猪胰高血糖素样肽2及其长效化物在大鼠体内的药代动力学研究

摘要

本试验旨在研究猪胰高血糖素样肽－2（ p[ Gly2] GLP⁃2）、聚乙二醇修饰猪胰高血糖素样肽2（PEG⁃p[Gly2]GLP⁃2）和 p[Gly2]GLP⁃2微球在大鼠体内的药代动力学过程，为利用p[ Gly2] GLP⁃2修复断奶仔猪肠道损伤提供参考依据。选取18只280 g左右的雄性SD大鼠，随机分为3组，分别单次皮下注射 p [ Gly2] GLP⁃2（5．64 nmol／kg ）、PEG⁃p [ Gly2] GLP⁃2（5．64 nmol／kg）和p[Gly2]GLP⁃2微球（15 mg／只），定点采血后，酶联免疫吸附测定（ELISA）法测定胰高血糖素样肽－2（ GLP⁃2）的血药浓度。结果表明：1） PEG⁃p[ Gly2] GLP⁃2的半衰期（t1／2）是p[Gly2]GLP⁃2的4倍，血药浓度－时间曲线下面积（AUC0－t）和平均滞留时间（MRT0－t）是p[Gly2]GLP⁃2的3倍，清除率（CL）是p[Gly2]GLP⁃2的1／2，两者的达峰浓度（Cmax）相差不大，PEG⁃p[Gly2]GLP⁃2的达峰时间（Tmax）滞后于p[Gly2]GLP⁃2。2）p[Gly2]GLP⁃2微球的达峰时间与p[Gly2]GLP⁃2、PEG⁃p[Gly2]GLP⁃2相差不大，但半衰期为（72．20±6．02） h，平均滞留时间为（90．66±7．41） h。结果提示，经聚乙二醇（PEG）修饰后p[Gly2]GLP⁃2的药代动力学行为发生了很大的改变，半衰期延长、达峰时间滞后、平均滞留时间延长、血浆清除减慢、生物利用度更高；p[ Gly2] GLP⁃2微球半衰期更长，且持续稳定的释放，操作便利。%This study aimed to analyze the pharmacokinetics of porcine glucagon⁃like peptide⁃2 [ Gly2 ] ( p[ Gly2] GLP⁃2) , PEGylated porcine glucagon⁃like peptide⁃2[ Gly2] ( PEG⁃p[ Gly2] GLP⁃2) and p[ Gly2] GLP⁃2 microspheres in rats, in order to provide references for the repairation of intestinal injury of weaned pigs by p[ Gly2] GLP⁃2. Eighteen Sprague⁃Dawley ( SD) male rats with 280 g body weight were randomly divided into 3 groups, which were p [ Gly2 ] GLP⁃2 group ( single subcutaneous administration of 5. 64 nmol/kg p[Gly2]GLP⁃2), PEG⁃p[Gly2]GLP⁃2 group (single subcutaneous administration of 5.64 nmol/kg PEG⁃p [ Gly2] GLP⁃2) and p[ Gly2] GLP⁃2 microspheres group ( single subcutaneous administration of 15 mg micro⁃spheres per rat) . After blood sampled, plasma drug concentration of GLP⁃2 was determined by enzyme linked immunosorbent assay ( ELISA ) . The results showed as follows: 1 ) compared to p [ Gly2 ] GLP⁃2, PEG⁃p [Gly2]GLP⁃2 increased the half⁃life(t1/2)by 4⁃fold, and increased the mean residence time (MRT0-t) and the area under the curve (AUC0-t) by 3⁃fold, but decreased the clearance (CL) to a half. The peak concentration (Cmax) was similar between two drugs, but peak time (Tmax) of PEG⁃p[Gly2]GLP⁃2 was later than p[Gly2] GLP⁃2. 2) The half time of p[Gly2]GLP⁃2 microspheres was (72.20±6.02) h and mean residence time was (90.66±7.41) h, but peak time was similar with p[ Gly2] GLP⁃2 and PEG⁃p[ Gly2] GLP⁃2. These results show that PEG⁃p[ Gly2] GLP⁃2 greatly improve the pharmacological profiles, increase half time, peak time and mean residence time, decrease clearance rate and improve bioavailability. p [ Gly2 ] GLP⁃2 microspheres with a longer half⁃life are released sustained and stable, and operated easily.