^(125)Ⅰ标记聚乙二醇化EILDVP肽的小鼠体内血药浓度  

Plasma concentration of ^(125)Ⅰ labeled and polyethylene glycol conjugation to EILDVP peptide in mice

作　　者：赵铁华[1] 史子惠[2] 张另沾 

机构地区：[1]河北师范大学药物研究所,河北石家庄050024 [2]安徽华星化工股份有限公司,安徽合肥230088

出　　处：《中国药理学通报》2015年第12期1745-1748,共4页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 30672561)

摘　　要：目的探讨聚乙二醇修饰改善EILDVP肽体内过程的效果。方法 KM小鼠以NaI饱和甲状腺后,按5 mL·kg^(-1)容积,分别尾静脉注射3.441GBq·L^(-1)浓度的^(125)Ⅰ标记的EILDVP-Tyr-NH_2、EILDVP-Cys(mP EG2000-MAL)-Tyr-NH_2和EILDVP-Cys(mPEG_(20000)-MAL)-Tyr-NH_2肽。给药后不同时间取血,分离血浆,经三氯乙酸处理后测定沉淀部分放射性;测定数据分别代入已制备的相应标准曲线方程,取得血药浓度-时间数据,经3P97药动学统计软件计算主要药代动力学参数。结果在3.75~480μg·L~(^(-1))浓度范围内,3种^(125)Ⅰ标记肽线性关系良好,回收率在88.92%~106.66%之间,日内变异系数(RSD)<10%;^(125)Ⅰ标记的mPEG2000和mPEG_(20000)修饰EILDVP-Tyr-NH_2肽的血浆半衰期(T1/2)分别为0.43 h和1.94 h、较原型肽(0.28 h)延长1.54倍和6.93倍,清除率(Cl)分别降低1.23倍和24.71倍;3种受试化合物表观分布容积(V)值均较小,主要分布在血浆中。结论适宜分子质量mPEG修饰有利于延长EILDVP肽的体内维持时间,对提高药效具有积极意义;在实验范围内,分子质量较大的mPEG_(20000)对EILDVP肽修饰效果较好。Aim To study the pharmacokinetics of polyethylene glycol conjugation on EILDVP peptide in mice by injection through tail vein. Methods KM mice,saturated thyroid gland with compound of Na I,were injected for ^(125)Ⅰ labeled EILDVP-Tyr-NH_2,EILDVP-Cys( mP EG2000-MAL)-Tyr-NH_2 and EILDVP-Cys( mPEG_(20000)-MAL)-Tyr-NH_2 peptides(^(125)Ⅰ: 5 mL ·kg^(-1)volume 3. 441 GBq · L^(-1)concentration) by tail intravenous,respectively. Blood samples at different time intervals were obtained,blood plasma was separated,and the radioactivity of precipitation after trichloroacetic acid( TCA) treatment was tested. According to standard curve equation, the plasma concentration curve and pharmocokinetic parameters were depicted by means of 3P97 pharmocokinetics software. Results Concentration range of 3. 75 ~ 480 μg·L^(-1)of three ^(125)Ⅰ labled peptides in plasma from mice had good linear relationship. Recovery of method was 88. 92% ~106. 66%,and RSD < 10%. The half-life time( T1 /2)of EILDVP-Tyr-NH_2 peptide modified by mP EG2000 and mP EG520000,labled by12 I was 0. 43 h and 1. 94 h,respectively,which was 1. 54 times and 6. 93 times that of prototype peptide( T1 /2= 0. 28h),and the clearances( Cl) were 1. 23 times and 24. 71 times,respectively. The apparent distribution volume( V) values of the three species were small,which might mainly distributed in the plasma. Conclusions Suitable for molecular mass mP EG modified the EILDVP peptides could extend to maintain time in vivo,which could play a positive role in improving efficacy. In the experimental range,EILDVP peptide modified by larger molecular mass of mPEG_(20000) has better effect.

关 键 词：VLA-4拮抗药 EILDVP肽 聚乙二醇修饰 药代动力学 血药浓度 小鼠 

分 类 号：R-332[医药卫生] R446.11