两性霉素B复合磷脂纳米脂质体Beagle犬体内药动学研究

Study on Parmacokinetic of Amphotericin B Liposome in Beagle Dogs

目的采用LC-MS/MS测定Beagle犬血浆中两性霉素B的含量,研究受试物两性霉素B复合磷脂纳米脂质体(liposomal amphotericin B,L-AmB)和参比药物AmBisome在Beagle犬体内的药动学行为。方法选取成年健康Beagle犬12只,♀♂各半。采用双交叉试验设计,周期间洗脱期为2周。经前肢静脉注射给药(6 mg·kg^(−1),1.0 mg·mL^(−1)),采集给药前以及给药后各时间点血浆样品,应用经验证的LC-MS/MS方法测定血浆中两性霉素B浓度,DAS 2.1.1中求算药动学参数。结果Beagle犬静脉注射给予6 mg·kg^(−1)的受试物和参比药物后,动物体内两性霉素B的AUC_((0-t))分别为(705520±178252),(677310±166326)μg·h·L^(−1);C_(max)分别为(142683±29823),(121992±37983)ng·mL^(−1);t_(1/2)分别为(8.9±1.5),(9.7±0.6)h。结论L-AmB及参比制剂AmBisome在Beagle犬体内的药动学参数差异无统计学意义。

OBJECTIVE To establish an LC-MS/MS method for the determination of amphotericin B in plasma of Beagle dogs,and to study the pharmacokinetic parameters of liposomal amphotericin B(L-AmB)and reference drug(AmBisome)in Beagle dogs.METHODS Twelve adult healthy Beagle dogs,half male and half female,were selected.The design of double cross experiment was adopted,and the period of washout was 2 weeks,6 mg·kg^(−1)(1.0 mg·mL^(−1))was injected intravenously.The whole blood was collected before and different timepoints after administration.The concentration of amphotericin B in the plasma was determined by the validated LC-MS/MS method,and the pharmacokinetic parameters were calculated by DAS 2.1.1.RESULTS The main pharmacokinetic parameters of L-AmB and AmBisome were as follows:AUC_((0-t)) was(705520±178252),(677310±166326)μg·h·L^(-1);C_(max) was(142683±29823),(121992±37983)ng·mL^(-1);t_(1/2) was(8.9±1.5),(9.7±0.6)h.CONCLUSION There is no significant difference between the Beagle dogs after intravenous injection of L-AmB and the reference drug(AmBisome).