重组人胰高血糖素类肽-1(7-36)的药动学与组织分布  

The pharmacokinetics and tissue distribution of recombinant human glucagon-like peptide 1(7-36)

作　　者：白静[1,2] 余刚 刘秀文[2] 孙效[2] 欧伦[2] 汤仲明[2] 宋海峰[2] 

机构地区：[1]河北联合大学药理学教研室,河北唐山063000 [2]军事医学科学院放射与辐射医学研究所,北京100850 [3]上海华谊生物技术有限公司,北京201321

出　　处：《中国药理学通报》2011年第1期62-65,共4页Chinese Pharmacological Bulletin

基　　金：国家高技术研究发展计划(863计划)资助项目(No2003AA2Z347B)

摘　　要：目的研究重组人胰高血糖素类肽-1(7-36)[rhGLP-1(7-36)]在动物体内的药动学与组织分布。方法猕猴给予不同剂量(3.5、14和56μg.kg-1)rhGLP-1(7-36),酶联免疫吸附分析法(ELISA)测定猕猴血浆中rhGLP-1(7-36)浓度,[125I]标记示踪法结合分子排阻色谱法(SEC)观察rh-GLP-1(7-36)在Wistar大鼠各组织中的分布。结果猕猴单次sc不同剂量rhGLP-1(7-36)后,血药浓度及AUC随剂量呈线性增加,各组达峰时间(Tmax)均为15 min,末端相半衰期(T12β)35～45 min,全身清除率(CL)1.0～1.3 L.min-1.kg-1,组间均无差别。sc给药绝对生物利用度22.2%。以3.5μg.kg-1剂量连续sc 7 d体内无蓄积。大鼠sc[125I]rh-GLP-1(7-36)后10 min血浆原形药物浓度达峰,降解物迅速出现。肾脏与胰腺此时总放射性浓度最高。结论在研究剂量范围内rhGLP-1(7-36)呈线性动力学。吸收、降解迅速是其动力学的特点。药物主要通过肾脏排泄,胰腺可能为药物的靶器官。Aim To study the pharmacokinetics and tissue distribution of recombinant human glucagon-like peptide 1（7-36）[rhGLP-1（7-36）]in animals.Methods M.mulatta were administered rhGLP-1（7-36）at various doses（3.5,14 and 56 μg·kg-1）.Enzyme-linked immunosorbent assay（ELISA）was used to determine the concentrations of rhGLP-1（7-36）in plasma of M.mulatta.labeled tracing method combined with size exclusion chromatography（SEC）method were utilized to investigate tissue distribution of rhGLP-1（7-36）in Wistar rats.Results rhGLP-1（7-36）complied with linear kinetics among doses of 3.5~56 μg·kg-1 after it was sc administered various doses to M.mulatta.The peak time（Tmax）was 15 min,half life of the terminal elimination（T1 2β） was 35~45 min,and the clearance（CL） was 1.0~1.3 L·min-1·kg-1.These parameters had no statistic differences in various groups.The absolute bioavailability was 22.2% after sc adminstration.After multiple sc administration（3.5 μg·kg-1,once a day,7 times in total）,rhGLP-1（7-36）was without accumulation in body.The concentration of intact rhGLP-1（7-36）in plasma of the rats was highest at 10 min after sc administration.The radioactive concentrations in kidney and pancreas were the highest at the moment.Conclusions In quantitative studies range,rhGLP-1（7-36） complied with linear kinetics.The kinetic remarkable characteristic of rhGLP-1（7-36）was that it was absorbed and eliminated rapidly in animal body.The drug mainly excreted by kidney,and its possible target organ was pancreas.

关 键 词：GLP-1 药动学 组织分布 酶脱免疫吸附分析法 [125I]标记 分子排阻色谱法 

分 类 号：R-332[医药卫生] R969.1