灵芝药材及其制剂双灵固本散的质量控制和体内代谢研究
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摘要
本文以传统中药灵芝及其制剂双灵固本散为研究对象，对其进行了质量控制、体内代谢、代谢指纹图谱及谱效学研究。
从灵芝制剂—双灵固本散中分离纯化得到7种灵芝三萜酸类化合物，经过色谱法和各种光谱技术鉴定了7种灵芝酸对照品的结构，分别是：灵芝酸C_2、G、B、K、AM_1、H和灵芝烯酸B。
通过对36批次不同来源的灵芝药材和10批次双灵固本散的研究，首次建立了灵芝三萜化学成分HPLC指纹图谱，并应用LC／MS技术对指纹图谱中主要的特征峰进行了指认。指纹图谱可分为2个区，Ⅰ区为指纹图谱特征区，其中三萜成分含量较高，但种类较少；Ⅱ区为指纹区，三萜成分含量较低，但种类较为丰富。
首次建立了灵芝药材多指标成分HPLC／DAD定量分析方法，测定了36批次不同来源灵芝药材中6种主要三萜酸的含量。研究表明，不同种的灵芝药材中三萜成分的种类和含量均有明显差别。赤灵芝中三萜成分的种类和含量较为丰富，而在紫芝中几乎不含有三萜成分，这表明两者可能具有不同的药理作用，临床应用时应加以区别。本研究建立的HPLC分析方法简单、稳定、准确适用于灵芝药材的质量控制。灵芝药材多指标成分的含量测定和指纹图谱研究，将对灵芝药材及其制剂质量的全面控制起到积极作用。
首次建立了不同生物样品中4种主要三萜酸类成分的HPLC／DAD含量测定方法。以灵芝酸C_2、B、K、H为指标，对灵芝三萜酸类成分在SD大鼠体内的吸收、分布、代谢及排泄进行了系统研究。研究结果表明，大鼠口服灵芝总三萜酸后，消化道吸收迅速，组织分布广泛，体内清除较快；灵芝三萜酸成分广泛分布于各主要脏器，肝脏是其主要的代谢器官，三萜酸成分将由其它脏器重新分布到肝脏，而后经胆汁排出体外；胆汁为体内药物的主要排泄途径，肾排泄作用较弱。
首次建立了SD大鼠口服灵芝总三萜酸后的血清代谢指纹图谱，并进行了不同采血时间的血清药理学研究。以HeLa细胞增殖抑制率为指标，采用化学统计学方法，将代谢指纹图谱和药物效应相关联，形成中药化学物质与药物效应相互关联的研究方法，从而建立了一种新的中药质量评价体系。代谢指纹图谱中共有16个特征峰，其中5个特征峰与药理作用密切相关，因此控制这部分化合物在药材中的含量，将有助于确保药材的整体药效和质量。
Ganoderma lucidum (Leyss. ex Fr.) Karst (Polyporaceae) is a well-known Chinese herbal medicine, which has long been used in traditional Chinese medicine for the promotion of longevity and maintenance of vitality. Owing to its satisfactory clinical effect, Ganoderma lucidum has been widely used as the major component of healthy foods and drugs in China. The Shanghai Green Vally Pharmaceutical Co. cultivated G. lucidum in GAP conditions and developed an anticancer complex prescription comprised with fruit body extract and sporoderm-broken spores of G. lucidum, namely SunRecome(?). The results of pharmacological research on SunRecome(?) showed that it not only has the anticancer activity but also has the benefit of reducing chemotherapy-induced side effects. In this thesis, the quality control, metabolism of total triterpenoids in SD rats, metabolic fingerprinting were systematically studied.
The chemical constituents of SunRecome(?) were systematically studied and 7 ganoderic acids were purified by silca gel, pre-TLC and pre-HPLC methods. Utilizing spectroscopic method (UV, NMR, MS), the structures of 7 compounds were fully characterized. These seven compounds were suitable as standard substances for quantitative purposes.
