鼠尾草酸在大鼠体内的药物动力学及代谢研究
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摘要
迷迭香(Rosmarinus officinalis L.)和鼠尾草(Salvia officinalis L.)均为著名的食用香辛料和药用植物,由于具有抗氧化活性,被广泛地用作天然抗氧化剂和防腐剂。鼠尾草酸是迷迭香和鼠尾草的主要抗氧化活性成分之一,对于鼠尾草酸的药理作用研究发现,除具有良好的抗氧化活性外,还具有抗炎、抗癌、抗菌、抗病毒、抗血小板聚集和神经保护等药理活性。但对于鼠尾草酸的体内过程,包括吸收、分布、代谢和排泄等相关方面的研究则未见文献报道。因此,对作为药食两用的CA进行体内过程和代谢产物的研究,对于其安全使用和临床应用具有指导意义。
本论文对鼠尾草酸在大鼠体内的过程,包括吸收、分布、代谢和排泄进行了系统的研究,旨在阐明其吸收、分布、代谢和排泄的规律,为深入开发鼠尾草酸以及鼠尾草酸二萜类成分代谢机理的阐明和临床应用提供科学依据。同时采用微生物转化和大鼠肝微粒体体外温孵模型对鼠尾草酸的体外转化和代谢情况进行了初步研究,并与体内代谢产物进行对比研究,旨在考察体外代谢模型与哺乳动物体内代谢的相关性。主要研究内容与相应结果如下:
1、建立并验证了测定大鼠血浆中鼠尾草酸含量的HPLC方法,方法学研究结果表明,该方法质控样品的日内RSD≤2.7%,日间RSD≤3.1%;准确度在92.15～110.7%之间,鼠尾草酸质控样品的提取回收率≥72.2%,RSD≤2.4%;短期和长期稳定性实验均证明:在实验过程中,处理好的血浆样品能够保持稳定。各项指标均符合生物样品分析方法指导原则的有关规定,该法可以用于准确测定大鼠血浆中鼠尾草酸的含量。
利用该方法对不同剂量灌胃给药(60、90和120 mg.kg~(-1))和静脉注射给药(1、5和10 mg.kg~(-1))后鼠尾草酸在大鼠血浆中的浓度进行了测定,并计算了灌胃和静脉注射给药后的药物动力学参数,以及灌胃给药后的生物利用度。结果表明,灌胃给药后鼠尾草酸在肠道的吸收缓慢;主要分布在血浆中,血药浓度长时间维持在较高的水平,且清除缓慢。以不同剂量灌胃给予鼠尾草酸后,其生物利用度均高于60%,平均值为63.29±1.60%。
2、建立并验证了HPLC法测定大鼠组织中鼠尾草酸含量的方法,方法学验证结果表明,该方法操作方便,灵敏度高,专一性好;准确度、精密度、回收率和稳定性考察结果均符合目前生物样品分析方法指导原则有关规定的要求。利用该方法对灌胃给药(90 mg.kg~(-1))后鼠尾草酸在大鼠组织中的分布情况进行研究,结果表明灌胃给药后,鼠尾草酸仅在胃、肠和肝中有分布,其中以胃中鼠尾草酸浓度最高,其它组织中均未检测到鼠尾草酸。
3、鉴于鼠尾草酸的血药浓度和生物利用度较高,而组织浓度却很低的现象,推测原因在于其蛋白结合率较高,故首次采用平衡透析法对鼠尾草酸与血浆蛋白的结合率进行了测定。结果发现,鼠尾草酸的血浆蛋白结合率高达61.9-87.7%,验证了所推测原因。
4、分别建立并验证了HPLC法测定大鼠胆汁、尿液和粪便中鼠尾草酸含量的方法,方法学验证结果表明,所建立方法操作简便,灵敏度高,专一性好、分析时间短。利用这些方法对灌胃给药后鼠尾草酸在大鼠胆汁、尿液和粪便中的排泄情况进行了研究。结果发现,鼠尾草酸灌胃给药(90 mg.kg~(-1))后,其在大鼠胆汁、尿液和粪便中的总排泄量分别为5.086、2.787和1499.6μg,在大鼠胆汁、尿液和粪便中的累积排泄分数分别为0.0205%、0.0135%和7.272%。鼠尾草酸原形在大鼠胆汁、尿液和粪便三种主要排泄途径中的总排泄量仅为1507.5μg,总排泄分数仅为7.306%。其余约92.7%的鼠尾草酸则去向不明,表明鼠尾草酸在大鼠体内发生了较广泛的代谢。
5、本文采用快速分离高效液相色谱-质谱联用法(RRLC-MS~n)分析和推测了灌胃给药后胆汁、尿液和粪便中的代谢产物。在胆汁中检测到4个代谢产物峰,推测了其中一个代谢产物的结构;在尿液中检测到15个代谢产物峰,推测了其中13个代谢产物的结构;在粪便中检测到3个代谢产物峰,并对其结构进行了推断。研究发现,灌胃给予鼠尾草酸(90 mg.kg~(-1))后,其在大鼠体内发生了广泛的代谢,其中以尿液中的代谢反应类型最为多样,氧化、还原和结合反应是鼠尾草酸的主要代谢方式。
6、本文采用微生物转化模型获得了鼠尾草酸的3个转化产物,并应用多级质谱鉴定了其结构。建立了大鼠肝微粒体孵育模型,用于研究鼠尾草酸在体外肝微粒体模型上的代谢,并应用多级质谱推测了其中2个代谢产物结构。比较了鼠尾草酸在微生物、肝微粒体和大鼠体内代谢的异同,初步研究了鼠尾草酸在体外代谢模型和大鼠体内代谢的相关性。结果表明,体外模型能够在一定程度上表征鼠尾草酸在大鼠体内的代谢过程,但仍存在一定的差异,尽管如此,微生物转化及肝微粒体体外温孵用于制备体内微量代谢产物不失为一条可行的途径。
