研究简报 Short communications

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

  • 吕佳佳 ,
  • 吴杰 ,
  • 齐珂珂 ,
  • 徐子伟
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  • 1. 安徽农业大学动物科技学院, 合肥 230036;
    2. 浙江省农业科学院畜牧兽医研究所, 杭州 310021

收稿日期: 2016-02-29

  网络出版日期: 2016-08-17

基金资助

现代农业产业技术体系(CARS-36);浙江省自然科学基金项目(LY15C170002)

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

  • LYU Jiajia ,
  • WU Jie ,
  • QI Keke ,
  • XU Ziwei
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  • 1. College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China;
    2. Institute of Animal Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China

Received date: 2016-02-29

  Online published: 2016-08-17

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。

本文引用格式

吕佳佳 , 吴杰 , 齐珂珂 , 徐子伟 . 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[J]. 动物营养学报, 2016 , 28(8) : 2650 -2656 . DOI: 10.3969/j.issn.1006-267x.2016.08.038

Abstract

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 microspheres 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.

参考文献

[1] TSAI C H,HILL M,ASA S L,et al.Intestinal growth-promoting properties of glucagon-like peptide-2 in mice[J].American Journal of Physiology-Endocrinology and Metabolism,1997,273(1):E77-E84.
[2] GUAN X F,STOLL B,LU X F,et al.GLP-2-mediated up-regulation of intestinal blood flow and glucose uptake is nitric oxide-dependent in TPN-fed piglets[J].Gastroenterology,2003,125(1):136-147.  
[3] BENJAMIN M A,MCKAY D M,YANG P C,et al.Glucagon-like peptide-2 enhances intestinal epithelial barrier function of both transcellular and paracellular pathways in the mouse[J].Gut,2000,47(1):112-119.  
[4] WØJDEMANN M,WETTERGREN A,HARTMANN B,et al.Inhibition of sham feeding-stimulated human gastric acid secretion by glucagon-like peptide-2[J].The Journal of Clinical Endocrinology & Metabolism,1999,84(7):2513-2517.  
[5] PEDERSEN N B,HJOLLUND K R,JOHNSEN A H,et al.Porcine glucagon-like peptide-2:structure,signaling,metabolism and effects[J].Regulatory Peptides,2008,146(1/2/3):310-320.
[6] JEPPESEN P B,PERTKIEWICZ M,MESSING B,et al.Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure[J].Gastroenterology,2012,143(6):1473-1481.  
[7] ALTERS S E,MCLAUGHLIN B,SPINK B,et al.GLP2-2G-XTEN:a pharmaceutical protein with improved serum half-life and efficacy in a rat Crohn's disease model[J].PLoS One,2012,7(11):50630.
[8] QI K K,WU J,DENG B,et al.PEGylated porcine glucagon-like peptide-2 improved the intestinal digestive function and prevented inflammation of weaning piglets challenged with LPS[J].Animal,2015,9(9):1481-1489.  
[9] QI K K,WU J,WAN J,et al.Purified PEGylated porcine glucagon-like peptide-2 reduces the severity of colonic injury in a murine model of experimental colitis[J].Peptide,2014,52:11-18.
[10] WU J,QI K K,XU Z W,et al.Glucagon-like peptide-2-loaded microspheres as treatment for ulcerative colitis in the murine model[J].Journal of Microencapsulation,2015,32(6):598-607.  
[11] DRUCKER D J,ERILICH P,ASA S L,et al.Induction of intestinal epithelial proliferation by glucagon-like peptide 2[J].Proceedings of the National Academy of Sciences of the United States of America,1996,93(15):7911-7916.  
[12] BOUSHEY R P,YUSTA B,DRUCKER D J.Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis[J].American Journal of Physiology:Endocrinology and Metabolism,1999,277(5):E937-E947.
[13] DRUCKER D J,YUSTA B,BOUSHEY R P,et al.Human[Gly2]GLP-2 reduces the severity of colonic injury in a murine model of experimental colitis[J].American Journal of Physiology:Gastrointestinal and Live Physiology,1999,276(1):G79-G91.
[14] ALAVI K,SCHWARTZ M Z,PALAZZO J P,et al.Treatment of inflammatory bowel disease in a rodent model with the intestinal growth factor glucagon-like peptide-2[J].Journal of Pediatric Surgery,2000,35(6):847-851.  
[15] BAILON P,WON C Y.PEG-modified biopharmaceuticals[J].Expert Opinion on Drug Delivery,2009,6(1):1-16.  
[16] HARRIS J M,CHESS R B.Effect of pegylation on pharmaceuticals[J].Nature Reviews Drug Discovery,2003,2(3):214-221.  
[17] VERONESE F M,PASUT G.PEGylation,successful approach to drug delivery[J].Drug Discovery Today,2005,10(21):1451-1458.  
[18] FEE C J,ALSTINE J M V.PEG-proteins:reaction engineering and separation issues[J].Chemical Engineering Science,2006,61(3):924-939.  
[19] LEE S H,LEE S,YOUN Y S,et al.Synthesis,characterization and pharmacokinetic studies of PEGylated glucagon-like peptide-1[J].Bioconjugate Chemistry,2005,16(2):377-382.  
[20] CHOI S,BAUDYS M,KIM S W.Control of blood glucose by novel GLP-1 delivery using biodegradable triblock copolymer of PLGA-PEG-PLGA in type 2 diabetic rats[J].Pharmaceutical Research,2004,21(5):827-831.  
[21] 刘琳娜,李欣,张琰等.胰高血糖素样肽-2/聚乳酸-羟基乙酸微球的制备及其体外释药性质研究[J].中国药房,2010(29):2755-2757.
[22] 张海松,刘卫红,张基展,等.口服胸腺肽微球在大鼠体内的药代动力学和生物利用度[J].中国生化药物杂志,2000,21(1):15-17.
[23] 陆蕾.干扰素α-2b PLGA缓释微球药代动力学及药效学研究[D].硕士学位论文.上海:第二军医大学,2006:18-29.
[24] 肖田安,怀彬彬,李帅鹏,等.伊维菌素PLA及PLGA微球混悬液在犬体内的药代动力学研究[J].华南农业大学学报,2014,35(3):8-12.
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