龙胆抗肝损伤活性成分的分离、纯化及药代动力学研究
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摘要
本文首先对龙胆环烯醚萜苷类化学成分进行了研究。采用反相硅胶色谱和制备高效液相色谱技术从龙胆70%乙醇提取物中分离得到6个环烯醚萜苷类化合物，通过UFLC/Q-TOF-MS和NMR解析鉴定了他们的结构，分别为：龙胆苦苷、獐牙菜苦苷、獐牙菜苷、马钱子酸、8-表马钱子酸和6'-O-β-D-吡喃葡萄糖基龙胆苦苷，其中，8-表马钱子酸和6'-O-β-D-吡喃葡萄糖基龙胆苦苷为从该植物中首次分离鉴定。
以正丁醇-水（1:1）为溶剂体系，采用高速逆流技术从龙胆粗提物中分离制备了纯度可达98%以上的龙胆苦苷，该方法分析成本低，环保低毒，而且简便快速。
建立了同时测定龙胆中龙胆苦苷、獐牙菜苦苷、獐牙菜苷的高效液相色谱法，该方法准确、简便、具有良好的重现性和稳定性，适合于龙胆的质量控制研究。同时采用大孔吸附树脂技术优化了龙胆中环烯醚萜苷类成分的纯化工艺，为药效学研究和体内药动学研究奠定了物质基础。
对龙胆有效部位抗肝损伤作用进行了体内外活性研究。首先建立了CCl4诱导化学性肝损伤的细胞模型，采用MTT法检测药物处理后各组细胞的存活率，体外研究结果表明，龙胆有效部位浓度低于20mg/L时，能增强细胞存活率；通过检测细胞培养上清液中ALT和AST的活力，细胞内SOD和MDA含量的变化，发现龙胆有效部位具有抗氧化和清除氧自由基的作用。通过建立CCl4诱导的小鼠急性肝损伤模型，观察血清生化指标和肝脏组织病理学变化，结果表明，龙胆有效部位对CCl4引起的急性肝损伤具有明显的保护作用。
对龙胆抗肝损伤活性成分在大鼠体内的药代动力学进行了研究。首次建立了同时测定大鼠血浆中龙胆苦苷和獐牙菜苦苷的超快速液相色谱-串联质谱分析方法，并将其成功应用于大鼠灌胃给予龙胆提取物后龙胆苦苷和獐牙菜苦苷的药动学行为研究。结果表明，龙胆苦苷和獐牙菜苦苷在雄、雌大鼠体内的药动学特征存在显著性差异（p<0.05）。
采用已建立的高效液相色谱法研究了龙胆抗肝损伤有效部位在大鼠体内药动学和组织分布特征。血药浓度-时间曲线符合二室模型，龙胆苦苷在大鼠体内主要部位的分布顺序为：肝脏＞肾脏＞肺脏＞心脏＞脾脏。
Gentian, the dry roots and rhizomes of a family of herbs such as Gentianamanshurica Kitag., Geniana scabra Bge., Geniiarur triflora Pall. and Gentianarigescens Franch. is widely used in traditional medicine for liver protection. Recently,more effects of Gentian including diuretic, anti-inflammatory, antioxidant andantihypertensive have been scientifically proven. Although it is well established thathepatoprotection is the major clinical activity of Gentian, the toxic ingradients intraditional medicine can cause negative effects. Therefore, further exploring thepharmacological properties and in vivo pharmacokinetics of the active ingredientsfrom gentian are important for the determination of its efficacy and safety as ananti-hepatotoxic drug.
1. Separation and identification of iridoid glycosides in Radix Gentianae
Iridoide glycosides that commonly found in medicinal plants are responsible formany pharmaceutical effects. With reversed phase ODS column chromatography andpreparative high performance liquid chromatography separation techniques, a total ofsix iridoid glycosides were separated from70%ethanol-Radix Gentianae extract.Their structures that identified through NMR and MS analysis were as follows:loganic acid (1), gentiopicroside (2),8-epiloganic acid (3), swertianlarin (4),6'-O-β-D-glucopyranosylgentiopicroside (5), and sweroside (6).8-epiloganic acid and6'-O-β-D-glucopyranosylgentiopicroside were separated from Gentianamanshurica Kitag for the first time.
