基于配伍理论的痹祺胶囊药代动力学研究
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摘要
中药复方配伍的药代动力学研究是中药现代化进程中的关键问题之一。痹祺胶囊作为临床治疗风湿痹症等慢性疾病的传世验方,其组方严谨,疗效确切。有关痹祺胶囊复方的化学成分和药理作用虽有一定研究基础,但未见对其药代动力学的研究报道。本文在中药复方配伍理论的指导下,以君药主要效应成分士的宁和马钱子碱为指标,对痹祺胶囊开展了以下几方面的药代动力学探索研究,结果如下:
1、首次建立了生物样品中士的宁和马钱子碱的LC-MS定量分析方法,其灵敏度高,专属性强,操作简单快捷,为进行不同配伍给药后马钱子效应成分的体内药代动力学研究提供了可靠的分析手段。
2、比较大鼠灌胃相同剂量后马钱子效应成分化学单体、痹祺胶囊君药以及全药的药代动力学差异。首次发现士的宁和马钱子碱在单体组和君药组的药动学参数没有显著差别,而痹祺胶囊全药组能够显著延长士的宁和马钱子碱的血药浓度达峰时间,降低峰浓度,并显著延长有效浓度在体内的滞留时间,但不影响其吸收总程度。表明痹祺胶囊复方中除君药外的其他配伍组分影响了士的宁和马钱子碱在大鼠体内的药动学行为,并且差异主要体现在吸收过程。
3、按照中药复方配伍的君臣佐使原则,对痹祺胶囊进行拆方配伍的药代动力学研究,结果表明臣药组和佐药组均能显著延长士的宁和马钱子碱的达峰时间,延缓吸收,避免过快产生毒副作用。将臣、佐药拆方的单味药组分别与君药配伍,未见明显的药代动力学差异。揭示了臣、佐、使药相互作用对君药药动学的影响,体现痹祺胶囊复方配伍的科学性。
4、以离体外翻肠囊为模型进行大鼠小肠吸收研究,结果表明士的宁和马钱子碱在单体组、痹祺胶囊君药和全药组中在小肠各区段均容易透过肠壁被吸收,其吸收呈线性,属于一级动力学过程,且最佳吸收位置为空肠。士的宁和马钱子碱在痹祺胶囊全药中的大鼠空肠吸收速率和累计吸收量低于单体组和君药组,有显著性差异。加入P-gp抑制剂维拉帕米后士的宁和马钱子碱的吸收没有显著增强,表明二者不是P-gp底物。本文首次从肠吸收角度探讨了痹祺胶囊配伍对士的宁和马钱子碱的影响,验证了大鼠体内药动学实验结果。
5、相同给药剂量的痹祺胶囊全方士的宁较之单体在脑组织分布的达峰时间显著减慢,峰浓度显著减小,维持AUC不变,但两个给药组脑血比没有显著差异。揭示吸收过程的配伍变化是痹祺胶囊对中枢系统增效减毒作用的影响因素。
Pharmacokinetic (PK) studies on complex prescriptions of traditional Chinese medicines (TCMs) play an important role in the course of TCM modernization. As an effective proved recipe inherited from the celebrated ancient Chinese doctor Huatuo, Biqi capsule has been frequently and clinically used to treat rheumatoid arthritis and related diseases. Although there were published reports about chemical and pharmacological researches of Biqi capsule, less was known on its pharmacokinetic development. In this dissertation, guided by the theory of TCM compatibility, pharmacokinetic studies were carried out to investigate the PK characteristics of Biqi capsule. And the results were as follows:
1. An LC-ESI-MS method has been established for simultaneous determination of strychnine and brucine in biological matrix for the first time. The method was demonstrated to be highly sensitive and selective, with a simple and rapid procedure for sample preparation. It was reliable and suitable for PK studies of the two effective strychnos alkaloids.