The method of HPLC fingerprinting analysis was established for the quality control of G. lucidum and its preparation - SunRecome(?), and the LC/MS method was applied for the identification of peaks in fingerprinting chromatograms. The developed fingerprinting methods were then used to identify and access the consistency of different samples, which were collected from GAP base and different drug stores in China. The fingerprinting chromatograms have two characteristic regions. The contents of triterpenoids in region I are higher than those in region II.
The six major active ganoderic acids of G. lucidum (ganoderic acids C_2, B, K, AM_1, H and D) were simultaneously quantified by HPLC/DAD method. These results showed that the content and composition of triterpenoids differed significantly in different species due to the difference in genetic source, cultivating conditions, or processing procedure. Both G. lucidum and the G. sinense are the official two species of Lingzhi recorded in Chinese Pharmacopoeia (2005 edition) and they were considered to have the same therapeutic effects. But the average content of total triterpenoids in G. lucidum was 10 times higher than that in G. sinense, which indicated that the therapeutic effects of these two species might be quite different. Therefore they are recommended to use as two different herbs in clinics.
The four triterpenoids, ganoderic acids C_1, B, K and H, were qualitatively analyzed by HPLC/DAD in different bio-matrices, such as plasma, bile, urine and tissues in SD rats. The absorption, distribution, metabolism and excretion of ganoderic acids in SD rats after oral administration of G. lucidum extract were preliminarily investigated. The results indicated that the four triterpenoids were rapidly absorbed into the body fluid from the gastrointestinal tract after oral administration and widely distributed in the organs. The triterpenoids were mainly excreted from inner-body through the bile fluid.
HPLC/DAD and LC/MS techniques were used to establish the metabolic fingerprinting of triterpinoids in rat serum after oral administration of G. lucidum extract, and the serum pharmacology was also applied to evaluate the pharmacological effects of serum. The mathematical statistics method was applied to analyze the relationship between metabolic fingerprinting and serum pharmacology studies. The 5 peaks in metabolic fingerprinting chromatograms have the significant relationship with the values of inhibition ratio of HeLa cell, and the 5 peaks could be chosen as the marker compound in quality control of crude drugs and their finished products.
从灵芝制剂—双灵固本散中分离纯化得到7种灵芝三萜酸类化合物，经过色谱法和各种光谱技术鉴定了7种灵芝酸对照品的结构，分别是：灵芝酸C_2、G、B、K、AM_1、H和灵芝烯酸B。
通过对36批次不同来源的灵芝药材和10批次双灵固本散的研究，首次建立了灵芝三萜化学成分HPLC指纹图谱，并应用LC／MS技术对指纹图谱中主要的特征峰进行了指认。指纹图谱可分为2个区，Ⅰ区为指纹图谱特征区，其中三萜成分含量较高，但种类较少；Ⅱ区为指纹区，三萜成分含量较低，但种类较为丰富。
首次建立了灵芝药材多指标成分HPLC／DAD定量分析方法，测定了36批次不同来源灵芝药材中6种主要三萜酸的含量。研究表明，不同种的灵芝药材中三萜成分的种类和含量均有明显差别。赤灵芝中三萜成分的种类和含量较为丰富，而在紫芝中几乎不含有三萜成分，这表明两者可能具有不同的药理作用，临床应用时应加以区别。本研究建立的HPLC分析方法简单、稳定、准确适用于灵芝药材的质量控制。灵芝药材多指标成分的含量测定和指纹图谱研究，将对灵芝药材及其制剂质量的全面控制起到积极作用。
首次建立了不同生物样品中4种主要三萜酸类成分的HPLC／DAD含量测定方法。以灵芝酸C_2、B、K、H为指标，对灵芝三萜酸类成分在SD大鼠体内的吸收、分布、代谢及排泄进行了系统研究。研究结果表明，大鼠口服灵芝总三萜酸后，消化道吸收迅速，组织分布广泛，体内清除较快；灵芝三萜酸成分广泛分布于各主要脏器，肝脏是其主要的代谢器官，三萜酸成分将由其它脏器重新分布到肝脏，而后经胆汁排出体外；胆汁为体内药物的主要排泄途径，肾排泄作用较弱。
首次建立了SD大鼠口服灵芝总三萜酸后的血清代谢指纹图谱，并进行了不同采血时间的血清药理学研究。以HeLa细胞增殖抑制率为指标，采用化学统计学方法，将代谢指纹图谱和药物效应相关联，形成中药化学物质与药物效应相互关联的研究方法，从而建立了一种新的中药质量评价体系。代谢指纹图谱中共有16个特征峰，其中5个特征峰与药理作用密切相关，因此控制这部分化合物在药材中的含量，将有助于确保药材的整体药效和质量。
