中药引经药醋柴胡对氧化苦参碱小鼠体内分布的影响
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摘要
目的:
探讨醋柴胡对氧化苦参碱及其主要代谢产物苦参碱在小鼠体内分布的影响,验证中药引经药醋柴胡对苦参类生物碱的肝经引经作用。
方法:
1.组织内氧化苦参碱(Oxymatrine OMT)和苦参碱(Matrine MT)含量测定采用液相色谱-质谱联用技术,色谱柱为(Interlsil ODS-SP,5μm 2.1×150mm);流动相:甲醇lOmmol·L~-1乙酸铵溶液(乙酸调PH值3.5)80:20;流速300μL·min~-1;柱温为室温;进样量10μL。
组织以1:10加水匀浆,组织匀浆液和血浆样品采用含2%正丁醇的氯仿液进行液一液萃取。用电喷雾离子化和正离子多离子反应监测(MRM)方式检测氧化苦参碱(m/z265.3→247.2),苦参碱(m/z249.5→148.2)和内标物非那雄胺(m/z373.5→305.6)。
2.醋柴胡(Vinegar processing Radix Bupleuric VPRB)对氧化苦参碱和苦参碱体内分布的影响采用体内分布实验法。336只雄性KM小鼠随机分为8组,氧化苦参碱高(10mg·kg~-1 )、低剂量(80 mg·kg~-1)各4组,即柴胡空白对照组、氧化苦参碱合并醋柴胡低、中、高剂量各1组,剂量分别为(400、800、1200 mg·kg~-1)。其中醋柴胡低剂量组选择O.167h、O.5h、1h、2h、4h、8h 6个时间点,高剂量组选择O.167h、0.333h、0.667h、1h、1.5h、2h、4h、8h 8个时间点,每个时间点6只动物。分别按对应剂量灌胃给药,于各时间点采集血浆、肝、心、脾、肺、肾组织,预处理后以HPLC-MS/MS法测定药物含量,分析其药动学过程,通过Tmax、Cmax、AUC、AUCo~/AUC_MT、AUCsum评价它对氧化苦参碱和苦参碱分布的影响。
3.以现代靶性药物相关方法选取相对摄取率(Re)和综合靶向效率(RTE)评价醋柴胡对氧化苦参碱和苦参碱小鼠体不同组织的靶向性。结果:
1.氧化苦参碱和苦参碱线性范围均为4-2000ng·ml~-1;定量下限均4ng·ml~-1;各组织方法回收率均在87.1-110.3%;批内、批间精密度小于14%;提取回收率大于58.6%。
2.氧化苦参碱高剂量组OMT和MT在血浆及肝、心、脾、肺、肾组织内过程符合二房室模型,而氧化苦参碱低剂量组则大部分组织符合一房室模型。氧化苦参碱高剂量组,联合用VPRB后,肝脏氧化苦参碱VPRB-M及H组Cmax较空白组增加80%以上,肝脏VPRB-M组和H组等苦参碱Cmax都有增加,氧化苦参碱AUC增大为对照组2.55倍和2.53倍,苦参碱增加12.09%和16.36%。氧化苦参碱低剂量组,肝脏VPRB-M组Cmax较空白组增加了20%,VPRB-L及H组苦参碱AUC较空白组有增加,其中VPRB-H组增加31.82%。同样给药条件下血浆、心、脾、肺、肾等组织Cmax和AUC等则主要呈现下降趋势,最大降幅可达85%。
3.肝脏VPRB-M和H组相对摄取率Re均大于1,其中氧化苦参碱高剂量组VPRB-M和H组氧化苦参碱Re高达2.55和2.53,0MT低剂量组VPRB-H组苦参碱Re值1.32其它组织大多小于1或接近1;肝脏VPRB组综合靶向效率增强,其中OMT高剂量组醋柴胡各组氧化苦参碱RTE分别为:O.40、2.16和2.11,苦参碱RTE值0.13、O.21和O.33;0MT低剂量组氧化苦参碱RTE分别为:O.04、0.10和O.33,苦参碱RTE分别为O.29、O.21和0.49,两个氧化苦参碱剂量组均以醋柴胡高剂量作用最为显著。
结论:
HPLC-MS/MS含量测定方法准确、灵敏、简便、省时,适用于小鼠各脏组织中氧化苦参碱和苦参碱的含量测定。醋柴胡对氧化苦参碱体内分布的影响与氧化苦参碱剂量和醋柴胡剂量均有关系,其中醋柴胡高剂量组可显著增加氧化苦参碱及其代谢产物苦参碱小鼠肝脏组织峰浓度和药物分布量,增强其相对摄取率和靶向效率,同时醋柴胡也可降低药物在其它组织的峰浓度、药物量及相对靶向效率,证实中药引经药可达到增效减毒的作用。
Speciality:Pharmaceutics
Author:Youjun Chen
Tutor:Ruizhi Zhao
AIM:
Study the influence of vinegar processing radix bupleuric(VPRB) on the distribution of Oxymatrine(OMT) and its main metabolite Matrine(MT),in rats body,and verify the liver target enhancing effect of VPRB on Matrine category alkaloids.
