基于“广枣—冰片”配伍设计的没食子酸冰片酯体内外代谢研究
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摘要
中药作为庞大的天然产物数据库吸引了全世界越来越多的关注,也为新药的研究与开发提供了重要来源。并且中药的应用在我国具有悠久的历史,是长期实践经验的总结,具有独特、丰富的理论基础,其安全性与有效性已历经两千多年临床验证,这使得以中药为源泉筛选的活性化合物分子具有更大的优势。中药最大的特点是复方配伍,即按病情需要和药性特点,有选择地将两味或以上药物配合同用。它体现了中医的整体观念和辨证论治的特色思想,可为创新药物的设计提供灵感。本文以广枣-冰片配伍为出发点,全面分析了广枣果肉的化学成分及其在大鼠体内的代谢产物；考察了冰片对广枣的入血活性成分没食子酸在药动学及组织分布上的影响,为冰片与没食子酸的组合提供佐证；在此基础上合成了可体现活血化瘀-芳香开窍“广枣-冰片”配伍特点的活性化合物——没食子酸冰片酯(Bornyl gallate, BG),并对其展开体内外药物代谢研究,拟揭示其在大鼠体内的动态变化规律,为其药理学、毒理学研究以及合理用药的安全性和有效性提供依据。全文共分为六部分,主要研究内容如下：
1.通过LC/Q-TOF/MS分析方法在广枣药材果肉提取物中检测了42个化学成分,并推测其结构,其中17个是在广枣中新发现的成分。广枣给药后,在大鼠血浆中检测到的成分包括入血原型成分13个；由原型成分转化生成的代谢产物7种,观察到有显著变化的应激成分3个。入血成分以有机酸类成分为主,代谢产物多为酸类的Ⅱ相反应结合产物。实验结果从血清药物化学的角度说明广枣的药效物质基础为有机酸类成分。
2.采用HPLC-DAD法测定了SD大鼠分别灌胃没食子酸药液和没食子酸加冰片药液后,没食子酸在大鼠血浆和组织样品中的含量,计算了给药后的药物动力学参数,并通过双侧非配对t检验进行统计学分析,研究了配伍冰片前后,没食子酸在大鼠体内的药动学参数和组织分布的显著性差异。结果表明：一方面,冰片可使没食子酸在大鼠体内的部分药代动力学参数发生显著变化,其中α,t1/2α增大,CL/F减小,MRTO-t增大,AUC增加了约1.6倍,各时间点的血药浓度略有增加。另一方面,冰片对没食子酸的组织分布总体上影响不大,但是使心和脑中的没食子酸含量有所增加,使肾中的含量显著减少。提示冰片可以增加没食子酸在体内的含量,增大生物利用度,进一步证明了冰片对没食子酸具有促进吸收,减慢代谢的增效作用。
3.将没食子酸与冰片组合,合成可体现活血化瘀-芳香开窍的“广枣-冰片”配伍特点的化合物3,4,5-三羟基苯甲酸冰片酯(BG)。对三种合成路线进行了考察,并对获得的产物进行了LC. MS、IR和NMR结构表征,确认所合成的产物均为没食子酸冰片酯,为下一步的体内外代谢研究提供了高纯度、结构确切的原型化合物。
4.对BG在鼠肝微粒体中的代谢进行了研究。首先通过HPLC-DAD法测定了BG的代谢稳定性并鉴定出参与BG代谢的CYP酶亚型。结果表明BG经过0.25mg/mL鼠肝微粒体代谢,t1/2为14.88±0.22min,内在清除率CLint值为0.932±0.014mL/min/mg;参与代谢肝药酶为CYP2C8酶系；提示BG在肝微粒体中有较好的稳定性,与对CYP2C8酶有抑制或诱导作用的药物合用时会产生相互影响。然后通过LC/Q-TOF/MS法鉴定了BG在鼠肝微粒体中的代谢产物,发现BG生成了5个羟基化代谢产物。
5.研究了BG在正常大鼠体内的药代动力学过程和组织分布情况。研究发现灌胃给药时BG在大鼠体内的药物代谢过程符合二室模型,静脉注射时为三室模型；t1/2≈3h说明BG属于快速代谢药物,生物利用度为27.3%。组织分布研究结果显示各组织中的药物浓度由高至低依次为肾>肝>脑>心。与没食子酸相比,BG在组织中的含量更高,脑中含量增大尤为显著,这与引入冰片基后,极性降低,亲脂性增强有关,说明BG更容易透过血脑屏障和组织膜,在治疗心脑血管疾病时能直达病所。药动学及组织分布结果表明BG具有继续开发的潜力。
6.应用HPLC/Q-TOF/MS分析方法检测并鉴定了BG在大鼠血浆和尿液中的9种代谢产物,包括同分异构体在内共18个化合物；初步推测BG在大鼠体内的代谢途径。结果表明BG在体内产生多种Ⅰ相和Ⅱ相代谢产物,包括羟基化、水解、O-甲基化、葡萄糖醛酸化产物,其中相对含量最高的是BG-O-葡萄糖醛酸和O-甲基-BG-O-葡萄糖醛酸,提示O-甲基化和葡萄糖醛酸化是BG最主要的代谢途径。
Traditional Chinese medicine (TCM), which serves as a resource of bioactive compounds for drug discovery, is attracting increasing global attention. Such ample Chinese natural medicinal resources provide valuable materials for the discovery and development of new drugs. More importantly, the clinic medicinal experience of more than2000years made the TCM-derived active compounds better lead compounds for further chemical improvements. As is well-known, multi-herb therapy is one of the most important characteristics of TCM. In TCM theory, compatibility refers to the combination of two or more herbs based on the clinical settings and the properties of herbs. Compatibility not only represents overall concept and differential treatment but also provides inspirations for the molecular design of new drug candidates. With the drug pair "GuangZao-borneol" were chosen as starting