虎杖质量控制方法与相关成分药物代谢动力学研究
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摘要
本文建立了同时测定虎杖中虎杖苷、白藜芦醇、蒽苷B、大黄素和大黄素甲醚含量的RP-HPLC方法。虎杖苷、白藜芦醇、蒽甙B、大黄素和大黄素甲醚分别在119.9～2876ng(r~2=1.0000),31.48～1007ng(r~2=1.0000),17.28～1728ng(r~2=1.0000),41.84～1339ng(r~2=1.0000),5.39～172.5ng(r~2=0.9998)范围内呈良好的线性关系,回收率分别为100.5%(RSD=2.6%),96.0%(RSD=0.6%),97.8%(RSD=1.5%),97.9%(RSD=1.1%)和98.1%(RSD=1.6%);以21批虎杖药材为样品,建立了测定虎杖药材的HPLC指纹图谱,得到共有峰31个,指认了其中5个;同时对虎杖供试品溶液、虎杖苷和白藜芦醇溶液进行了光照射试验,虎杖苷和白藜芦醇在45001x与自然光照射下含量明显下降,部分转化为顺式异构体。
建立了同时测定大鼠血浆中虎杖苷和白藜芦醇的HPLC方法,血浆经甲醇沉淀蛋白后进样分析,虎杖苷和白藜芦醇分别在0.263～33.68μg·mL~(-1)(r=0.9999)和0.059～37.43μg·mL~(-1)(r=0.9998)范围内线性关系良好,平均回收率分别为99.9%(RSD=1.8%)和93.9%(RSD=4.1%)。同时进行了白藜芦醇在大鼠体内的药动学研究,结果表明:大鼠口服给药白藜芦醇后,血浆白藜芦醇达峰时间为27min,峰浓度C_(max)为1.159μg·mL~(-1),血药浓度-时间曲线下面积AUC_(0-∞)值为165.2μg·min·mL~(-1)。
建立了测定大鼠脏器中虎杖苷和白藜芦醇的HPLC方法,脏器经甲醇沉淀蛋白后进样分析,虎杖苷在0.070～35.96μg·mL~(-1)(心r~2=0.9996,肝r~2=0.9996,脾r~2=0.9984,肺r~2=0.9997,肾r~2=0.9995,脑r~2=0.9984)范围内线性关系良好,方法定量下限为0.140μg·mL~(-1)。白藜芦醇在0.031～31.48μg·mL~(-1)(心r~2=0.9994,肝r~2=0.9995,脾r~2=0.9996,肺r~2=1.0000,肾r~2=0.9994,脑r~2=0.9985)范围内线性关系良好,方法定量下限为0.070μg·mL~(-1)。心脏组织虎杖苷和白藜芦醇的回收率分别为102.3%(RSD=3.6%)和102.3%(RSD=5.2%);肝脏组织虎杖苷和白藜芦醇的回收率分别为101.6%(RSD=3.7%)和101.7%(RSD=4.8%);脾脏组织虎杖苷和白藜芦醇的回收率分别为101.3%(RSD=4.0%)和101.0%(RSD=4.4%);肺脏组织虎杖苷和白藜芦醇的回收率分别为105.8%(RSD=4.6%)和106.4%(RSD=5.2%);肾脏组织虎杖苷和白藜芦醇的回收率分别为10.4%(RSD=3.1%)和100.0%(RSD=3.4%),脑组织虎杖苷和白藜芦醇的回收率分别为101.6%(RSD=3.2%)和101.0%(RSD=2.9%)。同时进行了白藜芦醇在大鼠体内主要脏器的分布研究,结果表明:大鼠口服给药白藜芦醇后各脏器组织中的药物含量除脑组织外均明显高于血浆,大鼠灌胃给药后20min,心、脾、肺、脑的组织浓度达到了最高,给药后90min肝、肾组织浓度达到最高,此后各组织的药物分布开始下降。从总体上来看,肝、肺药物浓度最高。
应用LC/MS/MS分析技术和代谢分析软件Metabolite ID,对大鼠口服给药虎杖苷和白藜芦醇后尿样进行了分析。结果表明:虎杖苷经过生物转化后除原型药外,主要代谢产物为白藜芦醇与其硫酸盐和葡醛酸结合物;白藜芦醇经过生物转化后主要以原型药与其硫酸盐和葡醛酸结合物直接从大鼠尿液中排出。两者在大鼠体内的生物转化主要是Ⅱ相代谢。