2. Isolation of gentiopicroside from Gentian with HSCCC
Separation and purification of gentiopicroside from Gentian extract wassuccessfully preformed by high-speed counter-current chromatography (HSCCC) withtwo-phase solvent system composed of n-butyl alcohol-water (1:1, v/v). The upper phase was used as stationary phase and lower phase was the mobile phase. At850rpmand a flow rate of2mL/min, the retention time of gentiopicroside was120.0-133.6min. The purity of gentiopicroside obtained by HSCCC was determined as98.48%byHPLC analysis. HSCCC method is simple, efficient, low toxicity, low costs andprovides an effective separation of the product, therefore it has been considered as anoptimum method for gentiopicroside purification.
3. Quantitation and purification of active parts of Radix Gentianae
Simultaneous determination of gentiopicroside, swertiamarin and sweroside inRadix Gentianae was achieved by reversed phase high performance liquidchromatography. This method is simple, accurate with high reproducibility andstability, which can be applied as a quality control strategy for isolating the activeingredients from Radix Gentianae. The resins with different pore size that used toseparate and purify iridoid glycoside from Radix Gentianae were screened by staticand dynamic adsorption， desorption assays. HPD300macro porous resin with thehighest adsorption and desorption efficiency was selected for purifiyingGentiopicroside, swertiamarin and sweroside from Radix Gentianae. This optimizedprocess was simple, stable and feasible, which supports further pharmacology and invivo pharmacokinetic investigations.
4. Anti-hepatotoxicity effect of the active parts in Radix Gentianae
In vitro activities: A CCl4-induced injury model in hepatic cells was established.MTT assay was employed to evaluate the anti-hepatotoxicity effect of the active partsin Radix Gentianae. Cells treated with the active ingredient showed an increasedsurvival rate compared to the control cells, indicting a hepatoprotective effect onCCl4-induced injury hepatic cells. However, a toxic effect that causing cell death wasshown with treatment concentration higher than20mg/L. In addition, activities ofALT and AST in the growth medium as well as the levels of SOD and MDA in theactive ingredient treated cells were determined, suggesting the antioxidant and radicaldeoxygenization activities of the active parts in Radix Gentianae.
In vivo activities: A CCl4-induced acute liver injury model in mice wasdeveloped. By monitoring the levels of serum biochemical indicators of liver function and liver histopathological changes, the preventive and protective effect of the activeparts in Radix Gentianae was shown on liver injury mice model.
5. Pharmacokinetics of active ingredients from Radix Gentianae in liver injuryrat model
A rapid and sensitive method based on ultra-fast liquid chromatography-tandemmass spectrometry (UFLC-MS/MS) has been developed for the simultaneousdetermination of gentiopicroside and swertiamarin in rat plasma. The method wasfully validated and applied to a pharmacokinetic study involving oral administrationof a Radix Gentianae extract to groups of male and female rats. Theconcentration-time curves of gentiopicroside and swertiamarin were both described bytwo compartment model. The Tmaxof gentiopicroside and swertiamarin was between2h to3h and the t1/2was between0.8h to2h. Compared with male rats, the Cmax，AUC0-t， AUC0-∞and t1/2of gentiopicroside and swertiamarin in female rats weresignificantly improved（p<0.05). However, no significant change of Tmax（p﹥0.05）was obtained, indicating the pharmacokinetic properties of gentiopicroside andswertiamarin are remarkably different between male and female rats.
6. Pharmacokinetics and distribution of active parts from Radix Gentianae in ratmodel
Since pharmacokinetics of gentiopicroside was highly influenced by otheringredients of Radix Gentianae, a high performance liquid chromatography methodwas developed to investigate the pharmacokinetic properties of gentiopicroside fromRadix Gentianae extract to avoid interference.
