桂枝茯苓胶囊的代谢组学与药代动力学研究
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摘要
桂枝茯苓胶囊源自汉代张仲景《金匮要略》桂枝茯苓丸,经现代工艺精致而成,由桂枝、茯苓、牡丹皮、桃仁和白芍五味药材组成。本研究以复方制剂桂枝茯苓胶囊为研究对象,对其化学成分、质量控制和体内药物动力学过程进行了研究,采用代谢组学方法对子宫肌瘤模型的识别与桂枝茯苓胶囊对模型大鼠的干预作用等进行了全面的研究。
采用溶剂法和各种色谱技术分别从桂枝、茯苓和白芍中分离得到7、8和8个化合物,利用化学方法和光谱学技术鉴定了其中19个化合物。其中桂枝中分离得到3种芳酸类化合物,茯苓中分离得到7个三萜酸类化合物,白芍中分离得到3种单萜苷类化合物,均为已知化合物。
对桂枝茯苓胶囊中指标成分进行了定量分析。采用HPLC-UV方法,在210 nm波长条件下同时定量分析茯苓酸和去氢茯苓酸,并应用于不同来源的茯苓药材测定,结果发现不同来源的药材中含量差异较大;在梯度洗脱模式下,建立了测定没食子酸、没食子酸乙酯、白芍苷、芍药苷、苯甲酰芍药苷和丹皮酚6种成分的HPLC-UV法,并用于桂枝茯苓胶囊复方制剂的测定:在梯度洗脱模式下,建立测定了7种三萜酸类化合物的HPLC-MS方法,并应用于茯苓药材和桂枝茯苓胶囊制剂的测定,结果发现茯苓酸和去氢茯苓酸在药材中的相对含量要显著高于其在制剂中的相对含量,而去氢土莫酸和土莫酸的相对含量则是制剂中更高,推测在制剂煎煮的过程中可能发生了水解。所建立的定量分析方法简单、快速、准确,符合定量分析要求,可为药材与该复方制剂的质量控制提供技术保证。
采用双模法制备子宫肌瘤大鼠模型,给予健康大鼠外源性性激素,通过病理形态检查和病理切片检查,结果表明采用双模法可以成功地制备大鼠子宫肌瘤模型。并将此病理模型用于代谢组学和桂枝茯苓胶囊中活性成分在模型大鼠体内的药动学研究。
建立了适合代谢组学研究的UPLC-MS测定方法。首先通过实验确定了尿液样品的处理方法和仪器测试条件,样品经过甲醇沉淀蛋白后,在12000 rpm下高速离心,直接进样分析。色谱柱:Waters BEH C_(18)(1.7μm,2 mm×50 mm,Waters);流速:0.25 mL/min;柱温:30℃;流动相:乙腈-0.1%甲酸水溶液梯度洗脱;UV:254/230 nm;MS:ESI离子化模式,m/z 70～870范围内正离子全扫描模式;气流:600.0 L/min;温度:350℃;毛细管电压:3000 V。方法学研究表明建立的方法重复性好、灵敏度高,适用于快速的高通量检测。
采用建立的UPLC-MS方法分析不同时间点空白对照组与子宫肌瘤模型组大鼠的代谢组特征。得到的原始数据首先经过Masslynex等统计软件而建立的多维数据处理和计算方法,进行PCA分析。Score图可揭示出对照组大鼠与模型大鼠的总体代谢物的差异,模型组和空白对照组得到了很好的区分;Loading图中远离原点的质荷比能够直观的表示出尿样中发生变化的重要的9种内源性代谢物,并通过提取离子的准确质荷比推测了其中的4种代谢物,即为标志物。
采用HPLC法建立了大鼠血浆、尿液和粪样中桂皮酸和丹皮酚的测定方法,以苯丁酸为内标,血浆经甲醇沉淀蛋白处理后进样分析。使用Synergi fusion RP C_(18)(250 mm×4.6 mm,5μm,Phenomenex)色谱柱,以乙腈-0.1%磷酸溶液为流动相,柱温为30℃,流速为1.0 mL·min~(-1),检测波长为280 nm,进样量为10μL。
