本文選題：大鼠原位腸-肝血管灌流模型 + Caco-2細(xì)胞模型��； 參考：《廣東藥學(xué)院》2012年碩士論文

【摘要】：目的：優(yōu)化大鼠原位腸-肝血管灌流模型，并驗(yàn)證該模型在預(yù)測(cè)藥物吸收方面的可行性。 方法：對(duì)灌流條件進(jìn)行優(yōu)化，分別對(duì)Krebs-Ringer緩沖液（K-R液）加牛血清白蛋白和甘露醇、K-R液加牛血清白蛋白和右旋糖酐T-40二者進(jìn)行對(duì)比，找出最佳的灌流介質(zhì)，然后對(duì)灌流液中牛血清白蛋白的含量進(jìn)行優(yōu)化；建立三種生物堿（氧化苦參堿、苦參堿和槐果堿）和六種有機(jī)酸（綠原酸、咖啡酸、阿魏酸、肉桂酸、甘草酸和甘草次酸）共九種化合物在灌流液、大鼠血漿和HBSS中的LC-MS/MS分析方法；以優(yōu)化的大鼠原位腸-肝血管灌流模型研究九種化合物的灌流吸收率；通過(guò)整體動(dòng)物實(shí)驗(yàn)研究九種化合物在大鼠體內(nèi)的藥動(dòng)學(xué)特征和絕對(duì)生物利用度（Fabs）；建立Caco-2細(xì)胞模型研究九種化合物的雙向轉(zhuǎn)運(yùn)過(guò)程并計(jì)算表觀滲透系數(shù)（Papp）；運(yùn)用灰色關(guān)聯(lián)分析法對(duì)九種化合物的灌流吸收率、Fabs和正向表觀滲透系數(shù)（PappA→B）進(jìn)行相關(guān)性分析。 結(jié)果：優(yōu)化的大鼠原位腸-肝血管灌流模型能更經(jīng)濟(jì)、準(zhǔn)確地預(yù)測(cè)藥物的吸收情況；氧化苦參堿、苦參堿、槐果堿、綠原酸、咖啡酸、阿魏酸、肉桂酸、甘草酸和甘草次酸在優(yōu)化的灌流模型中的吸收率分別為8.30%、14.03%、12.03%、1.37%、2.68%、59.00%、85.59%、0.47%和88.73%；在大鼠體內(nèi)的Fabs分別為15.69%、53.40%、39.63%、3.59%、14.70%、64.91%、81.15%、3.04%和96.72%；在Caco-2細(xì)胞模型中的PappA→B分別為（6.39±0.74）×10-6cm/s、（10.7±0.17）×10-6cm/s、（7.35±0.76）×10-6cm/s、（0.66±0.04）×10-6cm/s、（5.05±0.66）×10-6cm/s、（10.24±1.58）×10-6cm/s、（24.30±3.82）×10-6cm/s、（0.28±0.06）×10-6cm/s和（30.57±4.69）×10-6cm/s；灰色關(guān)聯(lián)分析表明灌流吸收率和Fabs的關(guān)聯(lián)度為0.7194，，PappA→B與Fabs的關(guān)聯(lián)度為0.7515，二者沒有顯著性差異（P＞0.05）。 結(jié)論：優(yōu)化的大鼠原位腸-肝血管灌流模型在藥物吸收研究領(lǐng)域具有良好的應(yīng)用前景。
[Abstract]:Aim: to optimize the in situ intestinal-hepatic vascular perfusion model in rats and to verify the feasibility of the model in predicting drug absorption. Methods: the perfusion conditions were optimized and the optimal perfusion medium was found by comparing the Krebs-Ringer buffer solution with bovine serum albumin and mannitol K-R solution with bovine serum albumin and dextran T-40. Three alkaloids (oxymatrine, matrine and sophorine) and six organic acids (Lv Yuan acid, caffeic acid, ferulic acid, cinnamic acid) were established. The method of LC-MS/MS analysis of nine compounds in perfusate, rat plasma and HBSS was used to study the perfusion absorption rate of nine compounds in the model of in situ enteric-hepatic vascular perfusion in rats with glycyrrhizic acid and glycyrrhetinic acid (glycyrrhizic acid). The pharmacokinetic characteristics and absolute bioavailability of nine compounds in rats were studied by whole animal experiment, the bidirectional transport process of nine compounds was studied by Caco-2 cell model and the apparent osmotic coefficient was calculated. Correlation analysis was carried out to analyze the correlation between the perfusion absorptivity (Fabs) and the forward apparent osmotic coefficient (PappA B) of nine compounds. Results: the optimized in situ enterohepatic vascular perfusion model could be more economical and accurate in predicting drug absorption, oxymatrine, sophoricine, Lv Yuan acid, caffeic acid, ferulic acid, cinnamic acid, 鐢樿崏閰稿拰鐢樿崏嬈￠吀鍦ㄤ紭鍖栫殑鐏屾祦妯″瀷涓殑鍚告敹鐜囧垎鍒負(fù)8.30%,14.03%,12.03%,1.37%,2.68%,59.00%,85.59%,0.47%鍜

本文編號(hào)：1924520