桃叶珊瑚苷和龙胆苦苷的热性能与生物代谢研究
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摘要
桃叶珊瑚苷和龙胆苦苷均是环烯醚萜苷类化合。桃叶珊瑚苷为传统中药杜仲、车前草、玄参等的天然活性成分,具有抗肿瘤、抗病毒、抗炎、抗氧化、抗白血病等活性,是潜在的抗肿瘤药、抗生素类药物。龙胆苦苷为龙胆科植物秦艽、龙胆、当药、獐牙菜等中药的苦味成分,具有非常显著的保肝、抗炎活性。本文从热性能、药代动力学性质、药物配伍、组织分布及生物转化五方面对两种化合物进行了研究。
一、桃叶珊瑚苷和龙胆苦苷的热性能研究
桃叶珊瑚苷和龙胆苦苷均是不稳定化合物,性质活泼,实验采用热重和差示扫描量热技术研究了多升温速率下化合物在氮气氛中的热失重过程和热动力学性质,采用热重-差示扫描量热-红外联用技术和原位热红外分析方法测试了桃叶珊瑚苷和龙胆苦苷的非等温热裂解反应,通过对逸出气体和残留物的分析推导热分解过程,结果表明不同类型环烯醚萜苷的分解规律和热稳定性不同。桃叶珊瑚苷有较低的热稳定性,其两步热分解的表观活化能分别为125.71 KJ·mol~(-1)和166.80 KJ·mol~(-1),龙胆苦苷的两步热分解的表观活化能分别为148.40 KJ·mol~(-1)和33.90 KJ·mol~(-1)。实验从热力学的角度证实了桃叶珊瑚苷和龙胆苦苷的相对热稳定性。
二、龙胆苦苷与甘草酸配伍后的药代动力学研究
配伍理论是中药基础理论最重要的组成之一,实验建立了同时测定龙胆苦苷和甘草酸的HPLC方法,考察秦艽药材与甘草药材配伍前后、龙胆苦苷和甘草酸配伍前后龙胆苦苷的药代动力学性质的变化,血药浓度-时间数据用DAS药代动力学软件分析,结果表明秦艽中的其他成分和甘草酸均可明显影响龙胆苦苷的药代动力学性质,导致其吸收减少、分布增加、消除减慢;甘草中的其他成分可促进甘草酸的分布,增加其表观分布容积,药时曲线下面积减少,但龙胆苦苷对甘草酸无影响。
三、桃叶珊瑚苷的药代动力学和组织分布研究
实验建立了灵敏、简单的测定大鼠血浆和组织器官中桃叶珊瑚苷的HPLC法,日内测定误差为0.22-4.18%,日间测定误差为0.25-4.53%,平均方法回收率为94.35%,平均提取回收率为91.02%。血药浓度-时间数据用DAS药代动力学软件分析,结果表明桃叶珊瑚苷静脉给药后在大鼠体内分布迅速,分布范围较广,药物体内过程符合二室模型,血中的t_(1/2β)、V_d、CL和AUC分别为32.23min、0.13L·kg~(-1)、0.003L·min~(-1)·kg~(-1)和27620 min·mg·L~(-1),桃叶珊瑚苷在大鼠肾脏和肝脏中分布量大,其次为肺、脾、心、睾丸,这与原药材杜仲的归经理论相符。
四、桃叶珊瑚苷和龙胆苦苷的胃代谢研究
采用人工胃液温孵法研究桃叶珊瑚苷与龙胆苦苷的胃代谢情况,考察了温孵时间和原形药物浓度与药物代谢转化的关系,确认代谢产物。结果表明桃叶珊瑚苷在人工胃液中可迅速发生苷键水解反应,0.5h后即可检测到桃叶珊瑚苷元,在0.5～5mg·mL~(-1)浓度范围内呈剂量依赖关系,生成的苷元不稳定容易发生氧化聚合。龙胆苦苷在人工胃液环境下比较稳定,温孵5h未检测到变化。提示桃叶珊瑚苷口服后在胃中可能转化成活性形式——桃叶珊瑚苷苷元而被吸收入血,说明杜仲、玄参、车前草等含有桃叶珊瑚苷的药材口服给药是有效和科学的给药方式;提示龙胆苦苷口服后在体内的代谢主要发生在肠道部位。
五、桃叶珊瑚苷和龙胆苦苷的肝代谢研究
用肝微粒体体外温孵法研究桃叶珊瑚苷和龙胆苦苷的肝代谢情况,经HPLC和TLSC检测,温孵4h后两化合物的量均无明显变化,提示这两化合物在大鼠肝循环中不代谢。给大鼠分别静脉注射桃叶珊瑚苷和龙胆苦苷,诱导3天后,以差速离心法制备肝微粒体,用CO还原示差法测定微粒体中P450酶的含量,结果发现诱导组大鼠肝微粒体中P450酶的活性均高于盐水对照组。同时整体动物实验表明桃叶珊瑚苷和龙胆苦苷对阈上剂量的戊巴比妥钠致小鼠催眠有明显的催醒作用,但对小鼠自主活动及小鼠平衡功能无影响。
Aucubin and gentiopicroside are both iridoids.Aucubin is the principal and abundant component of Eucommia ulmoides Oliv.,Plantago asiatica L.,Rehmannia glutinosa Libosch.,Scrophularia ningpocnsis Hemsl.It possesses liver-protective, antiviral,anti-inflammatory,antioxidant,antileukemic activities,and so on.Recently,it is found to be a novel topoisomeraseⅠinhibitor which increases interest in its possible use in cancer chemoprevention