2. Comparative pharmacokinetic studies were undertaken by orally administered pure strychnine, pure brucine, the king drug, and the whole recipe of Biqi capsule to Wistar rats respectively, with the same single dose. It was found for the first time that compared with the treatments of monomers and the king drug, which showed no significant statistical differences in the pharmacokinetic parameters of strychnine and brucine, Biqi capsule significantly increased the tmax, decreased the Cmaxs by half, and prolonged the mean residence time, but with almost unchanged AUCs. The results indicated that ingredients from Biqi capsule, except the king drug, affected the pharmacokinetic process of strychnine and brucine mainly through delay of absorption.
3. On the basis of the theory of TCM compatibility, pharmacokinetic differences were investigated by oral administration of the combination of the minister, assistant and guide drugs of Biqi capsule with the king drug, respectively, to Wistar rats. Both the minister drug and the assistant drug could significantly increase the tmax of strychnine and brucine. But the single herbs from the minister and assistant drugs did not have pharmacokinetic effects on the king drug. The results demonstrated the minister, assistant and guide drugs of Biqi capsule indeed delayed absorption of the king drug, only through reasonable compatibility into the whole recipe.
4. Absorption studies were undertaken in the rat everted sacs by treated with pure strychnine, pure brucine, the king drug and Biqi capsule, respectively. Strychnine and brucine could be absorbed into various regions of rat intestines, and the absorption was a first order rate process. The absorption of strychnine and brucine was also linear, with jejunum the main site of absorption. In terms of absorption of strychnine and brucine in rat everted jejunum sacs, the group of Biqi capsule showed significantly less absorption rate and accumulative amount of absorption than the groups of monomer and the king drug. Strychnine and brucine were not substrates of P-glycoprotein. Biqi capsule was found for the first time to have effects on strychnine and brucine in the view of intestinal absorption, which verified the pharmacokinetic results in rats.
5. At the same single oral dose of pure strychnine, Biqi capsule significantly increased the tmax, decreased the Cmax of strychnine in rat brain, with almost the same AUC. While there were no significant differences between the brain/blood ratios of strychnine in concentrations at different time intervals and pharmacokinetic parameters. The results showed that through prescription compatibility, Biqi capsule was more protective to central nervous system by reducing toxicity, which was due to absorption delay of strychnine into rat plasma.
1、首次建立了生物样品中士的宁和马钱子碱的LC-MS定量分析方法,其灵敏度高,专属性强,操作简单快捷,为进行不同配伍给药后马钱子效应成分的体内药代动力学研究提供了可靠的分析手段。
2、比较大鼠灌胃相同剂量后马钱子效应成分化学单体、痹祺胶囊君药以及全药的药代动力学差异。首次发现士的宁和马钱子碱在单体组和君药组的药动学参数没有显著差别,而痹祺胶囊全药组能够显著延长士的宁和马钱子碱的血药浓度达峰时间,降低峰浓度,并显著延长有效浓度在体内的滞留时间,但不影响其吸收总程度。表明痹祺胶囊复方中除君药外的其他配伍组分影响了士的宁和马钱子碱在大鼠体内的药动学行为,并且差异主要体现在吸收过程。
3、按照中药复方配伍的君臣佐使原则,对痹祺胶囊进行拆方配伍的药代动力学研究,结果表明臣药组和佐药组均能显著延长士的宁和马钱子碱的达峰时间,延缓吸收,避免过快产生毒副作用。将臣、佐药拆方的单味药组分别与君药配伍,未见明显的药代动力学差异。揭示了臣、佐、使药相互作用对君药药动学的影响,体现痹祺胶囊复方配伍的科学性。
4、以离体外翻肠囊为模型进行大鼠小肠吸收研究,结果表明士的宁和马钱子碱在单体组、痹祺胶囊君药和全药组中在小肠各区段均容易透过肠壁被吸收,其吸收呈线性,属于一级动力学过程,且最佳吸收位置为空肠。士的宁和马钱子碱在痹祺胶囊全药中的大鼠空肠吸收速率和累计吸收量低于单体组和君药组,有显著性差异。加入P-gp抑制剂维拉帕米后士的宁和马钱子碱的吸收没有显著增强,表明二者不是P-gp底物。本文首次从肠吸收角度探讨了痹祺胶囊配伍对士的宁和马钱子碱的影响,验证了大鼠体内药动学实验结果。
5、相同给药剂量的痹祺胶囊全方士的宁较之单体在脑组织分布的达峰时间显著减慢,峰浓度显著减小,维持AUC不变,但两个给药组脑血比没有显著差异。揭示吸收过程的配伍变化是痹祺胶囊对中枢系统增效减毒作用的影响因素。