建立了同时测定大鼠粪便中虎杖苷和白藜芦醇的HPLC方法,粪便样品经50%乙醇提取,并经固相萃取小柱纯化后进样分析,虎杖苷和白藜芦醇分别在0.803～642.6 ng(r=1.0000)和0.814～325.8ng(r=1.0000)范围内线性关系良好,平均回收率分别为102.2%(RSD=4.3%)和97.3%(RSD=6.5%)。同时应用肠道菌孵育技术和整体肠内菌代谢技术研究虎杖苷和白藜芦醇口服给药后在大鼠体内的转化。虎杖苷在体外肠道菌孵育下,4小时后51%被转化成白藜芦醇,6小时后87%被转化。大鼠整体肠内菌试验进一步证明了肠内菌对虎杖苷的代谢作用,经过胃肠道内的转运,虎杖苷的相对含量大大降低,白藜芦醇的含量相对升高,说明虎杖苷在肠道微生物酶的影响下发生水解反应,脱去一分子葡萄糖转化为白藜芦醇。
对虎杖苷、白藜芦醇和虎杖提取物进行了体外肿瘤细胞株增殖抑制试验,增殖抑制试验结果表明,白藜芦醇对瘤株人肺腺癌A549细胞的抑制优于虎杖提取物,而虎杖苷几乎无抑制作用。对于人白血病HL-60细胞、人卵巢癌H08910细胞,白藜芦醇与虎杖提取物对瘤株的增值抑制作用相近,虎杖苷作用较弱。对人乳腺癌MCF-7细胞的增值抑制,白藜芦醇优于虎杖提取物,虎杖苷作用较弱。
研究结果表明,虎杖苷口服给药后,首先在肠道被代谢为白藜芦醇,白藜芦醇吸收入血后主要分布在肺和肝,在体内生物转化主要是Ⅱ相代谢,部分原型与其Ⅱ相代谢产物通过肾脏排出体外,部分原型与肠道水解产物白藜芦醇通过粪便排出体外。
Polygonum cuspidatum was studied in this dissertation.RP-HPLC method was developed for the simultaneous determination of polydatin,resveratrol,anthraglycoside B,emodin and physcion in Polygonum cuspidatum.The linear ranges for polydatin, resveratrol,anthraglycoside B,emodin and physcion were 119.9-2876 ng(r~2=1.0000), 31.48-1007ng(r~2=1.0000),17.28-1728ng(r~2=1.0000),41.84-1339ng(r~2=1.0000) and 5.39-172.5ng(r~2=0.9998),respectively.The average recoveries were 100.5%(RSD =2.6%),96.0%(RSD=0.6%),97.8%(RSD=1.5%),97.9%(RSD=1.1%) and 98.1% (RSD=1.6%),respectively.
A HPLC fingerprint was developed based on 21 batches of Polygonum cuspidatum. There were 31 common peaks in the fingerprint and 5 were identified.In the meantime, the irradiation of Polygonum cuspidatum sample solution,polydatin solution and resveratrol solution were tested.The contents of polydatin and resveratrol in solutions reduced obviously.Some of them changed into their isomers.
