多西紫杉醇脂质体家兔体内药动学

Study on pharmacokinetics of docetaxel liposome in rabbits

目的:研究多西紫杉醇脂质体在家兔体内的药动学。方法:18只家兔随机分为3组,分别在耳缘静脉单剂量(7.5mg·kg-1)注射多西紫杉醇普通脂质体、长循环脂质体和市售注射液,用高效液相色谱法测定各时间点血药浓度。结果:血药浓度-时间数据均符合二房室模型;t1/2α分别为(0.31±0.11),(0.32±0.06),(0.17±0.04)h;t1/2β分别为(11.2±1.3),(10.5±1.1),(8.5±1.0)h;Vd分别为(8.6±1.1),(6.3±0.6),(13.7±3.6)L;AUC0→24分别为(22.8±3.6),(29.3±6.0),(13.4±2.4)mg.h.L-1;AUC0→∞分别为(28.7±5.0),(37.0±9.1),(15.1±2.8)mg.h.L-1;CL分别为(0.54±0.08),(0.42±0.07),(1.10±0.18)L.h-1。2种脂质体与注射液相比,t1/2α,t1/2β,Vd,CL,AUC0→24及AUC0→∞均有显著性或极显著性差异;脂质体之间Vd和CL差异有显著性。结论:与普通注射液相比,家兔静注两种脂质体后,均具有较长的消除半衰期,更大的药-时曲线下面积,较低的总体消除率和较小的表观分布容积,说明脂质体制剂具有长效和缓释的特点;经PEG修饰的长循环脂质体较之普通脂质体,在能够维持较长的体内循环时间的同时,能够更好地浓集于靶组织,减少药物对其他组织的不良反应并增加疗效。

OBJECTIVE To compare the pharmacokinetics characteristics of docetaxel liposome injection（ L-DOC） and pegdocetaxel long-circulating liposome injection（PEG-DOC-LCL）with market docetaxel injection（M-DOC） in rabbits by intravenous administration. METHODS L-DOC, PEG-DOC-LCL and M-DOC were intravenously administrated to rabbits a.t a single dosage of 7. 5 mg·kg^-1. The concentration-time data of docetaxel（DOC）in plasma samples were determined by HPLC, and the pharmacokinetic parameters were calculated and analyzed by means of 3p97 and SPSS software. RESULTS The concentrationtime data of L-DOC, PEG-DOC-LCL and M-DOC were all fitted to two compartment-model, and the main pharmacokinetie pa- rameters as follows： t1/2α were（0. 31 ± 0. 11 ）, （0. 32 ± 0. 06）, （0. 17 ± 0. 04） h respectively; t1/2β were （ 11.2 ± 1.3 ）, （ 10. 5 ± 1.1 ）, （8. 5 ± 1.0）h respectively;Vd were（8. 6 ± 1.1 ）, （6. 3 ±0. 6）, （ 13. 7 ± 3. 6）L respectively; AUC0→24 were （22. 8 ± 3. 6）, （29. 3 ± 6. 0）, （13. 4 ±2. 4）mg·h·L^-1 respectively; AUC0→∞ were（28. 7 ± 5.0）, （37. 0 ± 9. 1 ）, （15.07 ± 2. 76）mg·h·L^-1 respectively; CL were（0. 54 ± 0. 08）, （0. 42 ± 0. 07）, （ 1.10 ± 0. 18）L·h^-1 respectively, t1/2α, t1/2β, Vd, CL, AUC0→24 and AUC0→∞ of two kinds of docetaxel liposomes all had significant difference repectively from those of M-DOC,Vd and CL of PEG-DOC-LCL had signifi： cant difference from those of L-DOC. CONCLUSION There were several significant differences between the pharmacokinetics properties of L-DOC,PEG-DOC-LCL and M-DOC injection in rabbits. Compared with the M-DOC, L-DOC and PEG-DOC-LCL contained characteristic of sustained-release and higher effect. At the same time, the docetaxel of PEG-DOC-LCL could be concentrated at the target tissue and be advantageous to reduce toxicity and improve therapeutic effect.