point, we comprehensively analyzed the constituents and their metabolites in rat plasma after oral administration of the extract of Choerospondiatis Fructus (Guangzao in Chinese, GZ) by LC/Q-TOF/MS, and then investigated the influence of borneol in the pharmacokinetics and tissue distribution to gallic acid which is the bioactive compound of Choerospondiatis Fructus in rat plasma. Subsequently, bornyl gallate (BG) was synthesized based on those results from previous experiments. BG is designed to promote blood circulation, remove blood stasis and promoting active compounds penetrating the biological barriers, which represents the compatibility characteristic of the drug pair "Guangzao-borneol". In vivo and in vitro metabolisms of BG were investigated to reveal the rules of dynamic changes in rat. It will be helpful for the pharmacology and toxicology studies as well as the clinical security and effectiveness of BG. The full text included six parts listed as follows.
1. Identification of42constituents in the flushes of dried GZ by LC/Q-TOF/MS. Among them,17constituents are found firstly in GZ. After oral administration of extract of GZ, there are13prototype constituents,7kinds of metabolites and3endogenous response compounds detected in rat plasma. These prototype constituents in plasma are mainly organic acids. The metabolites are mainly Ⅱ phase conjugation products of organic acids. While only catechin and quercetin-O-glucuronide is the flavonoids compounds in plasma. These results indicated, from the perspective of serum pharmacochemistry, that the organic acids are the bioactive material basis of GZ.
2. Gallic acid, the bioactive compound in GZ, was chosen as leading compound. The concentration of gallic acid in plasma and tissues were determined after oral administration of gallic acid and gallic acid plus borneol. Then the pharmacokinetic parameters of gallic acid were calculated by DAS2.0Software. Finally, the significant differences of pharmacokinetic parameters and tissue distribution of gallic acid between gallic acid group and gallic acid plus borneol group were analyzed with two-sided unpaired t-test. These results showed that on one hand borneol could significantly influence some pharmacokinetic parameters of gallic acid such as decreasing CL/F, increasing a, t1/2a, MRTo-t and AUC. On the other hand, borneol could change tissue distributions of gallic acid to some extent such as increasing slightly the concentration in heart and brain, decreasing significantly the concentration of gallic acid in kidney. All the results demonstrated that borneol could increase the concentration and bioavailability of gallic acid in rat. It also proves the synergistic effect of borneol to enhance the absorption, distribution, permeability, and efficacy of gallic acid.