Rosemary(Rosmarinus officinalis L.) and sage(Salvia officinalis L.) have been widely used as natural antioxidants,due to their very high antioxidant activity.Carnosic acid(CA) is a phenolic diterpene,which is considered to be the most important antioxidant constituent of rosemary and sage,and its content represents a quality parameter for such products.In addition to its antioxidant activity,CA also shows anti-inflammatory,antiplatelet,antibacterial, anticancer,antivirus,and photo-protective activities.For the purpose of investigating and clarifying the physiological disposition of CA and promoting its rational application, systematical study on the absorption,distribution,metabolism,and excretion(ADME) of CA in plasma or other biological fluids were proceeded.In-vitro microbial transformation model and rat liver microsome incubation model were also established for predicting the metabolism of CA.The metabolic pathways of CA on these two different models were compared and the correlation between the in vitro and in vivo process of CA were evaluated.The results were as follows:
1.A simple and effective HPLC method with ultraviolet detection was firstly established for the quantification of CA in rat plasma.The intra-day and inter-day relative standard deviations(RSD) for the measurements of quality control samples were less than 2.7%and 3.1%,respectively.The recovery for plasma samples was≥72.2%.The stability of the plasma samples was also validated.The validated results of methodology were in accordance with relevant regulations,and all data and results showed that the HPLC method could be applied to determine the concentration of CA in rat plasma precisely.
The assay was successfully applied to the pharmacokinetic study and the absolute bioavailability assessing of CA in rat after different dosage of intragastric(60,90 and 120 mg·kg~(-1)) and intravenous(1,5 and 10 mg.kg~(-1)) administration,respectively.The absorption of CA was slow after intragastric administration.However,the maximum plasma concentration was high and retained for a long time.The absolute bioavailability of CA was more than 60%, the average value was 63.29±1.60%,which would be a useful feature in future clinical applications of the drug as an antioxidant.
