桑叶提取物中黄酮类化合物在大鼠体内的药动学研究
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摘要
桑叶为桑科植物桑(Morus alba L.)的树叶,为传统的中药材之一,广泛地应用在现代医药和食品领域。黄酮类化合物是桑叶中一类重要的有效成分,具有抗菌、降血压、清除自由基、抑制血清脂质增加和抑制动脉粥样硬化形成的作用,并与桑叶中的多糖、生物碱等成分在降血糖活性方面有一定的协同作用,是评价桑叶药材质量的标准之一。鉴于其丰富的生理和药理作用,除作为中药材应用于临床外,桑叶也被加工成各种保健品热销各国。但不同来源的桑叶提取物,黄酮类化合物的含量有一定差异。文献对不同产地、不同品种和不同季节采收的桑叶中的黄酮类成分的测定和效应成分的药理作用,如抗菌、抗氧化、降血糖、降血脂等有较多报道,但对桑叶提取物的质量评价和有效成分的药动学研究报道缺乏,因此对桑叶提取物的主要药效成分之一黄酮类化合物进行质量监控及其在大鼠体内的药代动力学行为进行研究显得十分必要,有助于桑叶药材及桑叶提取物的质量控制和具体效应成分的生物利用度研究。
本文首先对桑叶提取物进行酸水解,以正交试验设计优选出酸水解的最佳条件,即盐酸浓度2.0 mol·L~(-1)、水解温度90℃、水解时间60min。然后以HPLC法测定槲皮素和山萘酚的含量,从而达到对桑叶提取物中黄酮类化合物的含量进行控制的目的。在此基础上,本文建立了大鼠血浆中槲皮素、山萘酚及异鼠李素的总浓度的测定方法,并利用所建立的方法测定了大鼠口服桑叶提取物后血浆中药物浓度随时间的变化,应用DAS3.0软件,分析了血浆中槲皮素、山萘酚、异鼠李素的药代动力学特征,为进一步以桑叶为原料开发药物和保健品提供一定的理论依据。
1.桑叶提取物中黄酮类化合物的测定
目的:建立HPLC法测定桑叶提取物中水解产物槲皮素和山萘酚的含量,从而达到对桑叶提取物中黄酮类化合物的含量进行控制的目的。
方法:取桑叶提取物25mg,精密称定,加20mL盐酸甲醇溶液使之溶解,并使反应体系中盐酸终浓度为2.0mol·L~(-1)、甲醇终浓度为50%(v/v),水浴回流,使桑叶提取物中主要黄酮苷类成分水解为槲皮素和山萘酚,以HPLC法测定槲皮素和山萘酚含量。色谱柱为Diamonsil钻石G_(18)柱(4.6mm×250mm,5μm);流动相为甲醇-0.2%磷酸(63:37,v/v);流速为1.0mL·min~(-1);检测波长为370nm。
结果:槲皮素在0.84-26.8 mgL~(-1)之间,山萘酚在0.44-14.2mg·L~(-1)之间呈良好的线性关系(r=0.9999,0.9999,n=6);日内、日间精密度以RSD计分别小于1.8%,2.3%;加样回收率分别为97.0-103.4%,97.3-103.2%。
结论:HPLC法测定桑叶提取物中水解产物槲皮素和山萘酚的含量方法准确、重复性好,可用于桑叶提取物中黄酮类化合物的质量控制。测定结果表明,本研究桑叶提取物中水解产物槲皮素和山萘酚的含量分别为5.98±0.12%,1.98±0.04%。不同批次的桑叶提取物之间含量差别并不大。
2.桑叶提取物中黄酮类化合物在大鼠体内的药动学研究
目的:建立大鼠血浆中测定槲皮素、山萘酚及异鼠李素的浓度的高效液相色谱法,并研究大鼠口服桑叶提取物(Folium Mori Extract,简称FME)后血浆中效应成分-槲皮素、山萘酚及其代谢产物疑似异鼠李素(对这一名词的解释见第二章3.9)的药代动力学特征。
方法:精密移取大鼠血浆100.0μL,加入内标物木犀草素9.0μL,在3mol·L~(-1)盐酸条件下于90℃水浴中水解60min,水解后置于冰水中冷却,并精密加入乙醚-丙酮混合液(14:1,v/v)1.5mL进行漩涡萃取,萃取液减压挥干后加50%的甲醇溶解,超高速离心后取75μL上层清液进样分析。采用AgilentZorbax SB-C_(18)色谱柱,以甲醇-0.2%磷酸(50:50,v/v)为流动相,流速1.0mL·min~(-1),检测波长370nm,柱温37℃。大鼠口服106mg·kg~(-1)桑叶提取物后,收集给药前及给药后不同时间点血浆,以所建立的方法测定各时间点血浆中槲皮素、山萘酚和疑似异鼠李素的浓度,并根据所测定的浓度得出药物浓度-时间曲线,用DAS3.0软件计算三者的药代动力学参数。
结果:槲皮素、山萘酚和异鼠李素分别在0.060-2.40mg·L~(-1),0.105-4.20mg·L~(-1)和0.060-2.40mg·L~(-1)内呈良好线性关系,r分别为1.000,0.9991和0.9908;提取回收率分别在74.6-93.6%,81.7-85.6%,68.4-80.4%之间;方法回收率分别在96-103%,103-108%,87-108%之间。日间及日内精密度RSD均小于13.9%。大鼠灌胃给药FME后,血药浓度出现双峰现象;槲皮素、山萘酚和疑似异鼠李素分别于0.333h、0.333h、0.667h左右达第一个峰;4h、6h及6h左右达第二个峰;槲皮素、山萘酚和疑似异鼠李素的t_(1/2z)分别为66.8h、42.3h、64.2h,C_(max)分别为1.21 mg·L~(-1)、1.79 mg·L~(-1)、0.325 mg·L~(-1)。
结论:高效液相色谱法测定大鼠血浆中槲皮素、山萘酚和异鼠李素的浓度方法准确可靠,操作简便,重复性好。药动学参数显示,三者在大鼠体内分布迅速,消除缓慢。