RP-HPLC method was developed for the simultaneous determination of polydatin and resveratrol in rat plasma.After being deproteinized by methanol,the plasma samples were analyzed.The assay was shown to be linear over the range of 0.263-33.68μg·mL~(-1)(r=0.9999) for polydatin and 0.059-37.43μg·mL~(-1)(r=0.9998) for resveratrol.Mean recoveries were 99.9%(RSD=1.8%) and 93.9%(RSD=4.1%), respectively.The HPLC method developed has been applied to determine the pharmacokinetics of resveratrol in rat plasma after having taken resveratrol orally.The pharmacokinetic parameters were calculated.The time for peak plasma level(T_(max)) was 27 min and the peak plasma level(C_(max)) was 1.159μg·mL~(-1).The area under concentration-time curve(AUC_(0-∞)) was 165.2μg·min·mL~(-1).
RP-HPLC method was developed for the simultaneous determination of polydatin and resveratrol in rat viscus.After being deproteinized by methanol,the viscus samples were analyzed.The assay was shown to be linear over the range of 0.070～35.96μg·mL~(-1) (heart r~2=0.9996,liver r~2=0.9996,spleen r~2=0.9984,lung r~2=0.9997,kidney r~2= 0.9995,brain r~2=0.9984) for polydatin and 0.031～31.48μg·mL~(-1)(heart r~2=0.9994, liver r~2=0.9995,spleen r~2=0.9996,lung r~2=1.0000,kidney r~2=0.9994,brain r~2= 0.9985)) for resveratrol.Mean recoveries of heart were 102.3%(RSD=3.6%) and 102.3%(RSD=5.2%),respectively.Mean recoveries of liver were 101.6%(RSD=3.7%) and 101.7%(RSD=4.8%),respectively.Mean recoveries of spleen were 101.3%(RSD= 4.0%) and 101.0%(RSD=4.4%),respectively.Mean recoveries of lung were 105.8% (RSD=4.6%) and 106.4%(RSD=5.2%),respectively.Mean recoveries of kidney were 100.4%(RSD=3.1%) and 100.0%(RSD=3.4%),respectively.Mean recoveries of brain were 101.6%(RSD=3.2%) and 101.0%(RSD=2.9%),respectively.The HPLC method developed has been applied to determine the distribution of resveratrol in rat viscera after having taken resveratrol orally.The concentrations of viscus except brain were higher than plasma.They reached a high in 20min for heart,spleen,lung,brain,and in 90min for liver and kidney.Then,they went down.The most of resveratrol were collected in lung and liver.
LC/MS/MS method and metabolite ID software was applied to study metabolites of rat urine.The experimental result indicates that resveratrol was mainly excreted directly from rat urine as prototype and resveratrol glucuronide and resveratrol sulfate. Polydatin's metabolites were prototype,resveratrol,resveratrol glucuronide and resveratrol sulfate.Their biotransformations in the bodies were bothⅡphase metabolism.
RP-HPLC method was developed for the simultaneous determination of polydatin and resveratrol in rat excrement.After being treated with C_(18) Solid Phase Extraction(SPE), the samples were analyzed.The assay was shown to be linear over the range of 0.803-642.6 ng(r=1.0000) for polydatin and 0.814-325.8ng(r=1.0000) for resveratrol.Mean recoveries were 102.2%(RSD=4.3%) and 97.3%(RSD=6.5%),respectively.In the meantime,studied the metabolic transforming of polydatin exerted by rat intestinal bacteria in vitro and in vivo.Incubation experiment in vitro showed that 51%of polydatin was transformed to resveratrol in 4h and 87%in 6h.Through transfer in the stomach and intestine,in vivo experiment displayed that polydatin's relative content was decreased greatly and the resveratrol was relatively increased.It was suggested that polydatin can be metabolized by rat intestinal bacteria and can be transformed into resveratrol through desugarization.
The anti-tumour activity in vitro of polydatin,resveratrol and extracter of Polygonum cuspidatum were reported in this dissertation.The studies demonstrated that reaction of reaveratrol was stronger than extracter of Polygonum cuspidatum in inhibiting the proliferation of human A549 cells.Polydatin was almost empty of the reaction.For human HL-60 cells and HO8910 cells,reactions of resveratrol were as strong as extracter of Polygonum cuspidatum,and polydatin was weak.In inhibiting the proliferation of human MCF-7 cells,reaction of resveratrol was better than extracter of Polygonum cuspidatum,and polydatin was weak,too.