3. BG was synthesized by the reaction of two natural products, gallic acid and borneol. Three different synthetic routes were compared in this part. All the products were characterized by LC, MS, IR and NMR to confirm their structures were identical as BG in order to provide high purity prototype compound for the following metabolism experiments.
4. Investigation of the in vitro metabolism of BG in rat liver microsome (RLM). Firstly, a HPLC-DAD method was established to test the metabolic stability of BG in RLM and to identify the subtype of CYP enzymes involved in metabolism of BG. It showed that BG was metabolized by0.25mg/mL RLM with a t1/2=14.88±0.33min and a CLint=0.186±0.004mL/min/mg. CYP2C8was proved to be the subtype of CYP enzymes involved in metabolism of BG. Then, a LC/Q-TOF/MS method was applied to identify the in vitro metabolites of BG. The results showed BG was metabolized to five isomers of mono-hydroxylated BG.
5. Study on the in vivo pharmacokinetics and tissue distribution of BG in rat. The results showed the pharmacokinetic profiles of BG after oral administration was fitted to the two compartment model, while the concentration-time curve of BG after intravenous injection was fitted to three compartment model. BG was fast metabolized drug because of its tl/2≈3h. the bioavailability of BG was27.3%. The results of tissue distribution showed that the concentrations of BG in tissues from highness to lowness were kidney, liver, brain and heart. Compared with gallic acid, the concentration of BG in tissues were higher, especially in brain which should be relative to the lower polarity and higher lipophilicity of this molecule after importing the borneol moiety. It indicated BG was easier to pass blood-brain barrier and tissue membrane. All the results from pharmacokinetic and tissue distribution studies suggested BG is worthy of further investigation.
6. A reliable and sensitive HPLC/Q-TOF/MS method was successfully applied to identify the metabolites of bornyl gallate in rat.9kinds of potential metabolites, altogether18compounds including all isomers, were detected and identified. BG is believed to undergo various phases I and II metabolic pathways including hydroxylation, hydrolysis, O-methylation and glucuronidation. We also proved that BG mainly became products of glucuronidation and O-methylation in vivo, which were identified as BG-O-glucuronide and O-methyl BG-O-glucuronide.
1.通过LC/Q-TOF/MS分析方法在广枣药材果肉提取物中检测了42个化学成分,并推测其结构,其中17个是在广枣中新发现的成分。广枣给药后,在大鼠血浆中检测到的成分包括入血原型成分13个；由原型成分转化生成的代谢产物7种,观察到有显著变化的应激成分3个。入血成分以有机酸类成分为主,代谢产物多为酸类的Ⅱ相反应结合产物。实验结果从血清药物化学的角度说明广枣的药效物质基础为有机酸类成分。
2.采用HPLC-DAD法测定了SD大鼠分别灌胃没食子酸药液和没食子酸加冰片药液后,没食子酸在大鼠血浆和组织样品中的含量,计算了给药后的药物动力学参数,并通过双侧非配对t检验进行统计学分析,研究了配伍冰片前后,没食子酸在大鼠体内的药动学参数和组织分布的显著性差异。结果表明：一方面,冰片可使没食子酸在大鼠体内的部分药代动力学参数发生显著变化,其中α,t1/2α增大,CL/F减小,MRTO-t增大,AUC增加了约1.6倍,各时间点的血药浓度略有增加。另一方面,冰片对没食子酸的组织分布总体上影响不大,但是使心和脑中的没食子酸含量有所增加,使肾中的含量显著减少。提示冰片可以增加没食子酸在体内的含量,增大生物利用度,进一步证明了冰片对没食子酸具有促进吸收,减慢代谢的增效作用。