Pharmacokinetic (PK) studies on complex prescriptions of traditional Chinese medicines (TCMs) play an important role in the course of TCM modernization. As an effective proved recipe inherited from the celebrated ancient Chinese doctor Huatuo, Biqi capsule has been frequently and clinically used to treat rheumatoid arthritis and related diseases. Although there were published reports about chemical and pharmacological researches of Biqi capsule, less was known on its pharmacokinetic development. In this dissertation, guided by the theory of TCM compatibility, pharmacokinetic studies were carried out to investigate the PK characteristics of Biqi capsule. And the results were as follows:
1. An LC-ESI-MS method has been established for simultaneous determination of strychnine and brucine in biological matrix for the first time. The method was demonstrated to be highly sensitive and selective, with a simple and rapid procedure for sample preparation. It was reliable and suitable for PK studies of the two effective strychnos alkaloids.
2. Comparative pharmacokinetic studies were undertaken by orally administered pure strychnine, pure brucine, the king drug, and the whole recipe of Biqi capsule to Wistar rats respectively, with the same single dose. It was found for the first time that compared with the treatments of monomers and the king drug, which showed no significant statistical differences in the pharmacokinetic parameters of strychnine and brucine, Biqi capsule significantly increased the tmax, decreased the Cmaxs by half, and prolonged the mean residence time, but with almost unchanged AUCs. The results indicated that ingredients from Biqi capsule, except the king drug, affected the pharmacokinetic process of strychnine and brucine mainly through delay of absorption.
3. On the basis of the theory of TCM compatibility, pharmacokinetic differences were investigated by oral administration of the combination of the minister, assistant and guide drugs of Biqi capsule with the king drug, respectively, to Wistar rats. Both the minister drug and the assistant drug could significantly increase the tmax of strychnine and brucine. But the single herbs from the minister and assistant drugs did not have pharmacokinetic effects on the king drug. The results demonstrated the minister, assistant and guide drugs of Biqi capsule indeed delayed absorption of the king drug, only through reasonable compatibility into the whole recipe.
4. Absorption studies were undertaken in the rat everted sacs by treated with pure strychnine, pure brucine, the king drug and Biqi capsule, respectively. Strychnine and brucine could be absorbed into various regions of rat intestines, and the absorption was a first order rate process. The absorption of strychnine and brucine was also linear, with jejunum the main site of absorption. In terms of absorption of strychnine and brucine in rat everted jejunum sacs, the group of Biqi capsule showed significantly less absorption rate and accumulative amount of absorption than the groups of monomer and the king drug. Strychnine and brucine were not substrates of P-glycoprotein. Biqi capsule was found for the first time to have effects on strychnine and brucine in the view of intestinal absorption, which verified the pharmacokinetic results in rats.
5. At the same single oral dose of pure strychnine, Biqi capsule significantly increased the tmax, decreased the Cmax of strychnine in rat brain, with almost the same AUC. While there were no significant differences between the brain/blood ratios of strychnine in concentrations at different time intervals and pharmacokinetic parameters. The results showed that through prescription compatibility, Biqi capsule was more protective to central nervous system by reducing toxicity, which was due to absorption delay of strychnine into rat plasma.
引文
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