重复注射掺入不同形式PEG的大黄素脂质体对ABC现象的影响  

Effects of emodin liposomes mixed with different forms of PEG on ABC phenomenon by repeated injections

作　　者：沈丽萍 颜冬雪 赵善科 尹美林 孙玉琦 

机构地区：[1]锦州医科大学,锦州121001

出　　处：《中国新药杂志》2017年第7期818-824,共7页Chinese Journal of New Drugs

基　　金：辽宁省自然科学基金项目(201602312)

摘　　要：目的:考察不同组SD大鼠,间隔相同时间重复注射甲氧基聚乙二醇化大黄素脂质体(m PEGEmo-Lip)、二硬脂酰磷脂酰乙醇胺-聚乙二醇化大黄素脂质体(DSPE-Emo-Lip)、胆固醇-聚乙二醇化大黄素脂质体(Chol-Emo-Lip)3种掺入不同形式聚乙二醇(polyethylene glycol,PEG)的大黄素脂质体,产生加速血液清除(accelerated blood clearance,ABC)现象的强弱。方法:薄膜分散-超声法制备m PEG-Emo-Lip,DSPE-EmoLip,Chol-Emo-Lip 3种脂质体;FLD-HPLC法测定大黄素血药浓度,DAS 2.1.1药动学软件计算药动学参数;并通过酶联免疫分析试剂盒(enzyme-linked immunosorbent assay,ELISA)检测大鼠体内抗PEG Ig M抗体(PEG-Ig M)水平;比较重复注射3种脂质体所产生ABC现象的强弱。结果:与首次给药时各组对应药动学参数相比,m PEG-Emo-Lip,DSPE-Emo-Lip,Chol-Emo-Lip第3次给药时t1/2分别为(0.74±0.12),(0.77±0.05),(0.88±0.09)倍,MRT分别为(0.87±0.12),(0.69±0.07),(0.91±0.09)倍,AUC分别为(0.69±0.06),(0.53±0.06),(0.82±0.09)倍,CL分别为(1.45±0.11),(1.82±0.21),(1.20±0.14)倍。首次给药后d 3,大鼠体内开始大量产生PEG-Ig M;第2次给药,体内抗体数量急剧下降,第2次给药后d 3,仍有少量PEG-Ig M产生;第3次给药,体内抗体消耗至普通脂质体组水平,且不再增加。结论:重复注射掺入m PEG2000,DSPE-PEG2000,Chol-PEG2000 3种形式PEG的大黄素脂质体后,消除半衰期、平均滞留时间、生物利用度降低,血浆清除率加快,其中重复注射Chol-Emo-Lip产生的ABC现象最弱。首次注射产生较高水平的PEG-Ig M,能与重复注射的大黄素脂质体表面的PEG化分子结合,激活补体系统,使脂质体快速被网状内皮系统(RES)摄取,导致药物在体内循环时间减少,可能是ABC现象产生的原因。Objective： To inspect the accelerated blood clearance（ ABC） phenomenon in rats repeatedly injected with emodin liposomes mixed with three forms of PEG（ m PEG-Emo-Lip,DSPE-Emo-Lip and Chol-EmoLip） at the same time intervals. Methods： m PEG-Emo-Lip,DSPE-Emo-Lip and Chol-Emo-Lip were prepared by film-ultrasonic dispersion. FLD-HPLC was established to determine concentrations of emodin in plasma samples,and then the kinetics equations were used to fit pharmacokinetics of emodin liposomes in rats. The levels of anti-PEG Ig M（ PEG-Ig M） in rats were detected with enzyme-linked immunosorbent assay（ ELISA）. The ABC phenomena of 3 kinds of emodin liposomes injected repeatedly were compared. Results： Compared to thecorresponding pharmacokinetic parameters in the first administration,elimination half-life（ t1/2） of m PEG-EmoLip,DSPE-Emo-Lip and Chol-Emo-Lip in the third administration was decreased（ 0. 74 ± 0. 12）,（ 0. 77 ± 0. 05）,and（ 0. 88 ± 0. 09） folds. The mean residence time（ MRT） was decreased（ 0. 87 ± 0. 12）,（ 0. 69 ± 0. 07）,and（ 0. 91 ± 0. 09） folds. Areas under the concentration-time curve（ AUC） was decreased（ 0. 69 ± 0. 06）,（ 0. 53 ±0. 06）,and（ 0. 82 ± 0. 09） folds. Clearance（ CL） in plasma was increased（ 1. 45 ± 0. 11）,（ 1. 82 ± 0. 21）,and（ 1. 20 ± 0. 14） folds. PEG-Ig M began to be produced on the third day after the first administration in rats. The number of antibody decreased dramatically in vivo after the second administration,besides a small amount of PEGIg M was produced on the third day after the second administration. Antibody was consumed to the level of ordinary liposome group after the third dose,and did not increase any more. Conclusion： Emodin liposomes mixed with m PEG2000,DSPE-PEG2000 and Chol-PEG2000 can decrease T1/2,MRT and AUC after repeated injections.However,CL was increased,which demonstrate ABC phenomenon. The Chol-Emo-Lip shows less ABC phenomenon.A higher level of PEG-Ig M has been induce

关 键 词：大黄素 聚乙二醇 脂质体 重复注射 ABC现象 

分 类 号：R944.9[医药卫生—药剂学] R979.1[医药卫生—药学]