2.A HPLC method was established to determine the concentration of CA in tissues.This method was quick,precise,and reproducible,and could be used to quantify prototype in rat liver,stomach and small intestine after intragastric administration(90 mg·kg~(-1)).It was the first time to study the tissue distribution of CA in rats after intragastric administration.The result indicated that after intragastric administration CA distributed in stomach,liver and small intestine with the C_(max) of 1871.3,16.13 and 34.19μg.g~(-1) respectively,but it was not detected in other tissues,including high blood flow tissues such as heart,kidney and lung.
3.In order to clarify why the concentration of CA was high in rat plasma and very low in rat tissues,an equilibrium dialysis method was established to determine the concentration of CA in rat plasma and dialysis solutions.This method was successfully applied to study the plasma-protein bonding rate of CA.The result showed that the plasma-protein bonding rate of CA was among 61.9-87.7%,which indicated that the phenomenon mentioned above was the result of high plasma-protein bonding rate.
4.Simple and effective HPLC methods with ultraviolet detection were established for the quantification of CA in rat bile,urine and feces,respectively.These methods were quick, precise,and reproducible.The assays were successfully applied to the excretion study of CA prototype in rat bile,urine and feces,respectively.The result indicated that after intragastric administration(90 mg.kg~(-1)),the cumulative excretion amount of CA in bile,urine,and feces were 5.086,2.787 and 1499.6μg,respectively.The feces were proved to be the main excretion path of CA in rat and 7.272%prototype was excreted from this excretion path. While there were still about 92.7%of CA was proposed to be metabolized and excreted as the metabolites of CA.This indicates that CA is extensively metabolized in rat.
5.The metabolites of CA in rat bile,urine,and feces were identified by RRLC-MS~n.4 metabolites were detected in rat bile,and among them 1 was analyzed,15 metabolites were detected in rat urine,and 13 were identified among them.3 metabolites were detected and identified in rat feces,which indicated that CA was extensively metabolized in rat.The types of metabolite reaction were varied,among them,the oxidation,reduction and conjugation reactions were main metabolite types.The metabolism paths of CA in rats were tentatively proposed on the base of metabolites identification results.
6.The in-vitro microbial transformation model was used to study the in vitro metabolites of CA,and 3 metabolites were identified using RRLC-MS~n.In-vitro rat liver microsome incubation model was established,using this model 2 metabolites were detected and identified by RRLC-MS~n.The metabolic pathways of CA on these two different models were compared and the correlation of in-vitro and in-vivo metabolites of CA was also studied.
本论文对鼠尾草酸在大鼠体内的过程,包括吸收、分布、代谢和排泄进行了系统的研究,旨在阐明其吸收、分布、代谢和排泄的规律,为深入开发鼠尾草酸以及鼠尾草酸二萜类成分代谢机理的阐明和临床应用提供科学依据。同时采用微生物转化和大鼠肝微粒体体外温孵模型对鼠尾草酸的体外转化和代谢情况进行了初步研究,并与体内代谢产物进行对比研究,旨在考察体外代谢模型与哺乳动物体内代谢的相关性。主要研究内容与相应结果如下:
