【摘要】：目的：研究異綠原酸A大鼠體內(nèi)吸收特性與代謝動力學。 方法：建立大鼠離體腸外翻模型和在體單向腸灌流模型，研究異綠原酸A在大鼠十二指腸、空腸、回腸及結(jié)腸段的腸吸收特性，比較兩種模型研究異綠原酸A腸吸收的差異性；大鼠16,32,64mg·kg-1（i.v.）及90mg·kg-1（i.g.）給予異綠原酸A，HPLC法測定其血藥濃度，運用藥動學軟件3P97(中國數(shù)學藥理學會)，求算其藥動學參數(shù)及絕對生物利用度；運用SPSS軟件對通過腸灌流模型獲得異綠原酸A腸道吸收率(Fl%)與通過整體動物模型獲得的異綠原酸A吸收率(Fa%)進行相關(guān)性評價及以Fa%為橫坐標，，F(xiàn)l%為縱坐標進行直線回歸；建立大鼠原位單向腸血管灌流模型，以不同濃度異綠原酸A（60.98,84.63μg·mL-1）通過腸系膜上動脈對腸道進行灌流，研究異綠原酸A腸道首過效應，另外，建立大鼠原位單向肝血管灌流模型，以不同濃度異綠原酸A（5.39,12.2μg·mL-1）通過門靜脈進行肝臟灌流，研究異綠原酸A肝首過效應。 結(jié)果：大鼠離體腸外翻模型中，不同濃度異綠原酸A在各腸段（十二指腸、空腸、回腸、結(jié)腸段）均為線性吸收，吸收速率常數(shù)（Ka）均隨異綠原酸A給藥劑量的增加而增加，高濃度無飽和現(xiàn)象�；啬c段為最佳吸收部位。在大鼠單向腸灌流模型中，異綠原酸A在低、中、高3個濃度下，各腸段的有效滲透系數(shù)(Peff)有上升趨勢，具有顯著性差異（P＜0.05），在回腸的Peff值顯著大于其他腸段，由此可推斷回腸段可能是異綠原酸A的最佳吸收部位。大鼠靜脈注射后，異綠原酸A平均半衰期為29min，AUC隨著劑量的增加而增加。異綠原酸A在大鼠體內(nèi)的絕對生物利用度為30.71%。Fl%與Fa%存在顯著地正線性關(guān)系，相關(guān)性系數(shù)為0.974，呈正相關(guān)性，回歸方程為Fl%=0.523Fa%+3.715。當異綠原酸A的濃度分別為60.98與84.63μg·mL-1時，腸道攝取率（El%）分別為45.94%與52.37%，另外，當異綠原酸A的濃度為5.39與12.2μg·mL-1時，肝臟攝取率（Eh%）分別為48.01%與54.47%。 結(jié)論：異綠原酸A在腸道是以被動方式在腸道轉(zhuǎn)運，在回腸段吸收較好；在大鼠體內(nèi)半衰期短，生物利用較低，且藥動學行為為線性動力學；由Fl%與Fa%相關(guān)性評價可知，用腸灌流模型預測藥物的吸收率可靠性高。異綠原酸A在腸、肝首過效應大。
[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.
【學位授予單位】：廣東藥學院
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R965

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