The studies suggested that polydatin was firstly metabolized into resveratrol in intestines.Then resveratrol was absorbed and partly formed resveratrol glucuronide and resveratrol sulfate.They chiefly distributed in lung and liver.The biotransformations in the bodies wereⅡphase metabolism.Partly prototypes and itsⅡphase metabolites were excreted from rat urine,and partly prototypes and intestinal metabolites were excreted as stool.
建立了同时测定大鼠血浆中虎杖苷和白藜芦醇的HPLC方法,血浆经甲醇沉淀蛋白后进样分析,虎杖苷和白藜芦醇分别在0.263～33.68μg·mL~(-1)(r=0.9999)和0.059～37.43μg·mL~(-1)(r=0.9998)范围内线性关系良好,平均回收率分别为99.9%(RSD=1.8%)和93.9%(RSD=4.1%)。同时进行了白藜芦醇在大鼠体内的药动学研究,结果表明:大鼠口服给药白藜芦醇后,血浆白藜芦醇达峰时间为27min,峰浓度C_(max)为1.159μg·mL~(-1),血药浓度-时间曲线下面积AUC_(0-∞)值为165.2μg·min·mL~(-1)。
建立了测定大鼠脏器中虎杖苷和白藜芦醇的HPLC方法,脏器经甲醇沉淀蛋白后进样分析,虎杖苷在0.070～35.96μg·mL~(-1)(心r~2=0.9996,肝r~2=0.9996,脾r~2=0.9984,肺r~2=0.9997,肾r~2=0.9995,脑r~2=0.9984)范围内线性关系良好,方法定量下限为0.140μg·mL~(-1)。白藜芦醇在0.031～31.48μg·mL~(-1)(心r~2=0.9994,肝r~2=0.9995,脾r~2=0.9996,肺r~2=1.0000,肾r~2=0.9994,脑r~2=0.9985)范围内线性关系良好,方法定量下限为0.070μg·mL~(-1)。心脏组织虎杖苷和白藜芦醇的回收率分别为102.3%(RSD=3.6%)和102.3%(RSD=5.2%);肝脏组织虎杖苷和白藜芦醇的回收率分别为101.6%(RSD=3.7%)和101.7%(RSD=4.8%);脾脏组织虎杖苷和白藜芦醇的回收率分别为101.3%(RSD=4.0%)和101.0%(RSD=4.4%);肺脏组织虎杖苷和白藜芦醇的回收率分别为105.8%(RSD=4.6%)和106.4%(RSD=5.2%);肾脏组织虎杖苷和白藜芦醇的回收率分别为10.4%(RSD=3.1%)和100.0%(RSD=3.4%),脑组织虎杖苷和白藜芦醇的回收率分别为101.6%(RSD=3.2%)和101.0%(RSD=2.9%)。同时进行了白藜芦醇在大鼠体内主要脏器的分布研究,结果表明:大鼠口服给药白藜芦醇后各脏器组织中的药物含量除脑组织外均明显高于血浆,大鼠灌胃给药后20min,心、脾、肺、脑的组织浓度达到了最高,给药后90min肝、肾组织浓度达到最高,此后各组织的药物分布开始下降。从总体上来看,肝、肺药物浓度最高。
应用LC/MS/MS分析技术和代谢分析软件Metabolite ID,对大鼠口服给药虎杖苷和白藜芦醇后尿样进行了分析。结果表明:虎杖苷经过生物转化后除原型药外,主要代谢产物为白藜芦醇与其硫酸盐和葡醛酸结合物;白藜芦醇经过生物转化后主要以原型药与其硫酸盐和葡醛酸结合物直接从大鼠尿液中排出。两者在大鼠体内的生物转化主要是Ⅱ相代谢。
建立了同时测定大鼠粪便中虎杖苷和白藜芦醇的HPLC方法,粪便样品经50%乙醇提取,并经固相萃取小柱纯化后进样分析,虎杖苷和白藜芦醇分别在0.803～642.6 ng(r=1.0000)和0.814～325.8ng(r=1.0000)范围内线性关系良好,平均回收率分别为102.2%(RSD=4.3%)和97.3%(RSD=6.5%)。同时应用肠道菌孵育技术和整体肠内菌代谢技术研究虎杖苷和白藜芦醇口服给药后在大鼠体内的转化。虎杖苷在体外肠道菌孵育下,4小时后51%被转化成白藜芦醇,6小时后87%被转化。大鼠整体肠内菌试验进一步证明了肠内菌对虎杖苷的代谢作用,经过胃肠道内的转运,虎杖苷的相对含量大大降低,白藜芦醇的含量相对升高,说明虎杖苷在肠道微生物酶的影响下发生水解反应,脱去一分子葡萄糖转化为白藜芦醇。