采用HPLC-MS法建立了大鼠血浆、尿液和粪样中白芍苷和芍药苷的测定方法,以栀子苷为内标,经过乙酸乙酯萃取处理后进行分析。色谱柱为Luna C_(18)(150 mm×4.6mm,5μm,Phenomenex公司),流动相为乙腈-0.1%甲酸水溶液(25:75,v/v),流速为0.8 mL·min~(-1),柱温为30℃,分流比为1:3,进样量为10μL;离子源为电喷雾离子化(ESI)源,CDL温度为250℃,Heat block温度为200℃,雾化气流速为1.5 L/min,检测器电压为1.60 kV,检测方式为正离子、选择离子监测(SIM),用于定量分析的离子分别为m/z 503.15(白芍苷与芍药苷)和m/z 411.20(内标,栀子苷)。
采用HPLC-MS法建立了大鼠血浆和粪样中去氢土莫酸、土莫酸、猪苓酸C和3-表去氢土莫酸的测定方法,以己酸孕酮为内标,经过乙醚萃取处理后进行分析。色谱柱为Luna C_(18)(150 mm×4.6 mm,5μm,Phenomenex公司),流动相为乙腈-0.1%甲酸水溶液(75:25,v/v);离子源为电喷雾离子化(ESI)源,用于定量分析的离子反应分别为m/z467.30(去氢土莫酸与3-表去氢土莫酸),m/z469.35(土莫酸),m/z465.35(猪苓酸)和m/z 470.30(内标,己酸孕酮)。
所建立的方法均符合生物样品分析要求。用所建立的分析方法研究了灌胃给予健康大鼠桂枝单煎液、白芍单煎液、牡丹皮单煎液、茯苓单煎液和复方提取液后指标成分的体内药动学和排泄行为差异,并用于灌胃给予模型大鼠复方提取液后成分的药代动力学行为的研究。结果表明上述情况下虽然各成分的给药剂量相同,但药动学行为因不同存在形式的影响而表现出较大差异。
与给予大鼠单煎液后药动学参数比较发现,给予复方提取液后,多种成分在体内的V_z,CL_z和MRT_((0-t))显著增加,尿粪排泄率均降低,且最大排泄比率出现的时间延迟;与给予健康大鼠复方提取液后药动学参数的比较发现,给予子宫肌瘤模型大鼠后,化合物在体内的V_z和CL_z显著增加。结果表明,以复方制剂方式给药后活性成分在体内的作用时间延长;极性较大的成分经由肾脏排泄明显,而极性较弱的三萜酸类成分肾排泄较弱或基本不经过肾排泄。另外,部分三萜类成分在粪中最大的排泄比率有两个明显的排泄峰值,推测可能是由于与其共存组分间的相互作用。
本研究将中药化学、分析化学、药物分析学、病理学、药理学、生理学、生物化学、代谢组学、统计学和药代动力学等手段相结合,研究了桂枝茯苓胶囊所含药材的化学成分,建立了药材和复方制剂的质量评价标准,并提出质量评价方法,建立大鼠子宫肌瘤模型,采用代谢组学的方法对其病理模型的模式识别、疾病的诊断与桂枝茯苓胶囊对子宫肌瘤的干预作用进行了初步的探讨,考察了药材单煎液和复方制剂中相关活性成分在健康大鼠或子宫肌瘤模型大鼠体内的药代动力学和排泄过程,为中药现代化做了有意义的探索。
Guizhi-Fuling Capsule(GFC) is a TCM formulation,which is originated from Guizhi-Fuling Wan,first described in the Jin Kui Yao Lue(220 A.D.) written by a famous doctor of Han Dynasty named Zhang Zhongjing.Clinically,GFC is used to treat gynecological malignant tumor.GFC is composed of five kinds of crude herbs,Ramulus Cinnamomi,Poria,Cortex Moutan,Radix Paeoniae Alba,and Semen Persicae.The chemical constituents,quality control methods,the pharmacokinetics and metabolonomics of GFC were investigated in detail.
