大鼠多次给予染料木素甲氧基封端的聚乙二醇-乳酸羟基乙酸共聚物胶束的药动学研究  

Pharmacokinetic study of genistein-loaded methoxy-terminated polyethylene glycol-lactic acid glycolic acid copolymer micelles after multiple dosing in rats

作　　者：何礼[1] 韩瑞伟[1] 阎雪莹[2] HE Li;HAN Ruiwei;YAN Xueying(Laboratory for Medicinal Resources and Utilization in Northwest Sichuan,Sichuan University of Traditional Chinese Medicine,Sichuan Province,Mianyang621000,China;College of Pharmacy,Heilongjiang University of Traditional Chinese Medicine,Heilongjiang Province,Harbin150040,China)

机构地区：[1]四川中医药高等专科学校川西北药用资源研究与开发利用实验室,四川绵阳621000 [2]黑龙江中医药大学药学院,黑龙江哈尔滨150040

出　　处：《中国医药导报》2020年第15期17-21,共5页China Medical Herald

基　　金：黑龙江省教育厅研究生创新科研项目(YJSCX2011-459HLJ);四川中医药高等专科学校科研项目(17ZRYB01、19ZRYB05)。

摘　　要：目的讨论染料木素(GEN)甲氧基封端的聚乙二醇-乳酸羟基乙酸共聚物(MePEG-PLGA)胶束多次给药在健康大鼠体内的药动学行为。方法将24只健康Wistar大鼠按体重分成四组,每组6只,分别为GEN乳剂组,GEN胶束低、中、高剂量组。每组分别多次尾静脉注射GEN乳剂和GEN胶束,乳剂剂量为40 mg/kg,胶束剂量分别为20、40、60 mg/kg。采用高效液相色谱法(HPLC)测定给药后不同时间点血浆中GEN浓度。结果GEN乳剂组和GEN胶束组最小血药浓度(Cmin)、半衰期(t1/2)、药时曲线下面积(AUC0~t)、清除率(CL)、波动系数(DF)比较,差异均有高度统计学意义(P<0.01);GEN胶束低、中和高3个剂量组主要药动学参数Tmax、t1/2、CL、表观分布容积(Vd)和DF比较,差异无统计学意义(P>0.05)。与GEN胶束低剂量组比较,GEN胶束中剂量组最大血药浓度(Cmax)、AUC0~t升高,与GEN胶束低、中剂量组比较,GEN胶束高剂量组Cmax、AUC0~t升高,差异均有高度统计学意义(均P<0.01)。GEN胶束各剂量组AUC0~t、AUC0-∞、Cmax、平均稳态浓度(Cav)随给药剂量增大而增加,差异有高度统计学意义(P<0.01),AUC0-t、AUC0-∞、Cmax、Cav与剂量呈线性关系(r>0.97)。在相同剂量下,单次和多次给药后的主要药动学参数Cmax、t1/2、AUC0~t、CL、Vd、MRT0~t差异无统计学意义(P>0.05)。结论GEN胶束能明显延迟GEN在大鼠体内滞留时间,提高生物利用度,且血药浓度与剂量呈线性关系,多次给药后在大鼠体内不存在蓄积现象。Objective To discuss the pharmacokinetic behavior of genistein(GEN)methoxy-terminated polyethylene glycol-lactic acid glycolic acid copolymer(MePEG-PLGA)micelles administered multiple times in healthy rats.Methods Twenty-four healthy Wistar rats were randomly divided into four groups according to their body weight,with 6 rats in each group,namely the GEN emulsion group and the GEN micelle low,medium and high dose groups.In each group,GEN emulsion and GEN micelles were injected into the tail vein several times,respectively,with the emulsion dose of 40 mg/kg and the micelle dose of 20,40 and 60 mg/kg.The high performance liquid chromatography(HPLC)was used to analysis drug delivery in different time points after plasma GEN concentration.Results The differences in minimum blood drug concentration(Cmin),half-life(t1/2),area under the curve(AUC0-t),clearance rate(CL)and fluctuation coefficient(DF)between GEN emulsion group and GEN micelles group were statistically significant(P<0.01).There were no statistically significant differences in the major pharmacokinetic parameters Tmax,t1/2,CL,apparent distribution volume(Vd)and DF in the GEN micelles groups with low,medium and high doses(P>0.05).Compared with the low-dose group of GEN micelles,the maximum blood concentration(Cmax)and AUC0-t in the medium-dose group of GEN micelles were increased,while the Cmax and AUC0-t in the high-dose group of GEN micelles were increased compared with the low-dose and medium-dose group of GEN micelles,and the differences were highly statistically significant(all P<0.01).The differences of AUC0-t,AUC0-∞,Cmax and average steady stateconcentration(Cav)in each dose group of GEN micelles increased with the increase of the dose(P<0.01),and there was a linear relationship between AUC0-t,AUC0-∞,Cmax and Cav and the dose(r>0.97).There were no significant differences in the major pharmacokinetic parameters Cmax,t1/2,AUC0-t,CL,Vd,MRT0-t between single and multiple doses at the same dose(P>0.05).Conclusion GEN micelles can significantly delay th

关 键 词：染料木素 MePEG-PLGA胶束 多次给药 药动学 

分 类 号：R969.1[医药卫生—药理学]