异绿原酸A大鼠体内吸收特性与代谢动力学研究

发布时间：2019-02-16 00:17

【摘要】：目的：研究异绿原酸A大鼠体内吸收特性与代谢动力学。方法：建立大鼠离体肠外翻模型和在体单向肠灌流模型，研究异绿原酸A在大鼠十二指肠、空肠、回肠及结肠段的肠吸收特性，比较两种模型研究异绿原酸A肠吸收的差异性；大鼠16,32,64mg·kg-1（i.v.）及90mg·kg-1（i.g.）给予异绿原酸A，HPLC法测定其血药浓度，运用药动学软件3P97(中国数学药理学会)，求算其药动学参数及绝对生物利用度；运用SPSS软件对通过肠灌流模型获得异绿原酸A肠道吸收率(Fl%)与通过整体动物模型获得的异绿原酸A吸收率(Fa%)进行相关性评价及以Fa%为横坐标，，Fl%为纵坐标进行直线回归；建立大鼠原位单向肠血管灌流模型，以不同浓度异绿原酸A（60.98,84.63μg·mL-1）通过肠系膜上动脉对肠道进行灌流，研究异绿原酸A肠道首过效应，另外，建立大鼠原位单向肝血管灌流模型，以不同浓度异绿原酸A（5.39,12.2μg·mL-1）通过门静脉进行肝脏灌流，研究异绿原酸A肝首过效应。结果：大鼠离体肠外翻模型中，不同浓度异绿原酸A在各肠段（十二指肠、空肠、回肠、结肠段）均为线性吸收，吸收速率常数（Ka）均随异绿原酸A给药剂量的增加而增加，高浓度无饱和现象。回肠段为最佳吸收部位。在大鼠单向肠灌流模型中，异绿原酸A在低、中、高3个浓度下，各肠段的有效渗透系数(Peff)有上升趋势，具有显著性差异（P＜0.05），在回肠的Peff值显著大于其他肠段，由此可推断回肠段可能是异绿原酸A的最佳吸收部位。大鼠静脉注射后，异绿原酸A平均半衰期为29min，AUC随着剂量的增加而增加。异绿原酸A在大鼠体内的绝对生物利用度为30.71%。Fl%与Fa%存在显著地正线性关系，相关性系数为0.974，呈正相关性，回归方程为Fl%=0.523Fa%+3.715。当异绿原酸A的浓度分别为60.98与84.63μg·mL-1时，肠道摄取率（El%）分别为45.94%与52.37%，另外，当异绿原酸A的浓度为5.39与12.2μg·mL-1时，肝脏摄取率（Eh%）分别为48.01%与54.47%。结论：异绿原酸A在肠道是以被动方式在肠道转运，在回肠段吸收较好；在大鼠体内半衰期短，生物利用较低，且药动学行为为线性动力学；由Fl%与Fa%相关性评价可知，用肠灌流模型预测药物的吸收率可靠性高。异绿原酸A在肠、肝首过效应大。
[Abstract]:Objective: to study the absorption characteristics and metabolic kinetics of isoLv Yuan A rats. Methods: the intestinal absorption characteristics of isoLv Yuan A in the duodenum, jejunum, ileum and colon of rats were studied by establishing the model of isolated intestinal valgus and unilateral intestinal perfusion in vivo, and the difference of intestinal absorption of isoproteoic acid A in duodenum, jejunum, ileum and colon was compared between the two models. Rat 1632nb 64mg kg-1 (i.v.) And 90mg kg-1 (i.g.) The plasma drug concentration was determined by 3P97 (Chinese Association of Mathematical Pharmacology), and the pharmacokinetic parameters and absolute bioavailability were calculated. SPSS software was used to evaluate the correlation between intestinal absorptivity (Fl%) of isoLv Yuan A obtained from intestinal perfusion model and Fa% obtained from whole animal model. Fa% was taken as the horizontal coordinate. Fl% is linear regression in vertical coordinates. An in situ unidirectional intestinal vascular perfusion model was established in rats. The intestinal tract was perfused with different concentrations of isoLv Yuan A (60.98U 84.63 渭 g mL-1) through the superior mesenteric artery to study the intestinal first-pass effect of iso#china1# acid A. A rat model of in situ unilateral hepatic vascular perfusion was established to study the hepatic first-pass effect of isophosphoric acid A (5.39 渭 g mL-1) through portal vein. Results: in the isolated rat model of intestinal valgus, different concentrations of isoLv Yuan A were linearly absorbed in all intestinal segments (duodenum, jejunum, ileum and colon), and the absorption rate constant (Ka) was increased with the increase of the dosage of isob_person1# acid A to the intestinal segments (duodenum, jejunum, ileum and colon). High concentration without saturation. Ileum segment is the best absorption site. In the unidirectional intestinal perfusion model of rats, the effective osmotic coefficient (Peff) of each intestinal segment increased at three concentrations of isoLv Yuan A (P < 0. 05). The Peff value in the ileum was significantly higher than that in other intestinal segments, which suggested that the ileum segment might be the best site for the absorption of isoLv Yuan A. After intravenous injection, the average half-life of isoLv Yuan A was 29 min and AUC increased with the increase of dose. The absolute bioavailability of isoLv Yuan A in rats was 30.71. Fl% was significantly positive linear with Fa%, the correlation coefficient was 0.974, and the regression equation was Fl%=0.523Fa% 3.715. When the concentration of isoLv Yuan A was 60.98 渭 g / mL-1 and 84.63 渭 g / mL-1, the intestinal uptake rate (El%) was 45.94% and 52.37%, respectively. In addition, when the concentration of isoLv Yuan A was 5.39 渭 g / mL-1 and 12.2 渭 g / mL-1, The liver uptake rate (Eh%) was 48.01% and 54.47%, respectively. Conclusion: IsoLv Yuan A is transported in the intestinal tract in a passive manner and absorbed in the ileum segment, and in rats the half-life is short, the bioavailability is low, and the pharmacokinetic behavior is linear. According to the correlation evaluation of Fl% and Fa%, the model of intestinal perfusion has high reliability in predicting drug absorptivity. IsoLv Yuan A has a great effect on the first pass of liver in the intestine.
【学位授予单位】：广东药学院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R965

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