The chemical constituents of Ramulus Cinnamomi,Poria,and Radix Paeoniae Alba were systematically studied and 23 compounds were purified with silica gel,Sephadex LH-20 and ODS column chromatography.Utilizing chemical and spectroscopic methods(UV,NMR, MS),the structures of 19 compounds were fully characterized.There were seven triterpenes, three monoterpene glycosides,three aromatic acids,and so on.
The quality control methods of Poria were studies.A RP-HPLC method was established to determine pachymic acid and dehydro-pachymic acid in poria.A RP-HPLC method with gradient elution was established to determine gallic acid,ethyl gallicate,albiflorin,peoniflorin, benzoylpaeoniflorin and paeonol in GFC.An HPLC-MS method was established to determine dehydrotumulosic acid,tumulosic acid,polyporenic acid C,3-epi-dehydrotumulosic acid, dehydropachymic acid and pachymic acid in poria and GFC.The assay methods are simple, rapid and with good reproducibility and provide a quantitative basis for the quality assessment for herb and GFC.
An UPLC-MS method was developed to determine the urine samples.Urine samples were pretreated with protein precipitation using methanol,and the supernatants were separated on a reversed-phase C_(18) column with gradient elution using a mobile phase of acetonitrile-0.1% formic acid at a flow-rate of 0.25 mL·min~(-1).
Analysis of urine samples from two groups(the healthy control vs.uterine fibroids model rat) at pre-dose and the 16 th week with established method were illustrated.Visual examination of the LC/MS displayed a clear difference with each other.The analytical data were processed via multivariate analysis such as(Principle component analysis) PCA.PCA scores plot of analytical data describes the general differences between two different groups at the end point of the study whereas little variation is observed at pre-dose.The mechanism of pathological changes may be elucidated with the up- or down-regulated metabolic pathways. The dominant metabolites obtained from loading plot of Masslynex were the differential metabolites between healthy control and pathological rats.
A simple HPLC-UV method of determination of cinnamic acid and paeonol were developed in rat plasma,urine and feces.Phenylbutyric acid was selected as internal standard (IS).Plasma and urine samples were pretreated with protein precipitation using methanol,and the supernatants were separated on a reversed-phase C_(18) column,using a mobile phase of acetonitrile-0.1%phosphoric acid at a flow-rate of 1.0 mL·min~(-1).Feces samples were extracted with methanol.
A sensitive and specific method was developed and validated for the determination of albiflorin(AF) and paeoniflorin(PF) in rat plasma,urine and feces by liquid chromatography - mass spectrometry.Plasma and urine samples were extracted using ethyl acetate,and then were separated on a C_(18) column,using a mobile phase of acetonitrile-0.1%formic acid(25:75, v/v) at a flow-rate of 0.8 mL/min.Geniposide was used as IS.A mass spectrometer equipped with electrospray ionization source was operated in the positive ion mode.
A sensitive and specific method was developed and validated for the determination of dehydrotumulosic acid(DTA),tumulosic acid(TA),polyporenic acid C(PAC) and 3-epi-dehydrotumulosic acid(3-EDTA) in rat plasma and feces by liquid chromatography - mass spectrometry.Plasma samples were extracted using diethyl ether,and then were separated on a C_(18) column,using a mobile phase of acetonitrile-0.1%formic acid(75:25,v/v) at a flow-rate of 0.8 mL/min.Luteum was used as the IS.A mass spectrometer equipped with electrospray ionization source was operated in the positive ion mode.
These methods were applied to the pharmacokinetic and excretion study of them after intragastic administration of extract of single herbs or formula to rat.The pharmacokinetic and excretion characteristics were significantly different between rats with administration of herbs and rats of GFC or between healthy and pathological rats after administration of GFC because of the effects of co-existing compounds even with the same dosages.