3.将没食子酸与冰片组合,合成可体现活血化瘀-芳香开窍的“广枣-冰片”配伍特点的化合物3,4,5-三羟基苯甲酸冰片酯(BG)。对三种合成路线进行了考察,并对获得的产物进行了LC. MS、IR和NMR结构表征,确认所合成的产物均为没食子酸冰片酯,为下一步的体内外代谢研究提供了高纯度、结构确切的原型化合物。
4.对BG在鼠肝微粒体中的代谢进行了研究。首先通过HPLC-DAD法测定了BG的代谢稳定性并鉴定出参与BG代谢的CYP酶亚型。结果表明BG经过0.25mg/mL鼠肝微粒体代谢,t1/2为14.88±0.22min,内在清除率CLint值为0.932±0.014mL/min/mg;参与代谢肝药酶为CYP2C8酶系；提示BG在肝微粒体中有较好的稳定性,与对CYP2C8酶有抑制或诱导作用的药物合用时会产生相互影响。然后通过LC/Q-TOF/MS法鉴定了BG在鼠肝微粒体中的代谢产物,发现BG生成了5个羟基化代谢产物。
5.研究了BG在正常大鼠体内的药代动力学过程和组织分布情况。研究发现灌胃给药时BG在大鼠体内的药物代谢过程符合二室模型,静脉注射时为三室模型；t1/2≈3h说明BG属于快速代谢药物,生物利用度为27.3%。组织分布研究结果显示各组织中的药物浓度由高至低依次为肾>肝>脑>心。与没食子酸相比,BG在组织中的含量更高,脑中含量增大尤为显著,这与引入冰片基后,极性降低,亲脂性增强有关,说明BG更容易透过血脑屏障和组织膜,在治疗心脑血管疾病时能直达病所。药动学及组织分布结果表明BG具有继续开发的潜力。
6.应用HPLC/Q-TOF/MS分析方法检测并鉴定了BG在大鼠血浆和尿液中的9种代谢产物,包括同分异构体在内共18个化合物；初步推测BG在大鼠体内的代谢途径。结果表明BG在体内产生多种Ⅰ相和Ⅱ相代谢产物,包括羟基化、水解、O-甲基化、葡萄糖醛酸化产物,其中相对含量最高的是BG-O-葡萄糖醛酸和O-甲基-BG-O-葡萄糖醛酸,提示O-甲基化和葡萄糖醛酸化是BG最主要的代谢途径。
Traditional Chinese medicine (TCM), which serves as a resource of bioactive compounds for drug discovery, is attracting increasing global attention. Such ample Chinese natural medicinal resources provide valuable materials for the discovery and development of new drugs. More importantly, the clinic medicinal experience of more than2000years made the TCM-derived active compounds better lead compounds for further chemical improvements. As is well-known, multi-herb therapy is one of the most important characteristics of TCM. In TCM theory, compatibility refers to the combination of two or more herbs based on the clinical settings and the properties of herbs. Compatibility not only represents overall concept and differential treatment but also provides inspirations for the molecular design of new drug candidates. With the drug pair "GuangZao-borneol" were chosen as starting point, we comprehensively analyzed the constituents and their metabolites in rat plasma after oral administration of the extract of Choerospondiatis Fructus (Guangzao in Chinese, GZ) by LC/Q-TOF/MS, and then investigated the influence of borneol in the pharmacokinetics and tissue distribution to gallic acid which is the bioactive compound of Choerospondiatis Fructus in rat plasma. Subsequently, bornyl gallate (BG) was synthesized based on those results from previous experiments. BG is designed to promote blood circulation, remove blood stasis and promoting active compounds penetrating the biological barriers, which represents the compatibility characteristic of the drug pair "Guangzao-borneol". In vivo and in vitro metabolisms of BG were investigated to reveal the rules of dynamic changes in rat. It will be helpful for the pharmacology and toxicology studies as well as the clinical security and effectiveness of BG. The full text included six parts listed as follows.