Methods:
1.Oxymatrine and Matrine concerntration of tisssues were determinated by High-performance liquid chromatography mass spectrometry.The chromatographic column is Interlsil ODS-SP(5μm 2.1X150mm),the mobile phase consisted of methanol-10mmol ? L~(-1) NH_4Ac(adjust the pH value to 3.5 by acetic acid),flow rate is 300μL ? min(-1),column temperature is room temperature,the injection volumn is 10μL.
The tissues were homogenated with 10 times water,and the homogenate and plasma samples were extracted by trichlormethane with 2%n-butanol through liquid-liquid extraction.Oxymatrine(m/z265.3→247.2),Matrine(m/z 249.5→148.2) and internal standard Finasteride(m/z373.5→305.6) were detected by the positive electrospray ionization(ESI)-MS method under multiple reaction monitoring(MRM) mode.
2.The influence of VPRB on the distribution of OMT and MT in rat body was evaluated by vivo distribution experiment.336 male rats were divided into two big groups according the dose of oxymatrine,oxymatrine lower and higher group(10 and 80mg·kg(-1)).At each big group,oxymatrine group as control and oxymatrine coadministered with three different doses of VPRB(400,800,1200 mg·kg(-1)) intragastric administration.Samples were collected at the time points of 0.167,0.5,1,2,4,8 hours for oxymatrine lower group,and 0.167,0.333, 0.667,1,1.5,2,4,8 hours for oxymatrine higher group.The samples were detected by HPLC-MS/MS and analysis the pharmacokinetic process.The influences of VPRB on the distribution of OMT and MT were evaluated through the pharmacokinetic parameters,such as Tmax、Cmax、AUC、AUC_(OMT)/AUC_(MT) and AUCsum.
3.The target effect of different tissues of VPRB on OMT and MT was evaluated through the parameters of Relative uptake efficiency(Re) and Relative targeting efficiency(RTE).
Results:
1.The linearity of oxymatrine and matrine both ranged from 4 to 2000 ng ? ml(-1), the detection limits of them was 4ng ? mL(-1).The recovery of this method ranged from 87.1-110.3%.The values of RSD of within day and between day were less than 14%.The recovery rates of extraction were above 58.6%.
2.Oxymatrine and Matrine processing in plasma,liver,heart,spleen,lung and kidney for OMT higher dosage group fit an open two-compartment model,but in most tissues,they fit a one-cmpartment model for OMT lower dosage group.
VPRB increased the Cmax and AUC of both OMT and MT in liver.In OMT higher group,OMT Cmax of VPRB-M group and VPRB-H group increased by above 80 percent as compared with control group respectively,and the Cmax of MT in both groups were also increased.The AUC of OMT in VPRB-M group and H group were 2.55 and 2.53 times larger compared to control group,and the MT AUC of these two groups increased 12.09%and 16.36%respectively.
In OMT lower group,the AUC of OMT in VPRB-L group and VPRB-H group are larger than the control group,the increased value of VPRB-H group is 31.82%, and meanwhile the Cmax and AUC of plasma,heart lung and kidney were tending to decline.
In OMT higher group,compared to the control group,VPRB-M group and VPRB-H group increased the Re and RTE of liver OMT,the Re of VPRB-M and H group were 2.55 and 2.53 respectively,and the Re of other tissues were all less than 1.In all VPRB groups the liver RTE were positive value,the OMT RTE of VPRB-L, M,H groups were 0.40,2.16 and 2.11 respectively,and those of MT were 0.13, 0.21and 0.33 respectively.
In Oxymatrine lower group,the liver OMT RTE of VPRB-L,M and H groups were 0.04,0.10 and 0.33 respectively,and the RTE of MT were 0.29,0.1 and 0.49 respectively.VPRB high dose had the strongest effect in both OMT higher group and lower group.
Conclosion:
HPLC-MS/MS method is accurate,highly sensitive,simple and convenient, time saving for the simultaneous determination of oxymatrine and matrine concentrations in tissues and plasma of rat.
The targeting enforcing effect of VPRB was related with the dose of VPRB, high and medium dose of VPRB could enhance the targeting efficiency of OMT and MT significantly.VPRB focus the effect of other drug on liver by increasing the uptake of liver and meanwhile decreasing the uptake of other tissues.The results of this paper imply that VBRB might be a potential drug for target therapy.
