盐酸纳美芬鼻喷剂在大鼠体内的药动学及纤毛毒性研究  

Pharmacokinetics and ciliary toxicity of nalmefene hydrochloride nasal spray in rats

作　　者：张婷 李蒙 范冉冉 孙文军 王荣荣 高静 聂广军 郑爱萍 ZHANG Ting;LI Meng;FAN Ran-ran;SUN Wen-jun;Wang Rong-rong;GAO Jing;NIE Guang-jun;ZHENG Ai-ping(School of Basic Medical Sciences,Zhengzhou University,Zhengzhou 450001;Institute of Pharmacology and Toxicology,Academy of Military Medical Sciences,Academy of Military Sciences,Beijing 100850)

机构地区：[1]郑州大学基础医学院,郑州450001 [2]军事科学院军事医学研究院毒物药物研究所,北京100850

出　　处：《中南药学》2023年第1期1-6,共6页Central South Pharmacy

基　　金：国家科技重大专项(No.2018ZX09721003-007)。

摘　　要：目的建立LC-MS/MS法测定大鼠血浆中盐酸纳美芬的浓度,研究盐酸纳美芬鼻喷剂在大鼠体内的生物利用度及纤毛毒性。方法以盐酸纳美芬静脉注射为对照组,大鼠经鼻腔给药后,采用LC-MS/MS法测定血药浓度,并使用WinNonlin 5.2.1软件计算主要药动学参数。以离体蟾蜍上颚和大鼠鼻黏膜为模型,考察盐酸纳美芬经鼻给药后纤毛持续摆动时间及黏膜形态的变化。结果盐酸纳美芬在0.05~2.5μg·mL^(-1)内与峰面积线性关系良好(r=0.9999),定量下限为0.05μg·mL^(-1);回收率在96.81%~102.55%;日间和日内精密度的RSD分别在3.7%~5.5%和0.99%~7.0%,准确度(RE)在1.51%~7.13%;血浆样品稳定性良好。盐酸纳美芬鼻喷剂起效迅速,t_(max)约为1 min,绝对生物利用度可达81.64%。在蟾蜍上颚模型中观察到纤毛排列整齐,呈流水状摆动,相对运动百分率为66.52%,纤毛停止摆动后经生理盐水冲洗又可恢复摆动;在大鼠鼻黏膜模型中观察到,与生理盐水组相比,仅有少量纤毛出现簇状聚集和脱落现象。结论建立的LC-MS/MS法快速高效、专属性强、灵敏度高。盐酸纳美芬鼻喷剂在大鼠体内起效迅速、生物利用度高;其对离体蟾蜍上颚和大鼠鼻黏膜纤毛毒性小。Objective To establish an LC-MS/MS method to determine the concentration of nalmefene hydrochloride in rat plasma,and the bioavailability and ciliary toxicity of nalmefene hydrochloride nasal spray in rats.Methods Intravenous injection of nalmefene hydrochloride was used as the control.After the intranasal administration,the plasma concentration was determined by LC-MS/MS method,and main pharmacokinetic parameters were calculated by WinNonlin 5.2.1 software.With the isolated toad upper jaw and rat nasal mucosa as models,the continuous oscillation time of cilia and the changes of mucosal morphology after nasal administration of nalmefene hydrochloride were measured.Results The linear relationship of nalmefene hydrochloride was good at 0.05~2.5μg·m L^(-1)(r=0.9999),and the lower limit of quantification was 0.05μg·mL^(-1).The recovery rate was between 96.81%and 102.55%.The RSD of inter-day and intra-day precisions were 3.7%~5.5%and 0.99%~7.0%,respectively,and the accuracy was between 1.51%and 7.13%.The stability of plasma samples was good.Nalmefene hydrochloride nasal spray has a rapid onset of action,and t_(max) was 1 min and absolute bioavailability was 81.64%.In the toad upper jaw model,the cilia were neatly arranged and swayed like flowing water.The relative movement percentage was 66.52%.If the cilia stopped swinging,they were restored to swing after being washed with saline.In the rat nasal mucosa model,compared with the saline group,only a few cilia clustered and fell off.Conclusion The LC-MS/MS method is fast,efficient,specific and sensitive.Nalmefene hydrochloride nasal spray has a rapid onset of action with high bioavailability in rats.Its toxicity to isolated toad palate and rat nasal mucociliary is small.

关 键 词：盐酸纳美芬 鼻喷剂 药动学 纤毛毒性 绝对生物利用度 

分 类 号：R969.1[医药卫生—药理学]