Ganoderma lucidum (Leyss. ex Fr.) Karst (Polyporaceae) is a well-known Chinese herbal medicine, which has long been used in traditional Chinese medicine for the promotion of longevity and maintenance of vitality. Owing to its satisfactory clinical effect, Ganoderma lucidum has been widely used as the major component of healthy foods and drugs in China. The Shanghai Green Vally Pharmaceutical Co. cultivated G. lucidum in GAP conditions and developed an anticancer complex prescription comprised with fruit body extract and sporoderm-broken spores of G. lucidum, namely SunRecome(?). The results of pharmacological research on SunRecome(?) showed that it not only has the anticancer activity but also has the benefit of reducing chemotherapy-induced side effects. In this thesis, the quality control, metabolism of total triterpenoids in SD rats, metabolic fingerprinting were systematically studied.
The chemical constituents of SunRecome(?) were systematically studied and 7 ganoderic acids were purified by silca gel, pre-TLC and pre-HPLC methods. Utilizing spectroscopic method (UV, NMR, MS), the structures of 7 compounds were fully characterized. These seven compounds were suitable as standard substances for quantitative purposes.
The method of HPLC fingerprinting analysis was established for the quality control of G. lucidum and its preparation - SunRecome(?), and the LC/MS method was applied for the identification of peaks in fingerprinting chromatograms. The developed fingerprinting methods were then used to identify and access the consistency of different samples, which were collected from GAP base and different drug stores in China. The fingerprinting chromatograms have two characteristic regions. The contents of triterpenoids in region I are higher than those in region II.
The six major active ganoderic acids of G. lucidum (ganoderic acids C_2, B, K, AM_1, H and D) were simultaneously quantified by HPLC/DAD method. These results showed that the content and composition of triterpenoids differed significantly in different species due to the difference in genetic source, cultivating conditions, or processing procedure. Both G. lucidum and the G. sinense are the official two species of Lingzhi recorded in Chinese Pharmacopoeia (2005 edition) and they were considered to have the same therapeutic effects. But the average content of total triterpenoids in G. lucidum was 10 times higher than that in G. sinense, which indicated that the therapeutic effects of these two species might be quite different. Therefore they are recommended to use as two different herbs in clinics.
The four triterpenoids, ganoderic acids C_1, B, K and H, were qualitatively analyzed by HPLC/DAD in different bio-matrices, such as plasma, bile, urine and tissues in SD rats. The absorption, distribution, metabolism and excretion of ganoderic acids in SD rats after oral administration of G. lucidum extract were preliminarily investigated. The results indicated that the four triterpenoids were rapidly absorbed into the body fluid from the gastrointestinal tract after oral administration and widely distributed in the organs. The triterpenoids were mainly excreted from inner-body through the bile fluid.
HPLC/DAD and LC/MS techniques were used to establish the metabolic fingerprinting of triterpinoids in rat serum after oral administration of G. lucidum extract, and the serum pharmacology was also applied to evaluate the pharmacological effects of serum. The mathematical statistics method was applied to analyze the relationship between metabolic fingerprinting and serum pharmacology studies. The 5 peaks in metabolic fingerprinting chromatograms have the significant relationship with the values of inhibition ratio of HeLa cell, and the 5 peaks could be chosen as the marker compound in quality control of crude drugs and their finished products.
引文
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