This well established high performance liquid chromatography method was alsoused to study the pharmacokinetic and tissue distribution of gentiopicroside after oraladministration of the active parts of Radix Gentianae in rats. The concentration-timecurve of gentiopicroside was described by two compartment model. The sequence ofgentiopicroside distribution in rats was as follows: liver>kidney>lung>heart>spleen.
以正丁醇-水（1:1）为溶剂体系，采用高速逆流技术从龙胆粗提物中分离制备了纯度可达98%以上的龙胆苦苷，该方法分析成本低，环保低毒，而且简便快速。
建立了同时测定龙胆中龙胆苦苷、獐牙菜苦苷、獐牙菜苷的高效液相色谱法，该方法准确、简便、具有良好的重现性和稳定性，适合于龙胆的质量控制研究。同时采用大孔吸附树脂技术优化了龙胆中环烯醚萜苷类成分的纯化工艺，为药效学研究和体内药动学研究奠定了物质基础。
对龙胆有效部位抗肝损伤作用进行了体内外活性研究。首先建立了CCl4诱导化学性肝损伤的细胞模型，采用MTT法检测药物处理后各组细胞的存活率，体外研究结果表明，龙胆有效部位浓度低于20mg/L时，能增强细胞存活率；通过检测细胞培养上清液中ALT和AST的活力，细胞内SOD和MDA含量的变化，发现龙胆有效部位具有抗氧化和清除氧自由基的作用。通过建立CCl4诱导的小鼠急性肝损伤模型，观察血清生化指标和肝脏组织病理学变化，结果表明，龙胆有效部位对CCl4引起的急性肝损伤具有明显的保护作用。
对龙胆抗肝损伤活性成分在大鼠体内的药代动力学进行了研究。首次建立了同时测定大鼠血浆中龙胆苦苷和獐牙菜苦苷的超快速液相色谱-串联质谱分析方法，并将其成功应用于大鼠灌胃给予龙胆提取物后龙胆苦苷和獐牙菜苦苷的药动学行为研究。结果表明，龙胆苦苷和獐牙菜苦苷在雄、雌大鼠体内的药动学特征存在显著性差异（p<0.05）。
采用已建立的高效液相色谱法研究了龙胆抗肝损伤有效部位在大鼠体内药动学和组织分布特征。血药浓度-时间曲线符合二室模型，龙胆苦苷在大鼠体内主要部位的分布顺序为：肝脏＞肾脏＞肺脏＞心脏＞脾脏。
Gentian, the dry roots and rhizomes of a family of herbs such as Gentianamanshurica Kitag., Geniana scabra Bge., Geniiarur triflora Pall. and Gentianarigescens Franch. is widely used in traditional medicine for liver protection. Recently,more effects of Gentian including diuretic, anti-inflammatory, antioxidant andantihypertensive have been scientifically proven. Although it is well established thathepatoprotection is the major clinical activity of Gentian, the toxic ingradients intraditional medicine can cause negative effects. Therefore, further exploring thepharmacological properties and in vivo pharmacokinetics of the active ingredientsfrom gentian are important for the determination of its efficacy and safety as ananti-hepatotoxic drug.
1. Separation and identification of iridoid glycosides in Radix Gentianae
Iridoide glycosides that commonly found in medicinal plants are responsible formany pharmaceutical effects. With reversed phase ODS column chromatography andpreparative high performance liquid chromatography separation techniques, a total ofsix iridoid glycosides were separated from70%ethanol-Radix Gentianae extract.Their structures that identified through NMR and MS analysis were as follows:loganic acid (1), gentiopicroside (2),8-epiloganic acid (3), swertianlarin (4),6'-O-β-D-glucopyranosylgentiopicroside (5), and sweroside (6).8-epiloganic acid and6'-O-β-D-glucopyranosylgentiopicroside were separated from Gentianamanshurica Kitag for the first time.