and antitumoral therapy.Gentiopicroside is the principal component of Gentiana macrophylla Pall.and Gentiana straminea Maxim.It has remarkable liver-protective and anti-inflammatory activities.In this thesis,the thermal characters and metabolism of aucubin and gentiopicroside were investigated,including thermal decomposition kinetics,distribution in rat tissues,pharmacokinetics,metabolism in gastro and liver,and so on.The detailed descriptions are listed below.
Part one:The thermal analysis of aucubin and gentiopicroside
Thermolysis of aucubin and gentiopicroside were studied using various thermo-analytical techniques.Kinetic analysis of non-isothermal thermogravimetry data was done.The activation energy of aucubin at the two decomposed processes were 125.71 kJ·mol~(-1)and 166.80 kJ·mol~(-1),respectively.The activation energy of gentiopicroside at the two decomposed processes were 148.40 kJ·mol~(-1)and 33.90 kJ·mol~(-1), respectively.The pyrolysis process was investigated by online-coupled thermogravimetry-infrared spectroscopy technique.The possible thermal degradation mechanisms of aucubin and gentiopicroside were discussed according to the analysis results of the escaped gases and residues.
Part two:The effect study of compatibility on the pharmacokinetics of gentiopicroside
Compatibility of Chinese medicinal herbs is the main method of medicinal application in clinic and also the basis of making up formulae of Chinese medicinal herbs. A HPLC method was established for the simultaneously quantitative determination of gentiopicroside and glycyrrhizin in rabbit plasma,and it was applied to study the effect of compatibility on the pharmacokinetics of gentiopicroside and glycyrrhizin.Plasma samples from rabbits that were administrated intravenously with gentiopicroside and/or glycyrrhizin at the 50mg·kg~(-1)dosage,were detected using the HPLC method.The concentrations versus time data were analyzed using DAS program(2005).The results showed that glycyrrhizin and other components in Gentiana macrophylla Pall.could affect the pharmacokinetics of gentiopicroside,but gentiopicroside had no effects on glycyrrhizin.
