聚乙二醇化脑啡肽的镇痛药效和体内分布

Analgesic activity and biodistribution of polyethylene glycol conjugation to enkephalin

目的探讨聚乙二醇(PEG)修饰改善甲硫氨酸脑啡肽(MEK)体内半衰期短和对中枢神经系统(CNS)释放的作用。方法热板致痛小鼠侧脑室注射3.1μmol.kg-1MEK及其mPEG2000和mPEG5000修饰物,醋酸致痛小鼠尾静脉注射31μmol.kg-1同上受试物,比较镇痛活性;小鼠尾静脉注射0.2 ml.(10 g)-1容积5.55～7.40 GBq.L-1浓度的125I标记MEK及其mPEG2000修饰物,比较体内分布。结果 MEK及mPEG修饰物3组间F检验P<0.05或0.01(热板模型15 min除外);mPEG5000修饰物作用强于mPEG2000修饰物及未修饰MEK,镇痛活性可持续至120 min(P<0.01)。mPEG2000修饰物10 min时肝脏分布低于MEK、240 min时血液分布高于MEK(P<0.01),血液半衰期(T12)是原型肽的3倍、清除率(CL)降低2.2倍。结论适当分子量PEG修饰可降低MEK肝脏清除、增强镇痛活性、延长半衰期和镇痛时间,对改善脑啡肽成药性有积极意义;未直接证实mPEG修饰改善MEK的CNS释放。

Aim To study the effect of polyethylene glycol conjugation on met-enkephalin （MEK） improved short half-life time and the release of central nervous system （CNS）. Methods Lateral ventricle injection of the MEK （ 3.1 μmol · kg^-1 ） and MEK modified by mPEG2ooo and mPEGsooo was admistered to the painful mice induced by hot-plate, and tail vein injection of MEK （31 μmol · kg^-1 ） and the above tested drugs to the painful mice induced by acetic acid, then the analgesic activities were compared; tail vein injection of MEK [0. 2 ml · （10 g） ^-1 volume 5.55 -7.40 GBq · L^-1 concentration ] and mPEG2ooo modified MEK was adminstered, and the biodistribution of mice was compared. Results The result of F test of the 3 groups of MEK and its modified product was P 〈 0. 05 or 0. 01 （except the on hot plate pain model at 15 min）; the effect of MEK modified by mPEGsooo was stronger than MEK modified by mPEG2000 and MEK,and MEK modified by mPEG5000 could continue to 120 min （P 〈0. 01 ）. The liver distribution of MEK modified by mPEG2000 was lower than that of MEK at 10 min, the blood distribution of MEK modified by mPEG2000 was higher than that of MEK （ P 〈 0. 01 ） at 240 rain, and the blood half-life （T1/2） time of MEK modified by mPEG2000 was 3 times that of prototype peptide, the clearance （CL） was depressed by 2.2 times. Conclusions MEK modified by PEG with appropriate molecular weight can reduce the hepatobiliary clearance, enhance the analgesic activity, and prolong the half-life time and analgesic time. Besides, it has positive significance in improving the enkephalin to be a new drug; it fails to directly prove that MEK modi- fied by PEG can improve the release of CNS.