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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 investigate the effects of m PEGEmo-Lip, distearoylphosphatidylethanolamine-PEGylated emodin liposomes injected into SD rats of different groups at the same time intervals, (DSPE-Emo-Lip) and Cholesterol-PEGylated emodin liposomes (Chol-Emo-Lip) were incorporated into three different types of polyethylene glycol (PEG) Accelerate the phenomenon of accelerated blood clearance (ABC). METHODS: Three kinds of liposomes, m PEG-Emo-Lip, DSPE-EmoLip and Chol-Emo-Lip were prepared by membrane dispersion-ultrasonic method. The plasma concentrations of emodin were determined by FLD-HPLC. Pharmacokinetic parameters were determined. The levels of anti-PEG Ig M antibody (PEG-Ig M) in rats were detected by enzyme-linked immunosorbent assay (ELISA) The strength of the phenomenon. Results: The t1 / 2 of m PEG-Emo-Lip, DSPE-Emo-Lip and Chol-Emo-Lip at the third administration were (0.74 ± 0.12 (0.77 ± 0.12), (0.69 ± 0.07), (0.91 ± 0.09) and (0.69 ± 0.06), (0.53 ± 0.06) and ), (0.82 ± 0.09) times and CL (1.45 ± 0.11), (1.82 ± 0.21) and (1.20 ± 0.14) times respectively. After the first administration d 3, a large amount of PEG-Ig M started to be produced in the rat body. In the second administration, the amount of the antibody in vivo rapidly declined, and a small amount of PEG-Ig M remained after d 2 of the second administration. Administration, in vivo antibody depletion to normal liposome group level, and no longer increased. CONCLUSION: After repeated injection of emodin liposomes with PEG PEG2000, DSPE-PEG2000 and Chol-PEG2000, the elimination half-life, average residence time, bioavailability and plasma clearance were accelerated. Chol- Emo-Lip produces the weakest ABC phenomenon. The first injection produces a higher level of PEG-Ig M, which binds to pegylated molecules on the surface of the repeatedly injected emodin liposomes, activates the complement system, allowing the liposomes to rapidly be taken up by the reticuloendothelial system (RES) Circulation in the body to reduce the time may be the reason ABC phenomenon.