Folium Mori,leaves of Morus alba L.,one of the traditional Chinese herbal medicines,has been widely used as food and medicine.Flavonoids are the major effective ingredients in Folium Mori,with activities of exhibiting a wide range of biological effects,including bacteriostasis,antihyperlipidemia, reducing hypertensive,free radical scavenging,inhibition of atherosclerosis,and have a certain degree of synergy with polysaccharides,alkaloids and other constituents in the hypoglycemic activity.In view of its rich biological and pharmacological effects,in addition to being used in clinical as traditional chinese herbal medicines,also be processed into health care products in all countries.But different sources of mulberry leaf extracts,the contents of main effects will be different.More researches have been reported on the determination and pharmacodynamic of Folium Mori,but there is little information concerning the quality evaluation and pharmacokinetics of mulberry leaf extract.Therefore,it is essential to control the quality of flavonoids in FME and study on pharmacokinetic in rats,to properly evaluate the quality and bioavailability of FME.
In our study,a simple HPLC method was developed for determination of quercetin and kaemperfol in Folium Mori extract,and the best condition for acid hydrolysis by optimizating with orthogonal design is hydrochloric acid concentration of 2.0 mol·L~(-1),hydrolysis temperature of 90℃,hydrolysis time 60min.In addition,reversed-phase HPLC was employed for the quantitative analysis of total quercetin,kaempferol and isorhamnetin in rat plasma after an oral administration of FME.Drug concentration changes with time was detemined by the method established.Kinetics of drug metabolism was analyzed with DAS 2.0 software package.All above these may provide a firm basis for evaluating the clinical efficacy and the development of drugs and health products.
1.Determination of Flavonoids in Folium Mori Extract
Objective:To establish a method for the determination of quercetin and kaempferol in Folium Mori extract by HPLC to control the flavonoids content.
Method:Mulberry Leaf Extract 25 mg was dissolved in 20 mL mixed solution with hydrochloric acid concentration of 2.0 mol·L~(-1),methanol concentration of 50%(v/v).By bath reflux the flavonoids were hydrolyted into quercetin and kaempferol.The contents of quercetin and kaempferol were determined by HPLC method,performed on Diamonsil C_(18) column with the mobile phase consisted of methanol-0.20%phosphoric acid solution(63:37,v/v).The flow rate was 1.0 mL·min~(-1),and the UV wavelength was set at 370 nm.
Results:The linear ranges of quercetin and kaempferol were 0.84—26.8 mg·L~(-1), 0.44-14.2 mg·L~(-1) and the coefficient were 0.9999,0.9999.The precisions of intra-day and inter-day were less than 1.8%,2.3%with RSD.The average recoveries of quercetin and kaempferol were 97.0-103.4%,97.3-103.2% individually.