探讨醋柴胡对氧化苦参碱及其主要代谢产物苦参碱在小鼠体内分布的影响,验证中药引经药醋柴胡对苦参类生物碱的肝经引经作用。
方法:
1.组织内氧化苦参碱(Oxymatrine OMT)和苦参碱(Matrine MT)含量测定采用液相色谱-质谱联用技术,色谱柱为(Interlsil ODS-SP,5μm 2.1×150mm);流动相:甲醇lOmmol·L~-1乙酸铵溶液(乙酸调PH值3.5)80:20;流速300μL·min~-1;柱温为室温;进样量10μL。
组织以1:10加水匀浆,组织匀浆液和血浆样品采用含2%正丁醇的氯仿液进行液一液萃取。用电喷雾离子化和正离子多离子反应监测(MRM)方式检测氧化苦参碱(m/z265.3→247.2),苦参碱(m/z249.5→148.2)和内标物非那雄胺(m/z373.5→305.6)。
2.醋柴胡(Vinegar processing Radix Bupleuric VPRB)对氧化苦参碱和苦参碱体内分布的影响采用体内分布实验法。336只雄性KM小鼠随机分为8组,氧化苦参碱高(10mg·kg~-1 )、低剂量(80 mg·kg~-1)各4组,即柴胡空白对照组、氧化苦参碱合并醋柴胡低、中、高剂量各1组,剂量分别为(400、800、1200 mg·kg~-1)。其中醋柴胡低剂量组选择O.167h、O.5h、1h、2h、4h、8h 6个时间点,高剂量组选择O.167h、0.333h、0.667h、1h、1.5h、2h、4h、8h 8个时间点,每个时间点6只动物。分别按对应剂量灌胃给药,于各时间点采集血浆、肝、心、脾、肺、肾组织,预处理后以HPLC-MS/MS法测定药物含量,分析其药动学过程,通过Tmax、Cmax、AUC、AUCo~/AUC_MT、AUCsum评价它对氧化苦参碱和苦参碱分布的影响。
3.以现代靶性药物相关方法选取相对摄取率(Re)和综合靶向效率(RTE)评价醋柴胡对氧化苦参碱和苦参碱小鼠体不同组织的靶向性。结果:
1.氧化苦参碱和苦参碱线性范围均为4-2000ng·ml~-1;定量下限均4ng·ml~-1;各组织方法回收率均在87.1-110.3%;批内、批间精密度小于14%;提取回收率大于58.6%。
2.氧化苦参碱高剂量组OMT和MT在血浆及肝、心、脾、肺、肾组织内过程符合二房室模型,而氧化苦参碱低剂量组则大部分组织符合一房室模型。氧化苦参碱高剂量组,联合用VPRB后,肝脏氧化苦参碱VPRB-M及H组Cmax较空白组增加80%以上,肝脏VPRB-M组和H组等苦参碱Cmax都有增加,氧化苦参碱AUC增大为对照组2.55倍和2.53倍,苦参碱增加12.09%和16.36%。氧化苦参碱低剂量组,肝脏VPRB-M组Cmax较空白组增加了20%,VPRB-L及H组苦参碱AUC较空白组有增加,其中VPRB-H组增加31.82%。同样给药条件下血浆、心、脾、肺、肾等组织Cmax和AUC等则主要呈现下降趋势,最大降幅可达85%。
3.肝脏VPRB-M和H组相对摄取率Re均大于1,其中氧化苦参碱高剂量组VPRB-M和H组氧化苦参碱Re高达2.55和2.53,0MT低剂量组VPRB-H组苦参碱Re值1.32其它组织大多小于1或接近1;肝脏VPRB组综合靶向效率增强,其中OMT高剂量组醋柴胡各组氧化苦参碱RTE分别为:O.40、2.16和2.11,苦参碱RTE值0.13、O.21和O.33;0MT低剂量组氧化苦参碱RTE分别为:O.04、0.10和O.33,苦参碱RTE分别为O.29、O.21和0.49,两个氧化苦参碱剂量组均以醋柴胡高剂量作用最为显著。
结论:
HPLC-MS/MS含量测定方法准确、灵敏、简便、省时,适用于小鼠各脏组织中氧化苦参碱和苦参碱的含量测定。醋柴胡对氧化苦参碱体内分布的影响与氧化苦参碱剂量和醋柴胡剂量均有关系,其中醋柴胡高剂量组可显著增加氧化苦参碱及其代谢产物苦参碱小鼠肝脏组织峰浓度和药物分布量,增强其相对摄取率和靶向效率,同时醋柴胡也可降低药物在其它组织的峰浓度、药物量及相对靶向效率,证实中药引经药可达到增效减毒的作用。
Speciality:Pharmaceutics
Author:Youjun Chen
Tutor:Ruizhi Zhao
AIM:
Study the influence of vinegar processing radix bupleuric(VPRB) on the distribution of Oxymatrine(OMT) and its main metabolite Matrine(MT),in rats body,and verify the liver target enhancing effect of VPRB on Matrine category alkaloids.
