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

本试验旨在研究猪胰高血糖素样肽-2(pGly2]GLP-2)、聚乙二醇修饰猪胰高血糖素样肽2(PEG-pGly2]GLP-2)和pGly2]GLP-2微球在大鼠体内的药代动力学过程,为利用pGly2]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pGly2]GLP-2(5.64 nmol/kg)、PEG-pGly2]GLP-2(5.64 nmol/kg)和pGly2]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-pGly2]GLP-2的半衰期(t1/2)是pGly2]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pGly2]GLP-2的3倍,清除率(CL)是pGly2]GLP-2的1/2,两者的达峰浓度(Cm ax)相差不大,PEG-pGly2]GLP-2的达峰时间(Tm ax)滞后于pGly2]GLP-2。2)pGly2]GLP-2微球的达峰时间与pGly2]GLP-2、PEG-pGly2]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pGly2]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;pGly2]GLP-2微球半衰期更长,且持续稳定的释放,操作便利。

Pharmacokinetics Studies in Rats of Porcine Glucagon-Like Peptide-2 and Its Long-Acting Forms

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 pGly2]GLP?2), PEG?pGly2]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?pGly2]GLP?2 was later than pGly2] GLP?2. 2) The half time of pGly2]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.