Conclusion:The method is accurate,reliable and good reappearance for the determination of quercetin and kaempferol in Folium Mori extract,and could be used to control the flavonoids content.The contents of quercetin and kaempferol in FME were 5.98±0.12%,1.98±0.04%individually.The results indicated that the difference of contents of quercetin and kaempferol is not large among different batches of FME.
2.Study on Pharmacokinetics of Flavonoids in Folium Mori Extract in Rats
Objective:To establish a RP-HPLC method for the determination of total quercetin,kaempferol and isorhamnetin in rat plasma,and to study on pharmacokinetics in rats after an oral administration of FME.
Method:The rat plasma samples 100.0μL with luteolin of 9.0μL were hydrolyted at the condition of 3.0mol·L~(-1) hydrochloric acid,90℃water bath for 60min,then cooling in the ice bath.The mixed solution were extracted with ethylether-acetone mixture of 1.5 mL.The organic layer separated was blown to dry and dissolved reconstituted in 50%methanol solution.The upper clear liquid of 75μL was injected after ultra high-speed centrifugation.The HPLC separation was performed on an Agilent Zorbax SB-C_(18) column with the mobile phase consisted of methanol-0.20%phosphoric acid solution(50:50,v/v).The UV detector wavelength was set at 370 nm,the column temperature was set at 37℃and the flow rate was set at 1.0 ml·min~(-1).Collecting plasma at different times after an oral administration of FME in rats,these samples were analyzed by the HPLC method,to get the concentration-time curves of quercetin, kaempferol and isorhamnetin.Then all data of pharmacokinetic parameters were processed by the DAS 2.0 software package.
Results:The method was linear over the studied ranges of 0.060～2.40mg·L~(-1), 0.105～4.20mg·L~(-1) and 0.060～2.40mg·L~(-1) for quercetin,kaempferol and isorhamnetin,respectively(r=1.0000,0.9991,0.9908).The mean extracting recoveries were,74.6-93.6%,81.7-85.6%,68.4-80.4%and average recoveries were 96-103%,103-108%,87-108%.The precisions of intra-day and inter-day were less than13.9%.Double peaks of plasma concentration appeared.The first peak of quercetin,kaempferol and isorhamnetin appeared at about 0.333h、0.333h、0.667h,the second peak about 4 h、6h、6h after an oral administration of FME.T_(1/2z) were 66.8h、42.3h、64.2h and C_(max) were 1.21 mg·L~(-1)、1.79 mg·L~(-1)、0.325 mg·L~(-1)individually.
Conclusion:The method developed is sensitive,accurate and good reappearance, and has been successfully applied to study on pharmacokinetics of quercetin、kaempferol and isorhamnetin in rat plasma.Pharmacokinetic parameters showed that the distribution of the three is rapid and elimination is very slow in rats.
本文首先对桑叶提取物进行酸水解,以正交试验设计优选出酸水解的最佳条件,即盐酸浓度2.0 mol·L~(-1)、水解温度90℃、水解时间60min。然后以HPLC法测定槲皮素和山萘酚的含量,从而达到对桑叶提取物中黄酮类化合物的含量进行控制的目的。在此基础上,本文建立了大鼠血浆中槲皮素、山萘酚及异鼠李素的总浓度的测定方法,并利用所建立的方法测定了大鼠口服桑叶提取物后血浆中药物浓度随时间的变化,应用DAS3.0软件,分析了血浆中槲皮素、山萘酚、异鼠李素的药代动力学特征,为进一步以桑叶为原料开发药物和保健品提供一定的理论依据。