Methods:
1.Oxymatrine and Matrine concerntration of tisssues were determinated by High-performance liquid chromatography mass spectrometry.The chromatographic column is Interlsil ODS-SP(5μm 2.1X150mm),the mobile phase consisted of methanol-10mmol ? L~(-1) NH_4Ac(adjust the pH value to 3.5 by acetic acid),flow rate is 300μL ? min(-1),column temperature is room temperature,the injection volumn is 10μL.
The tissues were homogenated with 10 times water,and the homogenate and plasma samples were extracted by trichlormethane with 2%n-butanol through liquid-liquid extraction.Oxymatrine(m/z265.3→247.2),Matrine(m/z 249.5→148.2) and internal standard Finasteride(m/z373.5→305.6) were detected by the positive electrospray ionization(ESI)-MS method under multiple reaction monitoring(MRM) mode.
2.The influence of VPRB on the distribution of OMT and MT in rat body was evaluated by vivo distribution experiment.336 male rats were divided into two big groups according the dose of oxymatrine,oxymatrine lower and higher group(10 and 80mg·kg(-1)).At each big group,oxymatrine group as control and oxymatrine coadministered with three different doses of VPRB(400,800,1200 mg·kg(-1)) intragastric administration.Samples were collected at the time points of 0.167,0.5,1,2,4,8 hours for oxymatrine lower group,and 0.167,0.333, 0.667,1,1.5,2,4,8 hours for oxymatrine higher group.The samples were detected by HPLC-MS/MS and analysis the pharmacokinetic process.The influences of VPRB on the distribution of OMT and MT were evaluated through the pharmacokinetic parameters,such as Tmax、Cmax、AUC、AUC_(OMT)/AUC_(MT) and AUCsum.
3.The target effect of different tissues of VPRB on OMT and MT was evaluated through the parameters of Relative uptake efficiency(Re) and Relative targeting efficiency(RTE).
Results:
1.The linearity of oxymatrine and matrine both ranged from 4 to 2000 ng ? ml(-1), the detection limits of them was 4ng ? mL(-1).The recovery of this method ranged from 87.1-110.3%.The values of RSD of within day and between day were less than 14%.The recovery rates of extraction were above 58.6%.
2.Oxymatrine and Matrine processing in plasma,liver,heart,spleen,lung and kidney for OMT higher dosage group fit an open two-compartment model,but in most tissues,they fit a one-cmpartment model for OMT lower dosage group.
VPRB increased the Cmax and AUC of both OMT and MT in liver.In OMT higher group,OMT Cmax of VPRB-M group and VPRB-H group increased by above 80 percent as compared with control group respectively,and the Cmax of MT in both groups were also increased.The AUC of OMT in VPRB-M group and H group were 2.55 and 2.53 times larger compared to control group,and the MT AUC of these two groups increased 12.09%and 16.36%respectively.
In OMT lower group,the AUC of OMT in VPRB-L group and VPRB-H group are larger than the control group,the increased value of VPRB-H group is 31.82%, and meanwhile the Cmax and AUC of plasma,heart lung and kidney were tending to decline.
In OMT higher group,compared to the control group,VPRB-M group and VPRB-H group increased the Re and RTE of liver OMT,the Re of VPRB-M and H group were 2.55 and 2.53 respectively,and the Re of other tissues were all less than 1.In all VPRB groups the liver RTE were positive value,the OMT RTE of VPRB-L, M,H groups were 0.40,2.16 and 2.11 respectively,and those of MT were 0.13, 0.21and 0.33 respectively.
In Oxymatrine lower group,the liver OMT RTE of VPRB-L,M and H groups were 0.04,0.10 and 0.33 respectively,and the RTE of MT were 0.29,0.1 and 0.49 respectively.VPRB high dose had the strongest effect in both OMT higher group and lower group.
Conclosion:
HPLC-MS/MS method is accurate,highly sensitive,simple and convenient, time saving for the simultaneous determination of oxymatrine and matrine concentrations in tissues and plasma of rat.
The targeting enforcing effect of VPRB was related with the dose of VPRB, high and medium dose of VPRB could enhance the targeting efficiency of OMT and MT significantly.VPRB focus the effect of other drug on liver by increasing the uptake of liver and meanwhile decreasing the uptake of other tissues.The results of this paper imply that VBRB might be a potential drug for target therapy.
引文
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