Combining the utilization of phytochemistry,pharmaceutical analysis,matabonomics, analytical chemistry,statistics,pharmacology and pharmacokinetics,the quality assessment standards and pharmacokinetics for herbs and GFC were studied,and the metabolomics of uterine fibroids were also investigated.This research provided a beneficial exploration for the modernization of traditional Chinese medicine.
采用溶剂法和各种色谱技术分别从桂枝、茯苓和白芍中分离得到7、8和8个化合物,利用化学方法和光谱学技术鉴定了其中19个化合物。其中桂枝中分离得到3种芳酸类化合物,茯苓中分离得到7个三萜酸类化合物,白芍中分离得到3种单萜苷类化合物,均为已知化合物。
对桂枝茯苓胶囊中指标成分进行了定量分析。采用HPLC-UV方法,在210 nm波长条件下同时定量分析茯苓酸和去氢茯苓酸,并应用于不同来源的茯苓药材测定,结果发现不同来源的药材中含量差异较大;在梯度洗脱模式下,建立了测定没食子酸、没食子酸乙酯、白芍苷、芍药苷、苯甲酰芍药苷和丹皮酚6种成分的HPLC-UV法,并用于桂枝茯苓胶囊复方制剂的测定:在梯度洗脱模式下,建立测定了7种三萜酸类化合物的HPLC-MS方法,并应用于茯苓药材和桂枝茯苓胶囊制剂的测定,结果发现茯苓酸和去氢茯苓酸在药材中的相对含量要显著高于其在制剂中的相对含量,而去氢土莫酸和土莫酸的相对含量则是制剂中更高,推测在制剂煎煮的过程中可能发生了水解。所建立的定量分析方法简单、快速、准确,符合定量分析要求,可为药材与该复方制剂的质量控制提供技术保证。
采用双模法制备子宫肌瘤大鼠模型,给予健康大鼠外源性性激素,通过病理形态检查和病理切片检查,结果表明采用双模法可以成功地制备大鼠子宫肌瘤模型。并将此病理模型用于代谢组学和桂枝茯苓胶囊中活性成分在模型大鼠体内的药动学研究。
建立了适合代谢组学研究的UPLC-MS测定方法。首先通过实验确定了尿液样品的处理方法和仪器测试条件,样品经过甲醇沉淀蛋白后,在12000 rpm下高速离心,直接进样分析。色谱柱:Waters BEH C_(18)(1.7μm,2 mm×50 mm,Waters);流速:0.25 mL/min;柱温:30℃;流动相:乙腈-0.1%甲酸水溶液梯度洗脱;UV:254/230 nm;MS:ESI离子化模式,m/z 70～870范围内正离子全扫描模式;气流:600.0 L/min;温度:350℃;毛细管电压:3000 V。方法学研究表明建立的方法重复性好、灵敏度高,适用于快速的高通量检测。
采用建立的UPLC-MS方法分析不同时间点空白对照组与子宫肌瘤模型组大鼠的代谢组特征。得到的原始数据首先经过Masslynex等统计软件而建立的多维数据处理和计算方法,进行PCA分析。Score图可揭示出对照组大鼠与模型大鼠的总体代谢物的差异,模型组和空白对照组得到了很好的区分;Loading图中远离原点的质荷比能够直观的表示出尿样中发生变化的重要的9种内源性代谢物,并通过提取离子的准确质荷比推测了其中的4种代谢物,即为标志物。
采用HPLC法建立了大鼠血浆、尿液和粪样中桂皮酸和丹皮酚的测定方法,以苯丁酸为内标,血浆经甲醇沉淀蛋白处理后进样分析。使用Synergi fusion RP C_(18)(250 mm×4.6 mm,5μm,Phenomenex)色谱柱,以乙腈-0.1%磷酸溶液为流动相,柱温为30℃,流速为1.0 mL·min~(-1),检测波长为280 nm,进样量为10μL。