对虎杖苷、白藜芦醇和虎杖提取物进行了体外肿瘤细胞株增殖抑制试验,增殖抑制试验结果表明,白藜芦醇对瘤株人肺腺癌A549细胞的抑制优于虎杖提取物,而虎杖苷几乎无抑制作用。对于人白血病HL-60细胞、人卵巢癌H08910细胞,白藜芦醇与虎杖提取物对瘤株的增值抑制作用相近,虎杖苷作用较弱。对人乳腺癌MCF-7细胞的增值抑制,白藜芦醇优于虎杖提取物,虎杖苷作用较弱。
研究结果表明,虎杖苷口服给药后,首先在肠道被代谢为白藜芦醇,白藜芦醇吸收入血后主要分布在肺和肝,在体内生物转化主要是Ⅱ相代谢,部分原型与其Ⅱ相代谢产物通过肾脏排出体外,部分原型与肠道水解产物白藜芦醇通过粪便排出体外。
Polygonum cuspidatum was studied in this dissertation.RP-HPLC method was developed for the simultaneous determination of polydatin,resveratrol,anthraglycoside B,emodin and physcion in Polygonum cuspidatum.The linear ranges for polydatin, resveratrol,anthraglycoside B,emodin and physcion were 119.9-2876 ng(r~2=1.0000), 31.48-1007ng(r~2=1.0000),17.28-1728ng(r~2=1.0000),41.84-1339ng(r~2=1.0000) and 5.39-172.5ng(r~2=0.9998),respectively.The average recoveries were 100.5%(RSD =2.6%),96.0%(RSD=0.6%),97.8%(RSD=1.5%),97.9%(RSD=1.1%) and 98.1% (RSD=1.6%),respectively.
A HPLC fingerprint was developed based on 21 batches of Polygonum cuspidatum. There were 31 common peaks in the fingerprint and 5 were identified.In the meantime, the irradiation of Polygonum cuspidatum sample solution,polydatin solution and resveratrol solution were tested.The contents of polydatin and resveratrol in solutions reduced obviously.Some of them changed into their isomers.
RP-HPLC method was developed for the simultaneous determination of polydatin and resveratrol in rat plasma.After being deproteinized by methanol,the plasma samples were analyzed.The assay was shown to be linear over the range of 0.263-33.68μg·mL~(-1)(r=0.9999) for polydatin and 0.059-37.43μg·mL~(-1)(r=0.9998) for resveratrol.Mean recoveries were 99.9%(RSD=1.8%) and 93.9%(RSD=4.1%), respectively.The HPLC method developed has been applied to determine the pharmacokinetics of resveratrol in rat plasma after having taken resveratrol orally.The pharmacokinetic parameters were calculated.The time for peak plasma level(T_(max)) was 27 min and the peak plasma level(C_(max)) was 1.159μg·mL~(-1).The area under concentration-time curve(AUC_(0-∞)) was 165.2μg·min·mL~(-1).
