盐酸阿霉素壳聚糖纳米粒大鼠鼻腔给药的脑内药动学研究

目的研究盐酸阿霉素壳聚糖纳米粒(adriamycinhydrochloride chitosan nanoparticles,ADM-CS-NPs)大鼠鼻腔给药后的脑内药动学特征。方法以壳聚糖为载体材料,采用离子交联法制备ADM-CS-NPs。以清醒自由活动大鼠为实验动物模型,采用脑微透析取样技术,连续收集ADM-CS-NPs及阿霉素溶液经鼻腔给药与静脉注射给药后大鼠海马部位透析液,HPLC法测定药物浓度,分析数据计算药动学参数。结果 ADM-CS-NPs经大鼠鼻腔和尾静脉注射给药(给药剂量为1.45 mg.kg-1ADM)后,Tmax分别为(300.00±26.12)和(180.00±19.11)min,Cmax分别为(93.00±8.53)和(19.11±1.91)mg·L-1,AUC0→11h分别为(17809.05±650.24)和(5159.97±120.59)mg·h·L-1,MRT分别为(390.49±6.87)和(281.53±4.99)min;ADM-Sol经大鼠鼻腔和尾静脉注射给药后,Tmax分别为(20.00±2.91)和(20.00±2.00)min,Cmax分别为(90.00±7.31)和(10.70±0.96)mg·L-1,AUC0→11h分别为(4736.70±53.40)和(312.68±4.99)mg·h·L-1,MRT分别为(73.43±2.37)和(23.39±1.32)min。结论 ADM-CS-NPs鼻腔给药可增加药物脑内浓度,有效实现脑内递药,同时由于纳米粒的缓释作用,可延长脑内有效药物浓度的持续时间,发挥长效作用。

On brain pharmacokinetics of adriamycin hydrochloride chitosan nanoparticles via intranasal administration in rats

Aim To investigate the brain pharmacokinetics of adriamycin hydrochloride chitosan nanoparticles(ADM-CS-NPs) via intranasal administration in rats.Methods ADM-CS-NPs were prepared by ion-facilitated gelation process.Hippocampus dialysate samples were continuously collected by brain microdialysis technique in awake freely-moving rats via intranasal or intravenous administration.The drug concentration in dialysates were detected by HPLC after administration of ADM-CS-NPs and adriamycin hydrochloride solution(ADM-Sol)(i.v.or i.n.).The pharmacokinetic parameters were calculated and statistically analyzed.Results The pharmacokinetic parameters of ADM-CS-NPs via i.n.and i.v.administration were as follows: Tmax were(300.00±26.12) and(180.00±19.11) min,Cmax were(93.00±8.53) and(19.11±1.91) mg·L-1,AUC0→11h were(17809.05±650.24) and(5159.97±120.59) mg·h·L-1,MRT were(390.49±6.87) and(281.53±4.99) min,respectively.The pharmacokinetic parameters of ADM-Sol via i.n.and i.v.administration were as follows: Tmax were(20.00±2.91) and (20.00±2.00) min,Cmax were(90.00±7.31) and(10.70±0.96) mg·L-1,AUC0→11h were(4736.70±53.40) and(312.68±4.99) mg·h·L-1,MRT were(73.43±2.37) and(23.39±1.32) min,respectively.Conclusion i.n.administration of ADM-CS-NPs both increases the drug concentration and prolongs the drug retention time in cerebral fluids,resulting in more effective brain delivery of ADM compared with i.v.administration.