两性霉素B脂质体药代动力学及组织分布研究

目的：测定血浆及组织中两性霉素B的浓度,并比较受试与参比两性霉素B脂质体在犬体内药代动力学性质及大鼠主要组织分布特性。方法：6只犬静脉随机、交叉给予受试及参比药物,剂量为5 mg/kg,在不同时间点采集血浆样品;大鼠同样剂量静脉给予受试及参比药物,在给药后不同时间点取组织样品。用HPLC法测定生物样品中两性霉素B浓度,并用DAS 2.0软件拟合求算药代动力学参数。结果：犬i.v.给药两性霉素B脂质体后血药浓度-时间曲线符合二室模型,主要药代动力学参数为,受试药物：t1/2β（53.6±2.2）h,AUC（18.7±3.2）mg·L^-1.h,CL（0.23±0.05）L·h^-1·kg^-1,V1（11.6±2.8）L/kg;参比药物：t1/2β（52.8±0.9）h,AUC（19.6±2.2）mg·L^-1.h,CL（0.22±0.03）L·h^-1·kg^-1,V1（10.6±2.9）L/kg。结论：对上述参数以SAS统计软件进行双侧t检验,结果表明给予受试及参比药物后犬主要药代动力学参数差异无统计学意义（P〉0.05）。对各时间点主要脏器的药物浓度进行比较,差异无统计学意义（P〉0.05）。

Pharmacokinetics and distribution of amphotericin B liposome in animals

AIM: To determine amphotericin B concentrations in plasma and tissues and to compare the pharmacokinetic profile in dogs and distribution profile in SD rats main tissues of test and reference amphoteri-cin B liposome. METHODS:Six dogs were intraveno-usly administered of 5 mg/kg test and reference prepa-rations in an randomized cross-over study. Blood sam-ples were collected at various time-points after drug ad-ministration. Rats were intravenously administered of 5 mg/kg test and reference preparations, tissues were collected at various time-points after drug administra-tion. Analytical method based on HPLC method was established to determine the plasma and tissue concen-tration. The pharmacokinetic evaluation was carried out using the DAS 2.0 program. RESULTS:Six dogs were intravenously administered of 5 mg/kg amphotericin B liposome, and an open two compartment model best de-scribed the concentration-time profiles for amphotericin B liposome. The main pharmacokinetic parameters were t_(1/2β)(53.6±2.2) h, AUC(18.7±3.2) mg·L~(-1)·h; CL(0.23±0.05) L·h~(-1)·kg~(-1), V_1(11.6±2.8) L/kg for the test preparation and t_(1/2β) (52.8±0.9) h, AUC(19.6±2.2) mg·L~(-1)·h, CL(0.22±0.03) L·h~(-1)·kg~(-1), V_1(10.6±2.9) L/kg for the reference preparation. CONCLUSION: The statisties analysis shows that there are no significant differences (P > 0.05) between the test and reference preparation in major pharmaeokinetie parameters in dogs and tissue distribution in rats.