RP-HPLC method was developed for the simultaneous determination of polydatin and resveratrol in rat viscus.After being deproteinized by methanol,the viscus samples were analyzed.The assay was shown to be linear over the range of 0.070～35.96μg·mL~(-1) (heart r~2=0.9996,liver r~2=0.9996,spleen r~2=0.9984,lung r~2=0.9997,kidney r~2= 0.9995,brain r~2=0.9984) for polydatin and 0.031～31.48μg·mL~(-1)(heart r~2=0.9994, liver r~2=0.9995,spleen r~2=0.9996,lung r~2=1.0000,kidney r~2=0.9994,brain r~2= 0.9985)) for resveratrol.Mean recoveries of heart were 102.3%(RSD=3.6%) and 102.3%(RSD=5.2%),respectively.Mean recoveries of liver were 101.6%(RSD=3.7%) and 101.7%(RSD=4.8%),respectively.Mean recoveries of spleen were 101.3%(RSD= 4.0%) and 101.0%(RSD=4.4%),respectively.Mean recoveries of lung were 105.8% (RSD=4.6%) and 106.4%(RSD=5.2%),respectively.Mean recoveries of kidney were 100.4%(RSD=3.1%) and 100.0%(RSD=3.4%),respectively.Mean recoveries of brain were 101.6%(RSD=3.2%) and 101.0%(RSD=2.9%),respectively.The HPLC method developed has been applied to determine the distribution of resveratrol in rat viscera after having taken resveratrol orally.The concentrations of viscus except brain were higher than plasma.They reached a high in 20min for heart,spleen,lung,brain,and in 90min for liver and kidney.Then,they went down.The most of resveratrol were collected in lung and liver.
LC/MS/MS method and metabolite ID software was applied to study metabolites of rat urine.The experimental result indicates that resveratrol was mainly excreted directly from rat urine as prototype and resveratrol glucuronide and resveratrol sulfate. Polydatin's metabolites were prototype,resveratrol,resveratrol glucuronide and resveratrol sulfate.Their biotransformations in the bodies were bothⅡphase metabolism.
RP-HPLC method was developed for the simultaneous determination of polydatin and resveratrol in rat excrement.After being treated with C_(18) Solid Phase Extraction(SPE), the samples were analyzed.The assay was shown to be linear over the range of 0.803-642.6 ng(r=1.0000) for polydatin and 0.814-325.8ng(r=1.0000) for resveratrol.Mean recoveries were 102.2%(RSD=4.3%) and 97.3%(RSD=6.5%),respectively.In the meantime,studied the metabolic transforming of polydatin exerted by rat intestinal bacteria in vitro and in vivo.Incubation experiment in vitro showed that 51%of polydatin was transformed to resveratrol in 4h and 87%in 6h.Through transfer in the stomach and intestine,in vivo experiment displayed that polydatin's relative content was decreased greatly and the resveratrol was relatively increased.It was suggested that polydatin can be metabolized by rat intestinal bacteria and can be transformed into resveratrol through desugarization.
The anti-tumour activity in vitro of polydatin,resveratrol and extracter of Polygonum cuspidatum were reported in this dissertation.The studies demonstrated that reaction of reaveratrol was stronger than extracter of Polygonum cuspidatum in inhibiting the proliferation of human A549 cells.Polydatin was almost empty of the reaction.For human HL-60 cells and HO8910 cells,reactions of resveratrol were as strong as extracter of Polygonum cuspidatum,and polydatin was weak.In inhibiting the proliferation of human MCF-7 cells,reaction of resveratrol was better than extracter of Polygonum cuspidatum,and polydatin was weak,too.
The studies suggested that polydatin was firstly metabolized into resveratrol in intestines.Then resveratrol was absorbed and partly formed resveratrol glucuronide and resveratrol sulfate.They chiefly distributed in lung and liver.The biotransformations in the bodies wereⅡphase metabolism.Partly prototypes and itsⅡphase metabolites were excreted from rat urine,and partly prototypes and intestinal metabolites were excreted as stool.
引文
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