【作者】 徐伟娟；

【导师】 蒋学华；

【作者基本信息】 四川大学 ， 药剂学， 2007， 硕士

【摘要】 本课题的研究目的是考察千金藤素的口服吸收机理，为千金藤素的口服制剂选择、处方筛选、工艺优化、质量评价及临床应用提供依据。本课题以千金藤素为模型药物，建立了大鼠原位胃、肠灌注模型，大鼠肠襻法模型及整体动物模型，系统地研究了千金藤素在大鼠体内的吸收机理。实验包括四个部分：大鼠原位灌注实验、肠襻法实验、整体动物实验以及大鼠原位灌注实验与整体动物实验的相关性评价。采用大鼠原位灌注模型初步考察了千金藤素的吸收情况。建立了千金藤素在胃肠道灌注液中的HPLC分析测定方法。在体胃、肠灌注实验结果表明，给予不同剂量千金藤素后，大鼠胃内每小时平均吸收百分数分别为5．13％、5．99％、6．01％，在大鼠胃内有一定程度的吸收。不同剂量组全肠段每小时吸收百分率分别为18．89％、15．10％、14．32％，千金藤素在大鼠小肠内也有一定程度吸收。各肠段ka值从大到小的顺序为：回肠＞空肠＞十二指肠＞结肠，小肠中部是千金藤素的最佳吸收部位。为了进一步论证原位灌注实验的结果，揭示千金藤素在大鼠体内的吸收特征，进行了肠襻法实验。建立了千金藤素在大鼠血浆中的HPLC测定方法。实验结果表明，肠襻法给予大鼠千金藤素，千金藤素的符合二室模型，吸收过程为非线性动力学过程。整体动物实验考察了静脉注射与口服灌胃给药后，千金藤素的体内药动学过程。静脉注射千金藤素溶液后，各时间点血药浓度值经DAS软件分析拟合。结果显示，千金藤素为二室模型药物。灌胃给予千金藤素后，各时间点血药浓度值经DAS2．0软件分析拟合。结果显示，千金藤素为二室模型药物。千金藤素在大鼠体内的绝对生物利用度为1．02％。口服给药后血药浓度较低，生物利用度较低。研究工作用统计学的方法评价了各模型间的相关性，结果表明大鼠原位灌注模型与整体动物模型间有一定的定量相关性，但这种相关性在0．05的检验水平不显著。在体和体内的研究方法均可以作为研究千金藤素的吸收机理、预测药物吸收规律的有效辅助手段，两种研究方法结合应用，综合评价同一药物的体内过程可增加试验结果分析的合理性。本课题通过对千金藤素口服吸收机理的考察，为千金藤素的制剂选择、处方筛选、工艺优化、质量评价及临床应用提供依据；研究工作丰富了中药提取物的生物药剂学和药动学内容。在此基础上，为千金藤素在生物药剂学和药动力学理论指导下进行制剂处方工艺筛选和质量控制提供科学依据。更多还原

【Abstract】 The purpose of this study is to investigate the absorption kinetics of Cepharanthine (CEP) , it is to modernize the theoretical basis of dosage forms selected and the method for screening prescriptions, optimizing techniques, evaluating quality. In our research we use three different models (in situ perfusion model in rats; ansa intestinalis model; kinetic research in vivo) to investigate the absorption kinetics of CEP. There are four parts in our research: in sute perfusion model in rats, ansa intestinalis model, kinetic research in vivo, evaluation the correlation among models.The method of in situ perfusion in ratswas adopted, and the HPLC methods were established. In this study, we investigated the absorption activities of CEP in the gastrointestinal tract. The results are as follows: in the gaster, the P%/h are: 5.13%, 5.99%, 6.01%; in the intestinal tract, the P%/h are: 18.89%, 15.10%, 14.32%.Then, the method of ansa intestinalis model in rats was adopted, and the HPLC methods for detection the CEP in rat’s plasma were established. The results showed that: the absorption of CEP in rats is accord with two-compartment model. The result of in vivo models shows that: after i.v. and p.o. different doses of CEP, the physiological disposition of CEP in rats are both according with two-compartment model. The absolute bioavailability of CEP in rats is just 1.02%.Correlations between different models were evaluated by statistical test. There exist quantitative correlations between in situ model vs. in vivo. However the correlations aren’t significant when the level of confidence interval is at 0.05 value. In summary, in situ perfusion model and in vivo model can be effective optional ways to investigate absorption mechanisms and anticipate absorption pattern. Utilizing two or more methods to synthetically evaluate the absorption results could ensure to obtain more reliable conclusions.Our research is to find the ways and evidences of enhancement bioavailability by investigating absorption mechanism and influential factor about CEP, and further integrate the development of CEP preparations from multi points and multi models based on the ideas of biopharmaceutics. The accomplishment of the project is a great achieve of modernization of CEP as well as of biopharmaceutics and pharmacokinetics and provide a novel idea and method for researching and developing modern preparations of CEP.更多还原