双修饰壳聚糖载丝裂霉素C纳米粒在大鼠体内的药动学研究

Pharmacokinetics of Dual Conjugated Chitosan-mitomycin C Nanoparticles in Rats

关键词:  丝裂霉素C  壳聚糖  纳米粒  高效液相色谱-质谱联用  药动学

Key words:  mitomycin C  chitosan  nanoparticles  HPLC-MS  pharmacokinetics

摘要:

目的 研究双修饰壳聚糖载丝裂霉素C纳米粒在大鼠体内的药动学特征。方法 2组大鼠分别静脉注射4 mg·kg-1丝裂霉素C纳米粒和丝裂霉素C注射剂后，采用高效液相色谱-串联质谱法(HPLC-MS)测定给药后不同时间点血浆中丝裂霉素C的浓度，计算主要药动学参数。结果 丝裂霉素C的线性范围20~1 000 μg·L^-1，最低定量限为20 μg·L^-1，提取回收率均>95%，日内、日间精密度RSD均<15%。双修饰壳聚糖载丝裂霉素C纳米粒和丝裂霉素C注射剂t_1/2分别为(2.64±0.11)h、(0.49±0.049)h；AUC_0-∞分别为(2.01±0.11)mg·h^-1·L^-1、(0.93±0.075)mg·h^-1·L^-1；Vz分别为(1.52±0.18)L、(0.63±0.065)L；CL分别为(6.95±0.70)mL·min^-1、(15.47±1.89)mL·min^-1，2者均有显著性差异。结论 该方法灵敏、准确、专一，适用于丝裂霉素C的药动学研究。与丝裂霉素C注射剂相比，双修饰壳聚糖载丝裂霉素C纳米粒具有缓释和长循环的作用。

Abstract:

OBJECTIVE To study the pharmacokinetics of dual conjugated chitosan-mitomycin C nanoparticles (CS-MMC-NPs) in rats. METHODS The two groups of rats were injected with CS-MMC-NPs and MMC injection at the dose of 4 mg·kg^-1. The concentrations of MMC in plasma at different time were determined by HPLC-MS and the main pharmacokinetic parameters were calculated. RESULTS The calibration curves were linear over the range of 20-1 000 μg·L^-1. The limit of quantitation was 20 μg·L^-1. The within day and day to day relative standard deviation(RSD) was <15%. The main pharmacokinetic parameters of CS-MMC-NPs and MMC injection were as follows: t_1/2 were (2.64±0.11)h and (0.49±0.049)h, AUC_0-∞ were (2.01±0.11)mg·h^-1·L^-1 and (0.93±0.075)mg·h^-1·L^-1, Vz were (1.52±0.18)L and (0.63±0.065)L, CL were (6.95±0.70)mL·min^-1 and (15.47±1.89)mL·min^-1. The differences of parameters were significant between two preparations. CONCLUSION The method is sensitive, accurate, specific for the pharmacokinetic study of CS-MMC-NPs. Compared with MMC injection, CS-MMC-NPs has a controlled releasing rate, a high level of blood concentrations and a long blood circulation time, which benefits the control of acute toxicity of MMC for the rats.