Part three:The pharmacokinetic and distribution studies of aucubin in rat
A simple,inexpensive and accurate high-performance liquid chromatographic method was developed and validated for the determination of aucubin in rat plasma and tissues.Acceptable intra-day and inter-day precision and accuracy at high,medium and low concentration ranged from 0.22%to 4.18%and 0.25%to 4.53%,respectively.Good assay recoveries were obtained with a single and relatively fast precipitation protein step. The mean assay recovery and extraction recovery of aucubin were 94.35%and 91.02%, respectively.The parameters were calculated using DAS software.The values of t_(1/2β), V_d,CL and AUC were 32.23min,0.13L·kg~(-1),0.003 L·min~(-1)·kg~(-1)and 27620 min·mg·L~(-1)in the plasma,respectively.Considerable aucubin was present in kidney and liver. Aucubin concentration was highest in kidney and remained much higher than that in other tissues over the experiment course.Lung,heart,spleen and testis were also detected to contain aucubin.The results closely conformed to the meridian tropism of Cortex Eucommiae and clearly demonstrated that aucubin was one of the material bases of the meridian tropism of Cortex Eucommiae.
Part four:Study on the gastro metabolism of aucubin and gentiopicroside
The gastro metabolisms of ancubin and gentiopicroside in artificial gastric solution were studied by TLSC.The effects of incubation time and substrate's concentration on metabolism were investigated.Three volume of ethyl acetate were added to stop the metabolism,and to extract the metabolite for 10 times.The TLSC results showed aucubin could quickly transformed in artificial gastric solution at 37℃.The major metabolite of aucubin was aucubigenin,which was not stable and easily further polymerized.About 20%aucubin were not hydrolyzed after incubation for 4h. Gentiopicroside wasn't observed transformation.The research suggested that aucubin might be transformed to aucubigenin in gastro,and oral administration was the effective and scientific way of Chinese medicinal herbs that contained aucubin.
Part five:Study on the hepatic metabolism of aucubin and gentiopicroside
The metabolic transformation of aucubin and gentiopicroside were studied by using rat liver microsomal incubation in vitro that contained the NADPH-generating system. The concentrations of aucubin and gentiopicroside were detected by TLSC and HPLC method after incubation for 4h.No changes were observed.After intravenous injection with different dosage of aucubin or gentiopicroside to rat for three days,the content of rat liver microsomes P450 was determined to be increased.The two components also could shorten the duration of hypnosis induced by pentobarbital sodium in mice(P＜0.05).The effects of the two drugs on mice spontaneous movements and equilibrium function were also observed.
