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

摘要

目的 研究盐酸阿霉素壳聚糖纳米粒(adriamycin hydrochloride 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-1 ADM)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.%Aim To investigate the brain pharmacoki-netics of adriamycin hydrochloride chitosan nanoparti-cles ( 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 microdial -ysis 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 hydro-chloride solution ( ADM-Sol) ( I. V. Or I. N. ). Thepharmacokinetic parameters were calculated and statis -tically 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-l, 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 pro -longs the drug retention time in cerebral fluids , resulting in more effective brain delivery of ADM compared with I. V. Administration.