载异烟肼、利福平白蛋白纳米粒在兔体内的药代动力学研究

Study on pharmacokinetics of albumin nanoparticles loaded with isoniazid and rifampicin in rabbits

中文关键词:  异烟肼  利福平  白蛋白  纳米粒  药代动力学

英文关键词:Isoniazid  Rifampicin  Albumin  Nanoparticles  Pharmacokinetics

中文摘要:

  【摘要】 目的：研究载异烟肼（Isoniazid，INH）、利福平（Rifampicin，RFP）牛血清白蛋白（Bovine serum albumin,BSA）纳米粒经新西兰大白兔静脉给药后的体内药代动力学特征及其相关参数。方法：16只新西兰大白兔随机分为2组：纳米粒组8只，INH、RPP对照组8只。经耳缘静脉分别滴注等计量的载INH、RFP白蛋白纳米粒和普通对照品（INH 11.43mg/kg、RFP 12mg/kg）。采用高效液相色谱分析方法测定各自INH、RFP的血浆药物浓度。对比研究静脉给药后两种剂型药物在不同时间（0、0.5、1、1.5、2、2.5、3、4、6、8、12、24、36、48、72、96、120h）兔体内的血浆药代动力学参数，包括最大血药浓度（Cmax）、生物半衰期（T1/2）、血药浓度时间曲线下的面积（AUC）及体内平均驻留时间（MRT），以DAS 2.0药动学程序进行血药浓度数据拟合分析。结果：给药后两组药物的血药浓度-时间曲线显示：纳米粒药组INH、RFP血药浓度相对稳定，药物浓度持续缓慢下降，给药后96h INH仍能检测到，RFP则为48h。INH的Cmax=9.79±1.38（mg/L），T1/2=28.10±6.69（h），AUC=22.34±8.81（mg/L·h），MRT=15.13±5.48（h）；RFP的Cmax=16.79±3.74（mg/L），T1/2=14.13±3.78（h），AUC=116.64±66.26（mg/L·h），MRT=15.89±2.49（h）。对照组中INH的Cmax=9.52±2.19（mg/L），T1/2=1.92±0.80（h），AUC=20.97±3.11（mg/L·h），MRT=2.03±0.62（h）；RFP的Cmax=12.50±1.58（mg/L），T1/2=2.87±0.78（h），AUC=50.05±14.50（mg/L·h），MRT=3.70±0.99（h）。对照组INH、RFP血药浓度快速下降，分别在给药后24h和12h检测不到。结论：载异烟肼、利福平白蛋白纳米粒在兔体内的药代动力学过程符合双隔室模型（权重系数为1/cc）。白蛋白纳米粒可有效改变异烟肼和利福平的药动学行为并具有显著的缓释效果。

英文摘要:

  【Abstract】 Objectives: To study the pharmacokinetics characteristics and the relevant pharmacokinetic parameters of albumin nanoparticles loaded with isoniazid and rifampicin(INH-RFP-BSA-NPs) of the New Zealand rabbits after intravenous administration. Methods: Sixteen New Zealand rabbits were divided into 2 groups randomly as below, INH-RFP-BSA-NPs group(NPs group, 8 rabbits), control group(CON group, 8 rabbits). The rabbits in two groups were injected with NPs and common injection of INH and RFP according to the dosage of INH 11.43mg/kg, RFP 12mg/kg via ear veins, respectively. Then blood samples were obtained at certain time points(0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120h). High performance liquid chromatography(HPLC) was used to determine the concentrations of INH and RFP of plasma. Software program of DAS2.0 was used to study the difference of pharmacokinetic parameters. The pharmacokinetic parameters included maximal blood concentration(Cmax), biological half-life(T1/2), area under the time curve of blood concentration(AUC) and the mean retention time in the body(MRT). Results: The concentration of INH and RFP in NPs group was relatively stable with a sustained decline, it could be detected at 96 hours for INH and at 48 hours for RFP respectively after administration. The isoniazid pharmacokinetic parameters of NPs were as follows: Cmax=9.79±1.38(mg/L), T1/2=28.10±6.69(h), AUC=22.34±8.81(mg/L·h), MRT=15.13±5.48(h); thoses of rifampicin were Cmax=16.79±3.74(mg/L), T1/2=14.13±3.78(h), AUC=116.64±66.26(mg/L·h), MRT=15.89±2.49(h). While in control group, the plasma concentration of INH and RFP decreased rapidly and could not be detected at 24h and at 12h after administration, respectively. Meanwhile the isoniazid pharmacokinetic parameters in CON group were as follows: Cmax=9.52±2.19(mg/L), T1/2=1.92±0.80(h), AUC=20.97±3.11(mg/L·h), MRT=2.03±0.62(h); those of rifampicin were Cmax=12.50±1.58(mg/L), T1/2=2.87±0.78(h), AUC=50.05±14.50(mg/L·h)， MRT=3.70±0.99(h). Conclusions: The INH-RFP-BSA-NPs pharmacokinetics in rabbits process in line of double compartment model, albumin nanoparticles can effectively improve the pharmacokinetic behavior and has the advantage of significant prolonged release effect in vivo．