一、桃叶珊瑚苷和龙胆苦苷的热性能研究
桃叶珊瑚苷和龙胆苦苷均是不稳定化合物,性质活泼,实验采用热重和差示扫描量热技术研究了多升温速率下化合物在氮气氛中的热失重过程和热动力学性质,采用热重-差示扫描量热-红外联用技术和原位热红外分析方法测试了桃叶珊瑚苷和龙胆苦苷的非等温热裂解反应,通过对逸出气体和残留物的分析推导热分解过程,结果表明不同类型环烯醚萜苷的分解规律和热稳定性不同。桃叶珊瑚苷有较低的热稳定性,其两步热分解的表观活化能分别为125.71 KJ·mol~(-1)和166.80 KJ·mol~(-1),龙胆苦苷的两步热分解的表观活化能分别为148.40 KJ·mol~(-1)和33.90 KJ·mol~(-1)。实验从热力学的角度证实了桃叶珊瑚苷和龙胆苦苷的相对热稳定性。
二、龙胆苦苷与甘草酸配伍后的药代动力学研究
配伍理论是中药基础理论最重要的组成之一,实验建立了同时测定龙胆苦苷和甘草酸的HPLC方法,考察秦艽药材与甘草药材配伍前后、龙胆苦苷和甘草酸配伍前后龙胆苦苷的药代动力学性质的变化,血药浓度-时间数据用DAS药代动力学软件分析,结果表明秦艽中的其他成分和甘草酸均可明显影响龙胆苦苷的药代动力学性质,导致其吸收减少、分布增加、消除减慢;甘草中的其他成分可促进甘草酸的分布,增加其表观分布容积,药时曲线下面积减少,但龙胆苦苷对甘草酸无影响。
三、桃叶珊瑚苷的药代动力学和组织分布研究
实验建立了灵敏、简单的测定大鼠血浆和组织器官中桃叶珊瑚苷的HPLC法,日内测定误差为0.22-4.18%,日间测定误差为0.25-4.53%,平均方法回收率为94.35%,平均提取回收率为91.02%。血药浓度-时间数据用DAS药代动力学软件分析,结果表明桃叶珊瑚苷静脉给药后在大鼠体内分布迅速,分布范围较广,药物体内过程符合二室模型,血中的t_(1/2β)、V_d、CL和AUC分别为32.23min、0.13L·kg~(-1)、0.003L·min~(-1)·kg~(-1)和27620 min·mg·L~(-1),桃叶珊瑚苷在大鼠肾脏和肝脏中分布量大,其次为肺、脾、心、睾丸,这与原药材杜仲的归经理论相符。
四、桃叶珊瑚苷和龙胆苦苷的胃代谢研究
采用人工胃液温孵法研究桃叶珊瑚苷与龙胆苦苷的胃代谢情况,考察了温孵时间和原形药物浓度与药物代谢转化的关系,确认代谢产物。结果表明桃叶珊瑚苷在人工胃液中可迅速发生苷键水解反应,0.5h后即可检测到桃叶珊瑚苷元,在0.5～5mg·mL~(-1)浓度范围内呈剂量依赖关系,生成的苷元不稳定容易发生氧化聚合。龙胆苦苷在人工胃液环境下比较稳定,温孵5h未检测到变化。提示桃叶珊瑚苷口服后在胃中可能转化成活性形式——桃叶珊瑚苷苷元而被吸收入血,说明杜仲、玄参、车前草等含有桃叶珊瑚苷的药材口服给药是有效和科学的给药方式;提示龙胆苦苷口服后在体内的代谢主要发生在肠道部位。
五、桃叶珊瑚苷和龙胆苦苷的肝代谢研究
用肝微粒体体外温孵法研究桃叶珊瑚苷和龙胆苦苷的肝代谢情况,经HPLC和TLSC检测,温孵4h后两化合物的量均无明显变化,提示这两化合物在大鼠肝循环中不代谢。给大鼠分别静脉注射桃叶珊瑚苷和龙胆苦苷,诱导3天后,以差速离心法制备肝微粒体,用CO还原示差法测定微粒体中P450酶的含量,结果发现诱导组大鼠肝微粒体中P450酶的活性均高于盐水对照组。同时整体动物实验表明桃叶珊瑚苷和龙胆苦苷对阈上剂量的戊巴比妥钠致小鼠催眠有明显的催醒作用,但对小鼠自主活动及小鼠平衡功能无影响。
Aucubin and gentiopicroside are both iridoids.Aucubin is the principal and abundant component of Eucommia ulmoides Oliv.,Plantago asiatica L.,Rehmannia glutinosa Libosch.,Scrophularia ningpocnsis Hemsl.It possesses liver-protective, antiviral,anti-inflammatory,antioxidant,antileukemic activities,and so on.Recently,it is found to be a novel topoisomeraseⅠinhibitor which increases interest in its possible use in cancer chemoprevention and antitumoral therapy.Gentiopicroside is the principal component of Gentiana macrophylla Pall.and Gentiana straminea Maxim.It has remarkable liver-protective and anti-inflammatory activities.In this thesis,the thermal characters and metabolism of aucubin and gentiopicroside were investigated,including thermal decomposition kinetics,distribution in rat tissues,pharmacokinetics,metabolism in gastro and liver,and so on.The detailed descriptions are listed below.
