注射用紫杉醇聚合物胶束小鼠体内药代动力学

Pharmacokinetics of paclitaxel polymeric micelles for injection in mice

目的:建立一种测定小鼠血液中紫杉醇含量的HPLC方法,研究注射用紫杉醇聚合物胶束(PTX-PM)的药代动力学。方法:血样经乙醚提取后进行HPLC分析,色谱柱为Lichrospher C18(4.6mm×25mm,4.6μm),流动相为甲醇-水-乙腈(28∶36∶36),检测波长为227nm,地西泮为内标。小鼠尾静脉给药,特素(市售紫杉醇注射液)给药剂量为20mg/kg,PTX-PM给药剂量为50mg/kg(以药液中紫杉醇含量计)。采用3P87程序计算紫杉醇的药代动力学参数。考察PTX-PM给药剂量分别为30,40,50mg/kg时,剂量与药代动力学参数之间的相关性。结果:两种制剂体内过程均符合二室模型,特素和PTX-PM的cmax分别为(60.37±17.16)μg/mL和(84.17±12.29)μg/mL,AUC分别为56.02μg/mL.h和56.64μg/mL.h,t1/2(β)分别为1.31h和1.06h。在3种给药剂量下,PTX-PM的AUC0-8h与剂量之间有线性相关性。结论:PTX-PM给药后,紫杉醇迅速地分布于组织,血液中药物浓度低,降低了血液毒性。

Aim：To establish a HPLC method to determine paclitaxel in mice blood, and to investigate the pharmacokinetics of paclitaxel polymeric micelles （PTX-PM） in mice. Methods： The blood samples were extracted by ether. HPLC assay, of which diazepam was selected as internal standard, was carried out on a Lichrospher CIs column（4.6 mm × 25 mm ,4.6 μm） with the mobile phase of methanol-water-acetonitrile （28：36：36） and the UV detection wave- length set at 227 nm. PTX-PM at a dose of 50 mg/kg and paclitaxel injection （Tesu ） at a dose of 20 mg/kg were iv given to mice to study the pharmacokinetics. Relationship between the pharmacokinetic parameters and dose sizes of 30 mg/kg, 40 mg/kg and 50 mg/kg was studied following dosing of PTX-PM. Results： The plasma paclitaxel concentra- tion-time profiles after dosing of both preparations were best fitted to two-compartment model. The Cnax of paclitaxel injection and PTX-PM were found to be （60.37 ±17.16）μg/mL and （84.17±12.29）μg/mL, respectively, and esti- mated t 1/2（β） s of paclitaxel were 1.3 h and 1.06 h, respectively. The AUCo.s h S following dosing of Tesu and PTX-PM were 56.02 μg/mL· h and 56.64 μg/mL· h, respectively. There existed linear relationship between the pharmacokinetics parameters and paclitaxel dose after iv administration of PTX-PM at doses of 30 mg/kg, 40 mg/kg and 50 mg/kg. Conclusion：Mter dosing of PTX-PM, paclitaxel was rapidly distributed into tissues. Therefore, there might be decreased chances of the toxicity in blood.