Labrasol对紫杉醇经大鼠小肠定位吸收的影响

Improvement of Labrasol on the Intestine-Specific Absorption of Paclitaxel after Oral Administration of Enteric Coating Paclitaxel Gelatin Capsule in Rats

目的评价Labrasol作用下对紫杉醇经小肠吸收的影响。方法0.5mg紫杉醇和0.5mg Labrasol装入明胶胶囊中,并以羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)包裹胶囊,观察胶囊的体外释药性能。在乙醚麻醉下通过聚乙烯管给大鼠口服5粒胶囊,对照组口服同剂量的不含Labrasol的胶囊。于给定的时间间隔取血,用HPLC测定大鼠血液中的药物浓度。另同法制备含0.1mg荧光素钠和0.5mg Labrasol明胶胶囊和不含Labrasol的荧光素钠明胶胶囊,分别给大鼠口服5粒胶囊。用HPLC测定血药浓度。用WinNolin软件计算血药浓度曲线下面积。结果制备的肠溶性紫杉醇胶囊在人工胃液中2h无药物释放,而在人工肠液中4h内累积释药量几乎达到100%。大鼠口服肠溶性紫杉醇明胶胶囊时,大鼠血浆浓度-时间曲线下面积(AUC)为(582.43±181.99)μg.h.L-1,而在Labrasol作用下,AUC增加到(1379.43±487.29)μg.h.L-1,具有统计学意义(P<0.05),表明在Labrasol的作用下,将有更多的紫杉醇吸收到血液中。但同剂量的Labrasol对荧光素钠的吸收没有促进作用。结论Labrasol可能通过抑制小肠黏膜的P-糖蛋白而促进紫杉醇经小肠的吸收。

OBJECTIVE To evaluate the effect of Labrasol on the intestine-specific absorption of paclitaxel. METHODS 0.5 mg of paclitaxel with or without 0.5 mg of Labrasol was filled in the gelatin capsule and then the capsule was coated with hydroxypropylmethyl cellulose phthalate. Next, the in vitro release of the capsule in the artificial gastric juice or in the man-made small intestinal juice was carried out. Then, the 5 capsules （2.5 mg paclitaxel） were administered orally via a polyethylene cannula under light ether anesthesia. The control group was taken 5 capsules filled with 0.5 mg of fluorescein sodium with or without Labrasol at the same dose. Blood samples were taken periodically and were analyzed using HPLC. The area under the curve （AUC） in the plasma was calculated with WinNonlin software. RESULTS There was no release ofpaclitaxel from capsules in the artificial medium of stomach （2 h）, while the accumulated release of paclitaxel almost reached 100% in the artificial small intestinal juice （4 h） After oral administration of the capsules, AUC of paclitaxel was （582.43±181.99） μg·h·L^-1 for the formulation without Labrasol. On the other hand, AUC was increased to （1 379.43±487.29）μg·h·L^-1 with the co-administration of Labrasol. Therefore, Labrasol in the given dose improved the absorption of paelitaxel from the intestine. It showed the statistical significance （P〈0.05）, compared with the no Labrasol group. In addition, Labrasol at the same dose did not show the improvement to the absorption of fluorescein sodium via the intestinal tract. CONCLUSION Labrasol may inhibit the p-glucoprotein（p-gp） activity in the intestinal membrane to increase the absorption of paclitaxel, a p-gp substrate.