去氧鬼臼毒素聚合物胶束在大鼠体内的药动学  

Pharmacokinetics of deoxypodophyllotoxin polymeric micelles in rats

作　　者：赵锦[1] 史继峰[1] 熊晔蓉[1] 涂家生[1] 

机构地区：[1]中国药科大学药剂学教研室,南京210009

出　　处：《中国新药杂志》2014年第22期2659-2663,共5页Chinese Journal of New Drugs

基　　金：国家自然科学基金(81201182);中央高校基本科研业务费专项基金(JKPZ2013006)

摘　　要：目的：建立一种测定大鼠血液中去氧鬼臼毒素含量的HPLC方法,比较研究去氧鬼臼毒素聚合物胶束（DPT-PM）与去氧鬼臼毒素羟丙基-β-环糊精包合物（DPT-HP-β-CD）静脉注射后,药物在大鼠体内的药动学特征。方法：色谱分离采用C18色谱柱（250 mm×4.6 mm,5μm）,流动相为甲醇-水（75∶25）,检测波长为294 nm,柱温30℃,地西泮为内标。大鼠尾静脉给药,DPT-PM和DPT-HP-β-CD给药剂量均为15mg·kg-1（以药液中DPT含量计）,比较两者的药动学参数。考察DPT-PM给药剂量分别为10,15,20mg·kg-1时,剂量与药动学参数之间的相关性。结果：2种制剂体内过程均符合开放性双隔室模型特征,DPTHP-β-CD和DPT-PM的CL分别为（29.33±5.18）和（19.37±2.57）m L·kg-1,Vss为（1.78±0.35）和（1.00±0.08）L·kg-1,AUC0-∞（521.49±86.33）和（783.08±97.52）μg·m L-1·min。3种给药剂量下DPT-PM的AUC0-4h与剂量之间显示出非线性动力学特征。结论：与环糊精包合物相比,胶束给药系统可以使DPT的血浆清除率显著降低,在血液中循环时间延长,生物利用度显著提高。Objective： To establish a HPLC analysis method for determination of deoxypodophyllotoxin in rat plasma,and to investigate pharmacokinetic behaviors of deoxypodophyllotoxin polymeric micelles（ DPT-PM） in rats after intravenous injection compared with inclusion complex of deoxypodophyllotoxin hydroxypropyl-β-cyclodextrins（ DPT-HP-β-CD）. Methods： A C18column（ 250 mm × 4. 6 mm,5 μm） was used at column temperature of30 ℃,and the mobile phase contained methanol-water（ 75∶ 25） with the flow rate of 1. 0 m L·min- 1,and the UV detection wavelength was set at 294 nm. Diazepam was selected as the internal standard. DPT-PM and DPT-HP-β-CD at a dose of 15 mg·kg- 1were iv administered to rats to study the pharmacokinetics. Relationship between the pharmacokinetic parameters and doses（ 10,15 and 20 mg·kg- 1） of DPT-PM was studied. Results： The plasma DPT concentration-time profiles after dosing of both preparations were best fitted to the two-compartment model.The CLs of DPT-HP-β-CD and DPT-PM were（ 29. 33 ± 5. 18） and（ 19. 37 ± 2. 57） m L·kg- 1,and Vssof DPT were（ 1. 78 ± 0. 35） and（ 1. 00 ± 0. 08） L·kg- 1,respectively. AUC0 - ∞following dosing of DPT-HP-β-CD and DPT-PM were（ 521. 49 ± 86. 33） and（ 783. 08 ± 97. 52） μg·m L- 1·min,respectively. The nonlinear pharmacokinetics existed after iv. administration of DPT-PM at doses of 10,15 and 20 mg·kg- 1. Conclusion： The micelle formulation significantly decreases the plasma clearance of DPT,improves the bioavailability of DPT,and prolongs the blood circulation time of DPT compared with inclusion complex of hydroxypropyl-β-cyclodextrins.

关 键 词：去氧鬼臼毒素 聚合物胶束 高效液相色谱 血药浓度 药动学 

分 类 号：R969.1[医药卫生—药理学]