注射用依托泊苷纳米粒临床前的药动学及组织分布

Preclinical pharmacokinetics and tissue distribution of nanoparticle of etoposide for injection

目的比较试验制剂注射用依托泊苷纳米粒与参比制剂依托泊苷注射液的生物等效性及组织分布特征。方法比格犬随机交叉单次静脉注射给予试验制剂与参比制剂各10 mg.kg-1进行药动学试验,评价生物等效性。荷瘤小鼠(雌性)静脉注射给予25 mg.kg-1试验制剂与参比制剂,测定不同时间点各组织器官中的药物含量。药物浓度采用以替尼泊苷为内标的荧光检测法测定。结果试验制剂与参比制剂主要药动学参数分别为tmax:(1.500±0.000)、(1.500±0.000)h;ρmax:(3.033±0.644)、(3.323±0.552)mg.L-1;AUC(0-9.5 h):(5.566±0.592)、(7.173±0.920)h.mg.L-1。给药后5 min,注射用依托泊苷纳米粒在肝、肠、肌肉、脾及实体瘤中分布量较高,给药后3 h在实体瘤的含量显著高于参比制剂。结论试验制剂与参比制剂生物不等效,试验制剂在实体瘤中的含量高于参比制剂,静脉注射后3 h差异显著。

Objective To compare the bioequivalence and distribution of nanoparticle of etoposide for injection（T） and etoposide injection（R） in animals. Methods The randomized ,crossed-over study was conducted in beagles. A single dose of 10 mg.kg^-1 T and R were given by intravenous injection for pharmacokinetics and bioequiavailability studies. Tumor-bearing mouse（female） were given 25 mg.kg^-1 of T and R. The drug levels in plasma and tissues were determined by HPLC with fluorescence detection. Results The main pharmacokinetic parameters of T and R were as following ： tmax ： （ 1.500 ± 0. 000 ） h, （ 1. 500 ± 0. 000 ） h ;ρmax： （3.033 ±0. 644）mg.L^-1, （3.323 ±0. 552） mg.L^-1 ; AUC（0-0.95 h） ： （5.566 ± 0. 592） h·mg·L^-1, （7. 173 ±0. 920）h.mg.L^-1. Etoposide was high in liver, intestine, muscle, spleen and solid tumor 5 min after T was given. Three hours after injection, drug levels in tumor was significant higher in T groups than in R groups. Conclusions The results show that the two preparations are not bioequivalent. Etoposide in solid tumor is higher in T groups. Significant different is found 3 h after injection.