盐酸多奈哌齐鼻用温敏凝胶剂在大鼠脑组织内的药代动力学及脑靶向性研究  

Study on cerebral pharmacokinetics of donepezil hydrochloride thermo-sensitive nasal gel and its brain targeting in rats

作　　者：谷福根[1] 樊慧敏 丛志新 李爽 王毅[1] 吴春芝[1] GU Fu-gen;FAN Hui-min;CONG Zhi-xin;LI Shuang;WANG Yi;WU Chun-zhi(Department of Phramacy,The Affiliated Hospital of Inner Mongolia Medical University,Hohhot 010050,Inner Mongolia Autonomous Region,China;School of Pharmacy,Inner Mongolia Medical University,Hohhot 010110,Inner Mongolia Autonomous Region,China)

机构地区：[1]内蒙古医科大学附属医院药剂部,内蒙古自治区呼和浩特010050 [2]内蒙古医科大学药学院,内蒙古自治区呼和浩特010110

出　　处：《中国临床药理学杂志》2020年第19期3106-3109,共4页The Chinese Journal of Clinical Pharmacology

基　　金：内蒙古自然科学基金面上基金资助项目(2018MS08107)。

摘　　要：目的研究盐酸多奈哌齐(DPZ)鼻用温敏凝胶剂在大鼠脑组织内的药代动力学,并评价其脑靶向性。方法将110只雄性SD大鼠随机分为对照组和实验组,每组55只。对照组灌胃给予DPZ溶液,实验组鼻腔给予DPZ鼻用温敏凝胶剂,2组给药剂量均为10 mg·kg^-1,分别于不同时间断头处死大鼠,取嗅球(OB)、嗅束(OT)、大脑(CR)及小脑(CL)组织,用HPLC-荧光法测定不同脑组织匀浆中药物的浓度,用PKSolver2.0软件计算主要药代动力学参数。结果DPZ鼻用温敏凝胶剂鼻腔给药后,测得药物在大鼠OB、OT、CR及CL等脑组织的tmax分别为0.20,0.24,0.23和0.23 h,均远小于灌胃给药的1.40,1.40,1.80和1.80 h;Cmax分别为(2.28×10^4±3921.94),(1.89×10^4±4305.34),(1.03×10^4±1823.04)和(9920.49±2093.62)ng·g^-1,均显著大于灌胃给药的(1326.99±423.04),(1060.13±336.34),(746.26±121.94)和(645.91±168.14)ng·g^-1;AUC0-t分别为(1.89×10^4±835.15),(1.58×10^4±1371.32),(7990.08±1518.39)和(7577.04±1354.04)ng·h·g^-1,均显著大于灌胃给药的(2814.04±1194.74),(2519.24±987.04),(2125.42±581.89)和(1931.72±557.05)ng·h·g^-1,差异均有统计学意义(P<0.05或P<0.01)。鼻腔给药DPZ在OB、OT、CR及CL中的相对生物利用度分别为672%,706%,376%和392%。结论DPZ鼻用温敏凝胶剂经鼻腔给药,药物进入脑组织速度快,脑靶向性强,预期有良好的临床应用前景。Objective To study the pharmacokinetics of donepezil hydrochloride(DPZ)thermo-sensitive nasal gel in cerebral tissues of rats and further evaluate its brain targeting characteristics.Methods A total of 110 male SD rats were randomly divided into control and test groups,containing 55 animals per group.The animals of control group were intragastrically given DPZ solution and the drug thermo-sensitive nasal gel was nasally administered to the rats of test group,the dose for each group was 10 mg·kg^-1.The rats were decapitated at different time.The concentration of DPZ in homogenates of olfactory bulb(OB),olfactory tract(OT),cerebrum(CR)and cerebellum(CL)tissue were determined by HPLC-fluorescence method,and the main pharmacokinetic parameters were calculated by PKSolver2.0 software.Results The tmax values of the DPZ nasal gel for different brain tissues such as OB,OT,CR and CL were 0.20,0.24,0.23 and 0.23 h,all significantly less than 1.40,1.40,1.80 and1.80 h for intragastrical drug solution.However,Cm ax values of the nasal gel for all above brain tissues were(2.28×.104±3921.94),(1.89×.104±4305.34),(1.03×.104±1823.04)and(9920.49±2093.62)ng·g^-1,all significantly higher than(1326.99±423.04),(1060.13±336.34),(746.26±121.94)and(645.91±168.14)ng·g^-1 for the intragastrical route.Moreover,AUC0-t values of the nasal gel for all above brain tissues were(1.89×.104±835.15),(1.58×.104±1371.32),(7990.08±1518.39)and(7577.04±1354.04)ng·h·g^-1,significantly greater than(2814.04±1194.74),(2519.24±987.04),(2125.42±581.89)and(1931.72±557.05)ng·h·g^-1 for the intragastrical route.There were statistically significant differences in the above pharmacokinetic parameters between control and test groups(P<0.05 or P<0.01).The relative bioavailabilities of DPZ in OB,OT,CR and CL for the drug nasal gel were calculated to be 672%,706%,376%and 392%,respectively.Conclusion The DPZ thermo-sensitive gel following nasal administration is expected that the drug has a good clinical application prospect due to its fast en

关 键 词：盐酸多奈哌齐 鼻用温敏凝胶剂 大鼠 脑组织 药代动力学 脑靶向 

分 类 号：R97[医药卫生—药品]