1. Identification of42constituents in the flushes of dried GZ by LC/Q-TOF/MS. Among them,17constituents are found firstly in GZ. After oral administration of extract of GZ, there are13prototype constituents,7kinds of metabolites and3endogenous response compounds detected in rat plasma. These prototype constituents in plasma are mainly organic acids. The metabolites are mainly Ⅱ phase conjugation products of organic acids. While only catechin and quercetin-O-glucuronide is the flavonoids compounds in plasma. These results indicated, from the perspective of serum pharmacochemistry, that the organic acids are the bioactive material basis of GZ.
2. Gallic acid, the bioactive compound in GZ, was chosen as leading compound. The concentration of gallic acid in plasma and tissues were determined after oral administration of gallic acid and gallic acid plus borneol. Then the pharmacokinetic parameters of gallic acid were calculated by DAS2.0Software. Finally, the significant differences of pharmacokinetic parameters and tissue distribution of gallic acid between gallic acid group and gallic acid plus borneol group were analyzed with two-sided unpaired t-test. These results showed that on one hand borneol could significantly influence some pharmacokinetic parameters of gallic acid such as decreasing CL/F, increasing a, t1/2a, MRTo-t and AUC. On the other hand, borneol could change tissue distributions of gallic acid to some extent such as increasing slightly the concentration in heart and brain, decreasing significantly the concentration of gallic acid in kidney. All the results demonstrated that borneol could increase the concentration and bioavailability of gallic acid in rat. It also proves the synergistic effect of borneol to enhance the absorption, distribution, permeability, and efficacy of gallic acid.
3. BG was synthesized by the reaction of two natural products, gallic acid and borneol. Three different synthetic routes were compared in this part. All the products were characterized by LC, MS, IR and NMR to confirm their structures were identical as BG in order to provide high purity prototype compound for the following metabolism experiments.
4. Investigation of the in vitro metabolism of BG in rat liver microsome (RLM). Firstly, a HPLC-DAD method was established to test the metabolic stability of BG in RLM and to identify the subtype of CYP enzymes involved in metabolism of BG. It showed that BG was metabolized by0.25mg/mL RLM with a t1/2=14.88±0.33min and a CLint=0.186±0.004mL/min/mg. CYP2C8was proved to be the subtype of CYP enzymes involved in metabolism of BG. Then, a LC/Q-TOF/MS method was applied to identify the in vitro metabolites of BG. The results showed BG was metabolized to five isomers of mono-hydroxylated BG.
5. Study on the in vivo pharmacokinetics and tissue distribution of BG in rat. The results showed the pharmacokinetic profiles of BG after oral administration was fitted to the two compartment model, while the concentration-time curve of BG after intravenous injection was fitted to three compartment model. BG was fast metabolized drug because of its tl/2≈3h. the bioavailability of BG was27.3%. The results of tissue distribution showed that the concentrations of BG in tissues from highness to lowness were kidney, liver, brain and heart. Compared with gallic acid, the concentration of BG in tissues were higher, especially in brain which should be relative to the lower polarity and higher lipophilicity of this molecule after importing the borneol moiety. It indicated BG was easier to pass blood-brain barrier and tissue membrane. All the results from pharmacokinetic and tissue distribution studies suggested BG is worthy of further investigation.
6. A reliable and sensitive HPLC/Q-TOF/MS method was successfully applied to identify the metabolites of bornyl gallate in rat.9kinds of potential metabolites, altogether18compounds including all isomers, were detected and identified. BG is believed to undergo various phases I and II metabolic pathways including hydroxylation, hydrolysis, O-methylation and glucuronidation. We also proved that BG mainly became products of glucuronidation and O-methylation in vivo, which were identified as BG-O-glucuronide and O-methyl BG-O-glucuronide.
引文
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