1、建立并验证了测定大鼠血浆中鼠尾草酸含量的HPLC方法,方法学研究结果表明,该方法质控样品的日内RSD≤2.7%,日间RSD≤3.1%;准确度在92.15～110.7%之间,鼠尾草酸质控样品的提取回收率≥72.2%,RSD≤2.4%;短期和长期稳定性实验均证明:在实验过程中,处理好的血浆样品能够保持稳定。各项指标均符合生物样品分析方法指导原则的有关规定,该法可以用于准确测定大鼠血浆中鼠尾草酸的含量。
利用该方法对不同剂量灌胃给药(60、90和120 mg.kg~(-1))和静脉注射给药(1、5和10 mg.kg~(-1))后鼠尾草酸在大鼠血浆中的浓度进行了测定,并计算了灌胃和静脉注射给药后的药物动力学参数,以及灌胃给药后的生物利用度。结果表明,灌胃给药后鼠尾草酸在肠道的吸收缓慢;主要分布在血浆中,血药浓度长时间维持在较高的水平,且清除缓慢。以不同剂量灌胃给予鼠尾草酸后,其生物利用度均高于60%,平均值为63.29±1.60%。
2、建立并验证了HPLC法测定大鼠组织中鼠尾草酸含量的方法,方法学验证结果表明,该方法操作方便,灵敏度高,专一性好;准确度、精密度、回收率和稳定性考察结果均符合目前生物样品分析方法指导原则有关规定的要求。利用该方法对灌胃给药(90 mg.kg~(-1))后鼠尾草酸在大鼠组织中的分布情况进行研究,结果表明灌胃给药后,鼠尾草酸仅在胃、肠和肝中有分布,其中以胃中鼠尾草酸浓度最高,其它组织中均未检测到鼠尾草酸。
3、鉴于鼠尾草酸的血药浓度和生物利用度较高,而组织浓度却很低的现象,推测原因在于其蛋白结合率较高,故首次采用平衡透析法对鼠尾草酸与血浆蛋白的结合率进行了测定。结果发现,鼠尾草酸的血浆蛋白结合率高达61.9-87.7%,验证了所推测原因。
4、分别建立并验证了HPLC法测定大鼠胆汁、尿液和粪便中鼠尾草酸含量的方法,方法学验证结果表明,所建立方法操作简便,灵敏度高,专一性好、分析时间短。利用这些方法对灌胃给药后鼠尾草酸在大鼠胆汁、尿液和粪便中的排泄情况进行了研究。结果发现,鼠尾草酸灌胃给药(90 mg.kg~(-1))后,其在大鼠胆汁、尿液和粪便中的总排泄量分别为5.086、2.787和1499.6μg,在大鼠胆汁、尿液和粪便中的累积排泄分数分别为0.0205%、0.0135%和7.272%。鼠尾草酸原形在大鼠胆汁、尿液和粪便三种主要排泄途径中的总排泄量仅为1507.5μg,总排泄分数仅为7.306%。其余约92.7%的鼠尾草酸则去向不明,表明鼠尾草酸在大鼠体内发生了较广泛的代谢。
5、本文采用快速分离高效液相色谱-质谱联用法(RRLC-MS~n)分析和推测了灌胃给药后胆汁、尿液和粪便中的代谢产物。在胆汁中检测到4个代谢产物峰,推测了其中一个代谢产物的结构;在尿液中检测到15个代谢产物峰,推测了其中13个代谢产物的结构;在粪便中检测到3个代谢产物峰,并对其结构进行了推断。研究发现,灌胃给予鼠尾草酸(90 mg.kg~(-1))后,其在大鼠体内发生了广泛的代谢,其中以尿液中的代谢反应类型最为多样,氧化、还原和结合反应是鼠尾草酸的主要代谢方式。
6、本文采用微生物转化模型获得了鼠尾草酸的3个转化产物,并应用多级质谱鉴定了其结构。建立了大鼠肝微粒体孵育模型,用于研究鼠尾草酸在体外肝微粒体模型上的代谢,并应用多级质谱推测了其中2个代谢产物结构。比较了鼠尾草酸在微生物、肝微粒体和大鼠体内代谢的异同,初步研究了鼠尾草酸在体外代谢模型和大鼠体内代谢的相关性。结果表明,体外模型能够在一定程度上表征鼠尾草酸在大鼠体内的代谢过程,但仍存在一定的差异,尽管如此,微生物转化及肝微粒体体外温孵用于制备体内微量代谢产物不失为一条可行的途径。
Rosemary(Rosmarinus officinalis L.) and sage(Salvia officinalis L.) have been widely used as natural antioxidants,due to their very high antioxidant activity.Carnosic acid(CA) is a phenolic diterpene,which is considered to be the most important antioxidant constituent of rosemary and sage,and its content represents a quality parameter for such products.In addition to its antioxidant activity,CA also shows anti-inflammatory,antiplatelet,antibacterial, anticancer,antivirus,and photo-protective activities.For the purpose of investigating and clarifying the physiological disposition of CA and promoting its rational application, systematical study on the absorption,distribution,metabolism,and excretion(ADME) of CA in plasma or other biological fluids were proceeded.In-vitro microbial transformation model and rat liver microsome incubation model were also established for predicting the metabolism of CA.The metabolic pathways of CA on these two different models were compared and the correlation between the in vitro and in vivo process of CA were evaluated.The results were as follows:
1.A simple and effective HPLC method with ultraviolet detection was firstly established for the quantification of CA in rat plasma.The intra-day and inter-day relative standard deviations(RSD) for the measurements of quality control samples were less than 2.7%and 3.1%,respectively.The recovery for plasma samples was≥72.2%.The stability of the plasma samples was also validated.The validated results of methodology were in accordance with relevant regulations,and all data and results showed that the HPLC method could be applied to determine the concentration of CA in rat plasma precisely.