1.桑叶提取物中黄酮类化合物的测定
目的:建立HPLC法测定桑叶提取物中水解产物槲皮素和山萘酚的含量,从而达到对桑叶提取物中黄酮类化合物的含量进行控制的目的。
方法:取桑叶提取物25mg,精密称定,加20mL盐酸甲醇溶液使之溶解,并使反应体系中盐酸终浓度为2.0mol·L~(-1)、甲醇终浓度为50%(v/v),水浴回流,使桑叶提取物中主要黄酮苷类成分水解为槲皮素和山萘酚,以HPLC法测定槲皮素和山萘酚含量。色谱柱为Diamonsil钻石G_(18)柱(4.6mm×250mm,5μm);流动相为甲醇-0.2%磷酸(63:37,v/v);流速为1.0mL·min~(-1);检测波长为370nm。
结果:槲皮素在0.84-26.8 mgL~(-1)之间,山萘酚在0.44-14.2mg·L~(-1)之间呈良好的线性关系(r=0.9999,0.9999,n=6);日内、日间精密度以RSD计分别小于1.8%,2.3%;加样回收率分别为97.0-103.4%,97.3-103.2%。
结论:HPLC法测定桑叶提取物中水解产物槲皮素和山萘酚的含量方法准确、重复性好,可用于桑叶提取物中黄酮类化合物的质量控制。测定结果表明,本研究桑叶提取物中水解产物槲皮素和山萘酚的含量分别为5.98±0.12%,1.98±0.04%。不同批次的桑叶提取物之间含量差别并不大。
2.桑叶提取物中黄酮类化合物在大鼠体内的药动学研究
目的:建立大鼠血浆中测定槲皮素、山萘酚及异鼠李素的浓度的高效液相色谱法,并研究大鼠口服桑叶提取物(Folium Mori Extract,简称FME)后血浆中效应成分-槲皮素、山萘酚及其代谢产物疑似异鼠李素(对这一名词的解释见第二章3.9)的药代动力学特征。
方法:精密移取大鼠血浆100.0μL,加入内标物木犀草素9.0μL,在3mol·L~(-1)盐酸条件下于90℃水浴中水解60min,水解后置于冰水中冷却,并精密加入乙醚-丙酮混合液(14:1,v/v)1.5mL进行漩涡萃取,萃取液减压挥干后加50%的甲醇溶解,超高速离心后取75μL上层清液进样分析。采用AgilentZorbax SB-C_(18)色谱柱,以甲醇-0.2%磷酸(50:50,v/v)为流动相,流速1.0mL·min~(-1),检测波长370nm,柱温37℃。大鼠口服106mg·kg~(-1)桑叶提取物后,收集给药前及给药后不同时间点血浆,以所建立的方法测定各时间点血浆中槲皮素、山萘酚和疑似异鼠李素的浓度,并根据所测定的浓度得出药物浓度-时间曲线,用DAS3.0软件计算三者的药代动力学参数。
结果:槲皮素、山萘酚和异鼠李素分别在0.060-2.40mg·L~(-1),0.105-4.20mg·L~(-1)和0.060-2.40mg·L~(-1)内呈良好线性关系,r分别为1.000,0.9991和0.9908;提取回收率分别在74.6-93.6%,81.7-85.6%,68.4-80.4%之间;方法回收率分别在96-103%,103-108%,87-108%之间。日间及日内精密度RSD均小于13.9%。大鼠灌胃给药FME后,血药浓度出现双峰现象;槲皮素、山萘酚和疑似异鼠李素分别于0.333h、0.333h、0.667h左右达第一个峰;4h、6h及6h左右达第二个峰;槲皮素、山萘酚和疑似异鼠李素的t_(1/2z)分别为66.8h、42.3h、64.2h,C_(max)分别为1.21 mg·L~(-1)、1.79 mg·L~(-1)、0.325 mg·L~(-1)。
结论:高效液相色谱法测定大鼠血浆中槲皮素、山萘酚和异鼠李素的浓度方法准确可靠,操作简便,重复性好。药动学参数显示,三者在大鼠体内分布迅速,消除缓慢。
Folium Mori,leaves of Morus alba L.,one of the traditional Chinese herbal medicines,has been widely used as food and medicine.Flavonoids are the major effective ingredients in Folium Mori,with activities of exhibiting a wide range of biological effects,including bacteriostasis,antihyperlipidemia, reducing hypertensive,free radical scavenging,inhibition of atherosclerosis,and have a certain degree of synergy with polysaccharides,alkaloids and other constituents in the hypoglycemic activity.In view of its rich biological and pharmacological effects,in addition to being used in clinical as traditional chinese herbal medicines,also be processed into health care products in all countries.But different sources of mulberry leaf extracts,the contents of main effects will be different.More researches have been reported on the determination and pharmacodynamic of Folium Mori,but there is little information concerning the quality evaluation and pharmacokinetics of mulberry leaf extract.Therefore,it is essential to control the quality of flavonoids in FME and study on pharmacokinetic in rats,to properly evaluate the quality and bioavailability of FME.