Part one:The thermal analysis of aucubin and gentiopicroside
Thermolysis of aucubin and gentiopicroside were studied using various thermo-analytical techniques.Kinetic analysis of non-isothermal thermogravimetry data was done.The activation energy of aucubin at the two decomposed processes were 125.71 kJ·mol~(-1)and 166.80 kJ·mol~(-1),respectively.The activation energy of gentiopicroside at the two decomposed processes were 148.40 kJ·mol~(-1)and 33.90 kJ·mol~(-1), respectively.The pyrolysis process was investigated by online-coupled thermogravimetry-infrared spectroscopy technique.The possible thermal degradation mechanisms of aucubin and gentiopicroside were discussed according to the analysis results of the escaped gases and residues.
Part two:The effect study of compatibility on the pharmacokinetics of gentiopicroside
Compatibility of Chinese medicinal herbs is the main method of medicinal application in clinic and also the basis of making up formulae of Chinese medicinal herbs. A HPLC method was established for the simultaneously quantitative determination of gentiopicroside and glycyrrhizin in rabbit plasma,and it was applied to study the effect of compatibility on the pharmacokinetics of gentiopicroside and glycyrrhizin.Plasma samples from rabbits that were administrated intravenously with gentiopicroside and/or glycyrrhizin at the 50mg·kg~(-1)dosage,were detected using the HPLC method.The concentrations versus time data were analyzed using DAS program(2005).The results showed that glycyrrhizin and other components in Gentiana macrophylla Pall.could affect the pharmacokinetics of gentiopicroside,but gentiopicroside had no effects on glycyrrhizin.
Part three:The pharmacokinetic and distribution studies of aucubin in rat
A simple,inexpensive and accurate high-performance liquid chromatographic method was developed and validated for the determination of aucubin in rat plasma and tissues.Acceptable intra-day and inter-day precision and accuracy at high,medium and low concentration ranged from 0.22%to 4.18%and 0.25%to 4.53%,respectively.Good assay recoveries were obtained with a single and relatively fast precipitation protein step. The mean assay recovery and extraction recovery of aucubin were 94.35%and 91.02%, respectively.The parameters were calculated using DAS software.The values of t_(1/2β), V_d,CL and AUC were 32.23min,0.13L·kg~(-1),0.003 L·min~(-1)·kg~(-1)and 27620 min·mg·L~(-1)in the plasma,respectively.Considerable aucubin was present in kidney and liver. Aucubin concentration was highest in kidney and remained much higher than that in other tissues over the experiment course.Lung,heart,spleen and testis were also detected to contain aucubin.The results closely conformed to the meridian tropism of Cortex Eucommiae and clearly demonstrated that aucubin was one of the material bases of the meridian tropism of Cortex Eucommiae.
Part four:Study on the gastro metabolism of aucubin and gentiopicroside
The gastro metabolisms of ancubin and gentiopicroside in artificial gastric solution were studied by TLSC.The effects of incubation time and substrate's concentration on metabolism were investigated.Three volume of ethyl acetate were added to stop the metabolism,and to extract the metabolite for 10 times.The TLSC results showed aucubin could quickly transformed in artificial gastric solution at 37℃.The major metabolite of aucubin was aucubigenin,which was not stable and easily further polymerized.About 20%aucubin were not hydrolyzed after incubation for 4h. Gentiopicroside wasn't observed transformation.The research suggested that aucubin might be transformed to aucubigenin in gastro,and oral administration was the effective and scientific way of Chinese medicinal herbs that contained aucubin.
Part five:Study on the hepatic metabolism of aucubin and gentiopicroside
The metabolic transformation of aucubin and gentiopicroside were studied by using rat liver microsomal incubation in vitro that contained the NADPH-generating system. The concentrations of aucubin and gentiopicroside were detected by TLSC and HPLC method after incubation for 4h.No changes were observed.After intravenous injection with different dosage of aucubin or gentiopicroside to rat for three days,the content of rat liver microsomes P450 was determined to be increased.The two components also could shorten the duration of hypnosis induced by pentobarbital sodium in mice(P＜0.05).The effects of the two drugs on mice spontaneous movements and equilibrium function were also observed.
引文
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