The assay was successfully applied to the pharmacokinetic study and the absolute bioavailability assessing of CA in rat after different dosage of intragastric(60,90 and 120 mg·kg~(-1)) and intravenous(1,5 and 10 mg.kg~(-1)) administration,respectively.The absorption of CA was slow after intragastric administration.However,the maximum plasma concentration was high and retained for a long time.The absolute bioavailability of CA was more than 60%, the average value was 63.29±1.60%,which would be a useful feature in future clinical applications of the drug as an antioxidant.
2.A HPLC method was established to determine the concentration of CA in tissues.This method was quick,precise,and reproducible,and could be used to quantify prototype in rat liver,stomach and small intestine after intragastric administration(90 mg·kg~(-1)).It was the first time to study the tissue distribution of CA in rats after intragastric administration.The result indicated that after intragastric administration CA distributed in stomach,liver and small intestine with the C_(max) of 1871.3,16.13 and 34.19μg.g~(-1) respectively,but it was not detected in other tissues,including high blood flow tissues such as heart,kidney and lung.
3.In order to clarify why the concentration of CA was high in rat plasma and very low in rat tissues,an equilibrium dialysis method was established to determine the concentration of CA in rat plasma and dialysis solutions.This method was successfully applied to study the plasma-protein bonding rate of CA.The result showed that the plasma-protein bonding rate of CA was among 61.9-87.7%,which indicated that the phenomenon mentioned above was the result of high plasma-protein bonding rate.
4.Simple and effective HPLC methods with ultraviolet detection were established for the quantification of CA in rat bile,urine and feces,respectively.These methods were quick, precise,and reproducible.The assays were successfully applied to the excretion study of CA prototype in rat bile,urine and feces,respectively.The result indicated that after intragastric administration(90 mg.kg~(-1)),the cumulative excretion amount of CA in bile,urine,and feces were 5.086,2.787 and 1499.6μg,respectively.The feces were proved to be the main excretion path of CA in rat and 7.272%prototype was excreted from this excretion path. While there were still about 92.7%of CA was proposed to be metabolized and excreted as the metabolites of CA.This indicates that CA is extensively metabolized in rat.
5.The metabolites of CA in rat bile,urine,and feces were identified by RRLC-MS~n.4 metabolites were detected in rat bile,and among them 1 was analyzed,15 metabolites were detected in rat urine,and 13 were identified among them.3 metabolites were detected and identified in rat feces,which indicated that CA was extensively metabolized in rat.The types of metabolite reaction were varied,among them,the oxidation,reduction and conjugation reactions were main metabolite types.The metabolism paths of CA in rats were tentatively proposed on the base of metabolites identification results.
6.The in-vitro microbial transformation model was used to study the in vitro metabolites of CA,and 3 metabolites were identified using RRLC-MS~n.In-vitro rat liver microsome incubation model was established,using this model 2 metabolites were detected and identified by RRLC-MS~n.The metabolic pathways of CA on these two different models were compared and the correlation of in-vitro and in-vivo metabolites of CA was also studied.
引文
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