采用HPLC-MS法建立了大鼠血浆、尿液和粪样中白芍苷和芍药苷的测定方法,以栀子苷为内标,经过乙酸乙酯萃取处理后进行分析。色谱柱为Luna C_(18)(150 mm×4.6mm,5μm,Phenomenex公司),流动相为乙腈-0.1%甲酸水溶液(25:75,v/v),流速为0.8 mL·min~(-1),柱温为30℃,分流比为1:3,进样量为10μL;离子源为电喷雾离子化(ESI)源,CDL温度为250℃,Heat block温度为200℃,雾化气流速为1.5 L/min,检测器电压为1.60 kV,检测方式为正离子、选择离子监测(SIM),用于定量分析的离子分别为m/z 503.15(白芍苷与芍药苷)和m/z 411.20(内标,栀子苷)。
采用HPLC-MS法建立了大鼠血浆和粪样中去氢土莫酸、土莫酸、猪苓酸C和3-表去氢土莫酸的测定方法,以己酸孕酮为内标,经过乙醚萃取处理后进行分析。色谱柱为Luna C_(18)(150 mm×4.6 mm,5μm,Phenomenex公司),流动相为乙腈-0.1%甲酸水溶液(75:25,v/v);离子源为电喷雾离子化(ESI)源,用于定量分析的离子反应分别为m/z467.30(去氢土莫酸与3-表去氢土莫酸),m/z469.35(土莫酸),m/z465.35(猪苓酸)和m/z 470.30(内标,己酸孕酮)。
所建立的方法均符合生物样品分析要求。用所建立的分析方法研究了灌胃给予健康大鼠桂枝单煎液、白芍单煎液、牡丹皮单煎液、茯苓单煎液和复方提取液后指标成分的体内药动学和排泄行为差异,并用于灌胃给予模型大鼠复方提取液后成分的药代动力学行为的研究。结果表明上述情况下虽然各成分的给药剂量相同,但药动学行为因不同存在形式的影响而表现出较大差异。
与给予大鼠单煎液后药动学参数比较发现,给予复方提取液后,多种成分在体内的V_z,CL_z和MRT_((0-t))显著增加,尿粪排泄率均降低,且最大排泄比率出现的时间延迟;与给予健康大鼠复方提取液后药动学参数的比较发现,给予子宫肌瘤模型大鼠后,化合物在体内的V_z和CL_z显著增加。结果表明,以复方制剂方式给药后活性成分在体内的作用时间延长;极性较大的成分经由肾脏排泄明显,而极性较弱的三萜酸类成分肾排泄较弱或基本不经过肾排泄。另外,部分三萜类成分在粪中最大的排泄比率有两个明显的排泄峰值,推测可能是由于与其共存组分间的相互作用。
本研究将中药化学、分析化学、药物分析学、病理学、药理学、生理学、生物化学、代谢组学、统计学和药代动力学等手段相结合,研究了桂枝茯苓胶囊所含药材的化学成分,建立了药材和复方制剂的质量评价标准,并提出质量评价方法,建立大鼠子宫肌瘤模型,采用代谢组学的方法对其病理模型的模式识别、疾病的诊断与桂枝茯苓胶囊对子宫肌瘤的干预作用进行了初步的探讨,考察了药材单煎液和复方制剂中相关活性成分在健康大鼠或子宫肌瘤模型大鼠体内的药代动力学和排泄过程,为中药现代化做了有意义的探索。
Guizhi-Fuling Capsule(GFC) is a TCM formulation,which is originated from Guizhi-Fuling Wan,first described in the Jin Kui Yao Lue(220 A.D.) written by a famous doctor of Han Dynasty named Zhang Zhongjing.Clinically,GFC is used to treat gynecological malignant tumor.GFC is composed of five kinds of crude herbs,Ramulus Cinnamomi,Poria,Cortex Moutan,Radix Paeoniae Alba,and Semen Persicae.The chemical constituents,quality control methods,the pharmacokinetics and metabolonomics of GFC were investigated in detail.