In our study,a simple HPLC method was developed for determination of quercetin and kaemperfol in Folium Mori extract,and the best condition for acid hydrolysis by optimizating with orthogonal design is hydrochloric acid concentration of 2.0 mol·L~(-1),hydrolysis temperature of 90℃,hydrolysis time 60min.In addition,reversed-phase HPLC was employed for the quantitative analysis of total quercetin,kaempferol and isorhamnetin in rat plasma after an oral administration of FME.Drug concentration changes with time was detemined by the method established.Kinetics of drug metabolism was analyzed with DAS 2.0 software package.All above these may provide a firm basis for evaluating the clinical efficacy and the development of drugs and health products.
1.Determination of Flavonoids in Folium Mori Extract
Objective:To establish a method for the determination of quercetin and kaempferol in Folium Mori extract by HPLC to control the flavonoids content.
Method:Mulberry Leaf Extract 25 mg was dissolved in 20 mL mixed solution with hydrochloric acid concentration of 2.0 mol·L~(-1),methanol concentration of 50%(v/v).By bath reflux the flavonoids were hydrolyted into quercetin and kaempferol.The contents of quercetin and kaempferol were determined by HPLC method,performed on Diamonsil C_(18) column with the mobile phase consisted of methanol-0.20%phosphoric acid solution(63:37,v/v).The flow rate was 1.0 mL·min~(-1),and the UV wavelength was set at 370 nm.
Results:The linear ranges of quercetin and kaempferol were 0.84—26.8 mg·L~(-1), 0.44-14.2 mg·L~(-1) and the coefficient were 0.9999,0.9999.The precisions of intra-day and inter-day were less than 1.8%,2.3%with RSD.The average recoveries of quercetin and kaempferol were 97.0-103.4%,97.3-103.2% individually.
Conclusion:The method is accurate,reliable and good reappearance for the determination of quercetin and kaempferol in Folium Mori extract,and could be used to control the flavonoids content.The contents of quercetin and kaempferol in FME were 5.98±0.12%,1.98±0.04%individually.The results indicated that the difference of contents of quercetin and kaempferol is not large among different batches of FME.
2.Study on Pharmacokinetics of Flavonoids in Folium Mori Extract in Rats
Objective:To establish a RP-HPLC method for the determination of total quercetin,kaempferol and isorhamnetin in rat plasma,and to study on pharmacokinetics in rats after an oral administration of FME.
Method:The rat plasma samples 100.0μL with luteolin of 9.0μL were hydrolyted at the condition of 3.0mol·L~(-1) hydrochloric acid,90℃water bath for 60min,then cooling in the ice bath.The mixed solution were extracted with ethylether-acetone mixture of 1.5 mL.The organic layer separated was blown to dry and dissolved reconstituted in 50%methanol solution.The upper clear liquid of 75μL was injected after ultra high-speed centrifugation.The HPLC separation was performed on an Agilent Zorbax SB-C_(18) column with the mobile phase consisted of methanol-0.20%phosphoric acid solution(50:50,v/v).The UV detector wavelength was set at 370 nm,the column temperature was set at 37℃and the flow rate was set at 1.0 ml·min~(-1).Collecting plasma at different times after an oral administration of FME in rats,these samples were analyzed by the HPLC method,to get the concentration-time curves of quercetin, kaempferol and isorhamnetin.Then all data of pharmacokinetic parameters were processed by the DAS 2.0 software package.
Results:The method was linear over the studied ranges of 0.060～2.40mg·L~(-1), 0.105～4.20mg·L~(-1) and 0.060～2.40mg·L~(-1) for quercetin,kaempferol and isorhamnetin,respectively(r=1.0000,0.9991,0.9908).The mean extracting recoveries were,74.6-93.6%,81.7-85.6%,68.4-80.4%and average recoveries were 96-103%,103-108%,87-108%.The precisions of intra-day and inter-day were less than13.9%.Double peaks of plasma concentration appeared.The first peak of quercetin,kaempferol and isorhamnetin appeared at about 0.333h、0.333h、0.667h,the second peak about 4 h、6h、6h after an oral administration of FME.T_(1/2z) were 66.8h、42.3h、64.2h and C_(max) were 1.21 mg·L~(-1)、1.79 mg·L~(-1)、0.325 mg·L~(-1)individually.
Conclusion:The method developed is sensitive,accurate and good reappearance, and has been successfully applied to study on pharmacokinetics of quercetin、kaempferol and isorhamnetin in rat plasma.Pharmacokinetic parameters showed that the distribution of the three is rapid and elimination is very slow in rats.
引文
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