君—使化合物用于君—使药对体内作用机制研究
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摘要
药对组成规律的基础研究是阐明中药复方配伍基础的切入口,也是国家“十二五”基础研究规划中医药领域重点资助的研究内容之一。药理学效应法、高通量筛选法和临床归纳总结法等均是目前研究药对组成规律的常用方法,也为阐明该规律的物质基础作出了重要的贡献。然而,迄今为止,药对组成规律基础研究策略的构建及验证依然是上述研究领域的热点问题。本论文以君-使药对丹参和冰片为例,以“君-使化合物”为分子探针进行君使药对组成规律以及体内作用机制进行研究,有望为阐明药对组成规律奠定方法学基础并提供研究策略。全文共分五章,作者的主要贡献如下：
1、建立了大鼠血浆及组织中咖啡酸的高效液相色谱-质谱测定方法,并用该方法对丹参中咖啡酸在大鼠体内的药代动力学过程和组织分布特征进行研究。结果表明：血浆及组织中咖啡酸的检测限分别为0.12和0.05 ng·mL-1；线性范围分别为0.01～10.0μg·mL-1和0.005～5.0μg·mL-1；回收率、精密度和稳定性测定相对标准偏差符合FDA和SFDA生物样品分析方法的要求。应用该方法研究丹参中咖啡酸的药代动力学及组织分布特征发现,咖啡酸在大鼠体内的药代动力学过程符合二室开放模型,且起效迅速,作用持久；组织分布特征为c肾>c心>c肝>c肺>c脑>c脾,证明该方法有望用于咖啡酸的非临床和临床动力学研究。
2、采用上述方法研究了冰片对丹参中咖啡酸药代动力学和组织分布的影响。结果发现：丹参冰片配伍给药后,咖啡酸在大鼠体内的t1／2α、t1／2β、V1／F、AUC(0-t)、AUC(0-∞)和Ka等参数均有明显的增大,而参数CL／F、K10、K12、K21和t1／2Ka则明显降低,提示冰片能使丹参中咖啡酸在大鼠体内的作用更加持久,并能增加其由血液向组织中转移的能力；组织分布研究结果表明：冰片能使咖啡酸在心和脑中的含量明显增加,说明冰片能使丹参中咖啡酸与心和脑组织的生物亲和力增大,靶向性增强,一定程度上验证了中医有关使药“引药归经、载药上行”的论述。
3、以丹参的有效成分咖啡酸和使药冰片为原料,设计并合成了“君-使化合物”咖啡酸冰片酯,对其药代动力学和组织分布进行了研究。结果表明：与同等剂量的丹参提取液及咖啡酸单体给药相比,咖啡酸冰片酯能使其代谢产物咖啡酸的曲线下面积AUC(0-t)和AUC(0-∞)显著增大,提示咖啡酸冰片酯能增大其代谢产物咖啡酸吸收入血的能力；与冰片和咖啡酸单体联合给药相比,咖啡酸冰片酯能使其代谢产物咖啡酸在大鼠体内作用时间显著增长,提高其生物利用度；同时能使其在心、脑中富集,一定程度上体现了君药丹参与使药冰片的体内作用特征,证明咖啡酸冰片酯可作为君使药对体内作用机制和组成规律的研究切入点,从而也为该方面的研究提供了新的研究思路。
Investigation on the principle combination of couple herbs is the key to elucidate the combing foundation of complex prescription, and also the key researching area supported in the 12th five years proposed project by Chinese governments. Pharmacological effects method, high throughput screening technologies and the generalized methods in clinic are all the valid ways to study the combing rules of couple herbs in previous publications. The above methods also contributed much to elucidating foundational substance of the rules. However, up to date, the investigation on combing rules is still a hot topic of the above researching area. In this dissertation, the couple herbs of Salvia milltiorrhiza and borneol were selected as the example. Moreover, the construction of the researching strategy on combing rules of couple herbs was processed too, based on using "Jun-Shi compound" as the molecular probes, in this dissertation. Those researches would provide method and strategy to elucidate the combing rules of couple rules. The contents of this dissertation consist of five chapters, and the important contributions of the author are as follows:
1. A novel high performance liquid chromatography-tandem mass spectrometry method for the determination of caffeic acid in rat plasma and tissue was established and applied in its pharmacokinetic study and tissue distribution after administration of Salvia milltiorrhiza. The results showed that the detection limits of caffeic acid in plasma and tissue were 0.12 and 0.05 ng·mL-1. The calibration curves of caffeic acid in plasma and tissue had good linearity over the range concentration of 0.01～10.0μg·mL-1 and 0.005～5.0μg·mL-1. With regards to recovery, precision, and stability, the results of the methodological evaluation showed the relative standard deviation meet the requirements of FDA and SFDA biological samples determination. The proposed method was also applied in the investigation on pharcokinetic and tissue distribution of caffeic acid in rat. The statistical results indicated that the plasma concentration-time course of caffeic acid in rat confirmed to a 2-compartment open model and the its tissue distribution was of ckidney>cheart>cliver>clung>cbrain>cspleen, demonstrating that the method can be applied in studying the clinical and non-clinical pharmacokinetic of caffeic acid.