The chemical constituents of Ramulus Cinnamomi,Poria,and Radix Paeoniae Alba were systematically studied and 23 compounds were purified with silica gel,Sephadex LH-20 and ODS column chromatography.Utilizing chemical and spectroscopic methods(UV,NMR, MS),the structures of 19 compounds were fully characterized.There were seven triterpenes, three monoterpene glycosides,three aromatic acids,and so on.
The quality control methods of Poria were studies.A RP-HPLC method was established to determine pachymic acid and dehydro-pachymic acid in poria.A RP-HPLC method with gradient elution was established to determine gallic acid,ethyl gallicate,albiflorin,peoniflorin, benzoylpaeoniflorin and paeonol in GFC.An HPLC-MS method was established to determine dehydrotumulosic acid,tumulosic acid,polyporenic acid C,3-epi-dehydrotumulosic acid, dehydropachymic acid and pachymic acid in poria and GFC.The assay methods are simple, rapid and with good reproducibility and provide a quantitative basis for the quality assessment for herb and GFC.
An UPLC-MS method was developed to determine the urine samples.Urine samples were pretreated with protein precipitation using methanol,and the supernatants were separated on a reversed-phase C_(18) column with gradient elution using a mobile phase of acetonitrile-0.1% formic acid at a flow-rate of 0.25 mL·min~(-1).
Analysis of urine samples from two groups(the healthy control vs.uterine fibroids model rat) at pre-dose and the 16 th week with established method were illustrated.Visual examination of the LC/MS displayed a clear difference with each other.The analytical data were processed via multivariate analysis such as(Principle component analysis) PCA.PCA scores plot of analytical data describes the general differences between two different groups at the end point of the study whereas little variation is observed at pre-dose.The mechanism of pathological changes may be elucidated with the up- or down-regulated metabolic pathways. The dominant metabolites obtained from loading plot of Masslynex were the differential metabolites between healthy control and pathological rats.
A simple HPLC-UV method of determination of cinnamic acid and paeonol were developed in rat plasma,urine and feces.Phenylbutyric acid was selected as internal standard (IS).Plasma and urine samples were pretreated with protein precipitation using methanol,and the supernatants were separated on a reversed-phase C_(18) column,using a mobile phase of acetonitrile-0.1%phosphoric acid at a flow-rate of 1.0 mL·min~(-1).Feces samples were extracted with methanol.
A sensitive and specific method was developed and validated for the determination of albiflorin(AF) and paeoniflorin(PF) in rat plasma,urine and feces by liquid chromatography - mass spectrometry.Plasma and urine samples were extracted using ethyl acetate,and then were separated on a C_(18) column,using a mobile phase of acetonitrile-0.1%formic acid(25:75, v/v) at a flow-rate of 0.8 mL/min.Geniposide was used as IS.A mass spectrometer equipped with electrospray ionization source was operated in the positive ion mode.
A sensitive and specific method was developed and validated for the determination of dehydrotumulosic acid(DTA),tumulosic acid(TA),polyporenic acid C(PAC) and 3-epi-dehydrotumulosic acid(3-EDTA) in rat plasma and feces by liquid chromatography - mass spectrometry.Plasma samples were extracted using diethyl ether,and then were separated on a C_(18) column,using a mobile phase of acetonitrile-0.1%formic acid(75:25,v/v) at a flow-rate of 0.8 mL/min.Luteum was used as the IS.A mass spectrometer equipped with electrospray ionization source was operated in the positive ion mode.
These methods were applied to the pharmacokinetic and excretion study of them after intragastic administration of extract of single herbs or formula to rat.The pharmacokinetic and excretion characteristics were significantly different between rats with administration of herbs and rats of GFC or between healthy and pathological rats after administration of GFC because of the effects of co-existing compounds even with the same dosages.
Combining the utilization of phytochemistry,pharmaceutical analysis,matabonomics, analytical chemistry,statistics,pharmacology and pharmacokinetics,the quality assessment standards and pharmacokinetics for herbs and GFC were studied,and the metabolomics of uterine fibroids were also investigated.This research provided a beneficial exploration for the modernization of traditional Chinese medicine.
引文
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