinal florai metabolism. J Pharm Pharmacol, 1997,49: 35
[25] Heikal OA, Akao T, Takeda S, et al: Pharmacokinetic study of paeonimetabolin-Ⅰ, a major metabolite of paeoniflorin from Paeony Roots. Biol Pharm Bull, 1997, 20: 517
[26] Hasegawa H, sung JH, Matsumiya S, et al: Main ginseng saponin metabolites formed by intestinal bacteria. Plant Med, 1996,62: 453
[27] Wang Y, Wang BX, Liu TH, et al: Metabolism of ginsenoside Rgl by intestinal bacteria. Ⅱ. Immunological activity of ginsenoside Rgl and Rh1． Acta Pharmacol Sin, 2000,21:792
[28] Bae EA, Han MJ, Choo MK, et al: Metabolism of 20(S)-and 20(R)-ginsenoside Rg3 by human intestinal bacteria and its relation to in vitro biological activities. Biol
Pharm Bull, 2002, 25:58
[29] Hasegawa H, Sung JH, Benno Y: Role of human intestinal prevotella oris in Hydrolyzing ginseng saponins. Plant Med, 1997, 63:436
[30] Akao T, Kida H, Kanaoka M, et al: Intestinal bacterial hydrolysis is required for the appearance of compound K in rat plasma after oral administration of Ginsenoside Rb1 from Panax ginseng. J Pharm Pharmacol, 1998, 50:1155
[31] 陈昕，周秋丽，王本祥：人参皂苷Rb1在大鼠肠内菌代谢物吸收入血成分的研究。药学学报，1999，34(7)：481
[32] Hasegawa H, Uchiyama M: Antimetastatic efficacy of orally administered ginsenoside Rbl in dependence on intestinal bacterial hydrolyzing potential and significance of treatment with an active bacterial metabolite. Planta Med, 1998, 64:696
[33] Hasegawa H, Lee KS, Nagaoka T, et al: Pharmacokinetics of ginsenoside deglycosylated by intestinal bacteria and its transformation to biologicaJly active fatty acid esters. Biol Pharm Bull, 2000, 23:298
[34] 小桥恭一：和汉药配糖体天然-踢内细菌役割．汉方研究，1995，279：74
[35] Akao T, Kawabata K, Yanaginsawa E, et al: Balicalin, the predominant flavone glucuronide of Scutellariae Radix, is absorbed from the rat gastrointestinal tract as the aglycone and restored to its original form. J Pharm Pharmacol, 2000, 52:1563
[36] Dreessen M, Eyssen H, Lemli J: The metabolism of sennosides A and B by the intestinal microflora: in vitro and in vivo studies on the rat and the mouse. J Pharm Pharmacol, 1981, 33:679
[37] Yang L, Akao T, Kobashi K, et al: Purification and characterization of a novel sennoside-hydrolyzing beta-glucoside from Bifidobacterium sp. Strain SEN, a human intestinal anaerobe. Biol Pharm Bull, 1996, 19:705
[38] Akao T, Che QM, Kobashi K, et al: A purgative action of Barbaloin is induced by Eubacterium sp. Strain BAR, a human intestinal Anaerobe, capable of transforming Barbaloin to Aloe-Emoin Anthron. Biol Pharm Bull, 1996, 19:136
[39] Kida H, Akao T, Meselhy MR, et al: Enzymea responsible for the metabolism of saikosaponins from Eubacterium sp. A-44, a human intestinal anaerobe. Biol Pharm Bull, 1997, 20:1274
[40] Kida H, Akao T, Meselhy MR, et al: Metabolism and pharmacokinetic of oral administration saikosaponin B1 in conventional, germ-free and Eubacterium sp. A-44-infected gnoyobiote rats. Biol Pharm Bull, 1998, 21:588
[41] Akao T, Kobashi K, Aburada M: Enzymic studies on the animal and intestinal bacterial metabolism of geniposide. Biol Pharm Bull, 1994, 17:1573
[42] Kim DH, Yu KU, Bae EA, et al: Metablolism of Puerarin and Daidzin by human intestinal bacteria and their relation to in vitro cytotoxicity. Biol Phaxm Bull, 1998, 21:628
[43] Kim DH, Park EK, Bae EA, et al: Metabolism of Rhaponticin and chrysophanol 8-O-β-D-glucopyranoside from the rhizome of Rheum undulatum by human intestinal bacteria and their anti-allergic actions. Biol Pharm Bull, 2000, 23:830
[44] 谷黎红，李铣，陈英杰，等：大丁草中抗菌活性成分的研究：人肠道微生物对大丁苷及其类似物的代谢产物．药学学报，1988，23(7)：511
[45] DH Kim, et al: Metabolism of quercitrin by human intestinal bacteria and its relation to some biological activities. Biol Phann Bull, 1999, 22:749
[46] Kim DH, Bae EA, Han MJ, et al: Metabolism of kalopanaxsaponin K by human intestinal bacteria and antirheumatoid arthritis activity of their metabolites. Biol Pharm Bull, 2002, 25:68
[47] Bae EA, Took CS, Oh OJ, et al: Metabolism of chiisanoside from Acanthopanax divaricatus var. albeofructus by human intestinal bacteria and its relation to some biological activities. Biol Pharm Bull, 2001, 24:582
[48] 雷厉，宋志宏，李寅增，等：管花肉苁蓉苯乙醇总苷在狗胃肠道内的生物转化。药学学报，2001，36(6)：432
[49] 王金辉，李铣：拟人参皂苷F11在大鼠体内的代谢研究。药学学报，2001，36(6)：427
[50] 杨秀伟，邢增涛，崔景荣，等：华蟾毒精和羟基华蟾毒精的人肠内细菌代谢研究。北京大学学报：医学版，2001，33(3)：199
[51] Kawata Y, Ma CM, Meselhy MR, et al: Conversion of aconitine to lipoaconitine by human intestinal bacteria and their antinociceptive effects in mice. J Tradit Med, 1999, 16:15
[52] Carter JH, Mclafferty MA, Goldman P: Role of the gastrointestinal microflora in amygdalin-induced toxicity. Biochem Phannacol, 1980, 29:301
[53] Kansmuller S, Mohn GR: On the distribution of genotoxic factors in various organs of mice treated with cycasin. Chem Biol Interact, 1986, 58:109
[54] 沈燕，吴立军，王本祥，等：参附汤体内代谢化学成分的初步研究。沈阳药科大学学报，2001，18(1)：23