2. The effects of borneol on the pharmacokinetic and tissue distribution of caffeic acid after admistrated with couple herbs of Salvia milltiorrhiza and borneol was carried out by the above method. The results showed the pharmacokinetic parameters of t1/2α, t1/2βV1/F, AUC(0-t), AUC(0-∞) and Ka in rat increased significantly, while the parameters of CL/F, K10, K12, K21 and t1/2Ka decreased obviously as compared with administration of Salvia milltiorrhiza. Those results indicated that caffeic acid had longer therapeutic time and stronger transfer capacity from blood into tissue in rat. The study of tissue distribution showed more caffeic acid distributed in heart and brain. Borneol enhanced the targeting power and affinity of caffeic acid to heart and brain, which was consisted with the illustration and definition of shi herb in Chinese medical works.
3. The "Jun-shi compound"—bornyl caffeiate was designed and synthesed with using the bioactive compound of Salvia milltiorrhiza and borneol as the materials. Then, its pharmacokinetic and tissue distribution were performed. Compared with the same dose of Salvia milltiorrhiza and caffeic acid, bornyl caffeinate increased AUC(0-t) and AUC(0-∞) of its metabolic product(caffeic acid) greatly, which indicated more caffeic acid could be absorbed into blood. Compared with administration of caffeic acid combined with borneol, bornyl caffeinate could increase the bioavailability of caffeic acid. Caffeic acid concentrated in heart and brain reflected the interacting characteristics of Jun herb (Salvia milltiorrhiza) and Shi herb (borneol) in rat. All those results indicate that bornyl caffeinate can be selected as the molecular probe to investigate the principle combination of couple herbs, and provide the method and strategy for the research of this area.
1、建立了大鼠血浆及组织中咖啡酸的高效液相色谱-质谱测定方法,并用该方法对丹参中咖啡酸在大鼠体内的药代动力学过程和组织分布特征进行研究。结果表明：血浆及组织中咖啡酸的检测限分别为0.12和0.05 ng·mL-1；线性范围分别为0.01～10.0μg·mL-1和0.005～5.0μg·mL-1；回收率、精密度和稳定性测定相对标准偏差符合FDA和SFDA生物样品分析方法的要求。应用该方法研究丹参中咖啡酸的药代动力学及组织分布特征发现,咖啡酸在大鼠体内的药代动力学过程符合二室开放模型,且起效迅速,作用持久；组织分布特征为c肾>c心>c肝>c肺>c脑>c脾,证明该方法有望用于咖啡酸的非临床和临床动力学研究。
2、采用上述方法研究了冰片对丹参中咖啡酸药代动力学和组织分布的影响。结果发现：丹参冰片配伍给药后,咖啡酸在大鼠体内的t1／2α、t1／2β、V1／F、AUC(0-t)、AUC(0-∞)和Ka等参数均有明显的增大,而参数CL／F、K10、K12、K21和t1／2Ka则明显降低,提示冰片能使丹参中咖啡酸在大鼠体内的作用更加持久,并能增加其由血液向组织中转移的能力；组织分布研究结果表明：冰片能使咖啡酸在心和脑中的含量明显增加,说明冰片能使丹参中咖啡酸与心和脑组织的生物亲和力增大,靶向性增强,一定程度上验证了中医有关使药“引药归经、载药上行”的论述。
3、以丹参的有效成分咖啡酸和使药冰片为原料,设计并合成了“君-使化合物”咖啡酸冰片酯,对其药代动力学和组织分布进行了研究。结果表明：与同等剂量的丹参提取液及咖啡酸单体给药相比,咖啡酸冰片酯能使其代谢产物咖啡酸的曲线下面积AUC(0-t)和AUC(0-∞)显著增大,提示咖啡酸冰片酯能增大其代谢产物咖啡酸吸收入血的能力；与冰片和咖啡酸单体联合给药相比,咖啡酸冰片酯能使其代谢产物咖啡酸在大鼠体内作用时间显著增长,提高其生物利用度；同时能使其在心、脑中富集,一定程度上体现了君药丹参与使药冰片的体内作用特征,证明咖啡酸冰片酯可作为君使药对体内作用机制和组成规律的研究切入点,从而也为该方面的研究提供了新的研究思路。
Investigation on the principle combination of couple herbs is the key to elucidate the combing foundation of complex prescription, and also the key researching area supported in the 12th five years proposed project by Chinese governments. Pharmacological effects method, high throughput screening technologies and the generalized methods in clinic are all the valid ways to study the combing rules of couple herbs in previous publications. The above methods also contributed much to elucidating foundational substance of the rules. However, up to date, the investigation on combing rules is still a hot topic of the above researching area. In this dissertation, the couple herbs of Salvia milltiorrhiza and borneol were selected as the example. Moreover, the construction of the researching strategy on combing rules of couple herbs was processed too, based on using "Jun-Shi compound" as the molecular probes, in this dissertation. Those researches would provide method and strategy to elucidate the combing rules of couple rules. The contents of this dissertation consist of five chapters, and the important contributions of the author are as follows:
1. A novel high performance liquid chromatography-tandem mass spectrometry method for the determination of caffeic acid in rat plasma and tissue was established and applied in its pharmacokinetic study and tissue distribution after administration of Salvia milltiorrhiza. The results showed that the detection limits of caffeic acid in plasma and tissue were 0.12 and 0.05 ng·mL-1. The calibration curves of caffeic acid in plasma and tissue had good linearity over the range concentration of 0.01～10.0μg·mL-1 and 0.005～5.0μg·mL-1. With regards to recovery, precision, and stability, the results of the methodological evaluation showed the relative standard deviation meet the requirements of FDA and SFDA biological samples determination. The proposed method was also applied in the investigation on pharcokinetic and tissue distribution of caffeic acid in rat. The statistical results indicated that the plasma concentration-time course of caffeic acid in rat confirmed to a 2-compartment open model and the its tissue distribution was of ckidney>cheart>cliver>clung>cbrain>cspleen, demonstrating that the method can be applied in studying the clinical and non-clinical pharmacokinetic of caffeic acid.
2. The effects of borneol on the pharmacokinetic and tissue distribution of caffeic acid after admistrated with couple herbs of Salvia milltiorrhiza and borneol was carried out by the above method. The results showed the pharmacokinetic parameters of t1/2α, t1/2βV1/F, AUC(0-t), AUC(0-∞) and Ka in rat increased significantly, while the parameters of CL/F, K10, K12, K21 and t1/2Ka decreased obviously as compared with administration of Salvia milltiorrhiza. Those results indicated that caffeic acid had longer therapeutic time and stronger transfer capacity from blood into tissue in rat. The study of tissue distribution showed more caffeic acid distributed in heart and brain. Borneol enhanced the targeting power and affinity of caffeic acid to heart and brain, which was consisted with the illustration and definition of shi herb in Chinese medical works.
3. The "Jun-shi compound"—bornyl caffeiate was designed and synthesed with using the bioactive compound of Salvia milltiorrhiza and borneol as the materials. Then, its pharmacokinetic and tissue distribution were performed. Compared with the same dose of Salvia milltiorrhiza and caffeic acid, bornyl caffeinate increased AUC(0-t) and AUC(0-∞) of its metabolic product(caffeic acid) greatly, which indicated more caffeic acid could be absorbed into blood. Compared with administration of caffeic acid combined with borneol, bornyl caffeinate could increase the bioavailability of caffeic acid. Caffeic acid concentrated in heart and brain reflected the interacting characteristics of Jun herb (Salvia milltiorrhiza) and Shi herb (borneol) in rat. All those results indicate that bornyl caffeinate can be selected as the molecular probe to investigate the principle combination of couple herbs, and provide the method and strategy for the research of this area.
引文
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