2. Isolation of gentiopicroside from Gentian with HSCCC
Separation and purification of gentiopicroside from Gentian extract wassuccessfully preformed by high-speed counter-current chromatography (HSCCC) withtwo-phase solvent system composed of n-butyl alcohol-water (1:1, v/v). The upper phase was used as stationary phase and lower phase was the mobile phase. At850rpmand a flow rate of2mL/min, the retention time of gentiopicroside was120.0-133.6min. The purity of gentiopicroside obtained by HSCCC was determined as98.48%byHPLC analysis. HSCCC method is simple, efficient, low toxicity, low costs andprovides an effective separation of the product, therefore it has been considered as anoptimum method for gentiopicroside purification.
3. Quantitation and purification of active parts of Radix Gentianae
Simultaneous determination of gentiopicroside, swertiamarin and sweroside inRadix Gentianae was achieved by reversed phase high performance liquidchromatography. This method is simple, accurate with high reproducibility andstability, which can be applied as a quality control strategy for isolating the activeingredients from Radix Gentianae. The resins with different pore size that used toseparate and purify iridoid glycoside from Radix Gentianae were screened by staticand dynamic adsorption， desorption assays. HPD300macro porous resin with thehighest adsorption and desorption efficiency was selected for purifiyingGentiopicroside, swertiamarin and sweroside from Radix Gentianae. This optimizedprocess was simple, stable and feasible, which supports further pharmacology and invivo pharmacokinetic investigations.
4. Anti-hepatotoxicity effect of the active parts in Radix Gentianae
In vitro activities: A CCl4-induced injury model in hepatic cells was established.MTT assay was employed to evaluate the anti-hepatotoxicity effect of the active partsin Radix Gentianae. Cells treated with the active ingredient showed an increasedsurvival rate compared to the control cells, indicting a hepatoprotective effect onCCl4-induced injury hepatic cells. However, a toxic effect that causing cell death wasshown with treatment concentration higher than20mg/L. In addition, activities ofALT and AST in the growth medium as well as the levels of SOD and MDA in theactive ingredient treated cells were determined, suggesting the antioxidant and radicaldeoxygenization activities of the active parts in Radix Gentianae.
In vivo activities: A CCl4-induced acute liver injury model in mice wasdeveloped. By monitoring the levels of serum biochemical indicators of liver function and liver histopathological changes, the preventive and protective effect of the activeparts in Radix Gentianae was shown on liver injury mice model.
5. Pharmacokinetics of active ingredients from Radix Gentianae in liver injuryrat model
A rapid and sensitive method based on ultra-fast liquid chromatography-tandemmass spectrometry (UFLC-MS/MS) has been developed for the simultaneousdetermination of gentiopicroside and swertiamarin in rat plasma. The method wasfully validated and applied to a pharmacokinetic study involving oral administrationof a Radix Gentianae extract to groups of male and female rats. Theconcentration-time curves of gentiopicroside and swertiamarin were both described bytwo compartment model. The Tmaxof gentiopicroside and swertiamarin was between2h to3h and the t1/2was between0.8h to2h. Compared with male rats, the Cmax，AUC0-t， AUC0-∞and t1/2of gentiopicroside and swertiamarin in female rats weresignificantly improved（p<0.05). However, no significant change of Tmax（p﹥0.05）was obtained, indicating the pharmacokinetic properties of gentiopicroside andswertiamarin are remarkably different between male and female rats.
6. Pharmacokinetics and distribution of active parts from Radix Gentianae in ratmodel
Since pharmacokinetics of gentiopicroside was highly influenced by otheringredients of Radix Gentianae, a high performance liquid chromatography methodwas developed to investigate the pharmacokinetic properties of gentiopicroside fromRadix Gentianae extract to avoid interference.
This well established high performance liquid chromatography method was alsoused to study the pharmacokinetic and tissue distribution of gentiopicroside after oraladministration of the active parts of Radix Gentianae in rats. The concentration-timecurve of gentiopicroside was described by two compartment model. The sequence ofgentiopicroside distribution in rats was as follows: liver>kidney>lung>heart>spleen.
引文
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