加替沙星眼用凝胶不同点眼频次兔眼组织药代动力学比较  

Comparison of the pharmacokinetics of gatifloxacin ophthalmic gel in rabbit ocular tissues with different dosing frequencies

作　　者：王小桐 赵欣 祖薇 沈旭 陈世超 杨强[1] Wang Xiaotong;Zhao Xin;Zu Wei;Shen Xu;Chen Shichao;Yang Qiang(Shenyang Xingqi Pharmaceutical Co.,Ltd.,Shenyang 110164,China)

机构地区：[1]沈阳兴齐眼药股份有限公司,沈阳110164

出　　处：《中华实验眼科杂志》2024年第7期621-628,共8页Chinese Journal Of Experimental Ophthalmology

摘　　要：目的建立一种测定兔眼组织中加替沙星浓度的方法,并比较加替沙星眼用凝胶兔眼单次和多次点眼后在眼组织及血浆中的药代动力学特征。方法取94只健康新西兰兔。任意选取10只新西兰兔不给予任何药物用于空白组织获取,将剩余84只按照随机数字表法随机分成单次给药组36只和多次给药组48只,雌雄各半,均取左眼为实验眼。单次给药组左眼给予1滴加替沙星眼用凝胶,分别于点眼后0.5、1、3、5、7、10 h收集泪液后进行心脏取血并处死,分别取房水、结膜、角膜、巩膜、虹膜-睫状体、晶状体、玻璃体、视网膜和脉络膜;多次给药组左眼每次给予1滴加替沙星眼用凝胶,每天3次,分别于连续给药第4和第6天首次给药后0.5 h,第7天首次给药后0.5、1、3、5、7、10 h进行心脏取血和眼组织收集。采用甲醇沉淀蛋白法预处理各样本,采用高效液相色谱串联质谱法测定并计算实验兔血浆及眼组织中加替沙星的达峰浓度(C_(max))、达峰时间(T_(max))、曲线下面积(AUC)等药代动力学参数,流动相采用甲醇-0.1%乙酸水溶液(体积比=70∶30),采用正离子多反应检测模式,以环丙沙星为内标物,并参照《中国药典》(2020年版)9012生物样品定量分析方法验证指导原则对方法的选择性、标准曲线和定量下限、准确度和精密度、提取回收率和基质效应、稳定性进行验证。结合加替沙星对眼部常见感染菌的最小抑菌浓度(MIC_(90)),计算各组织和血浆C_(max)/MIC_(90)和AUC/MIC_(90)值。结果加替沙星在各眼组织和血浆中线性关系良好;角膜组织中的日间准确度为-1.5%~6.0%,日间精密度≤15%;角膜组织中的提取回收率为92.0%~94.8%,经内标归一化计算得到的低、中、高浓度的基质效应精密度均不大于3.3%,单次给药后加替沙星在眼前节和后节组织均有较高的药物浓度分布,AUC 0-t从高到低分别为泪液、角膜、结膜、虹膜-睫Objective To establish a method for determining the concentration of gatifloxacin in rabbit ocular tissue and compare the ocular pharmacokinetics of 0.3%gatifloxacin eye gel after a single and multiple topical instillations in rabbits.Methods Ninety-four healthy New Zealand rabbits were selected.Ten rabbits were randomly selected without any treatment for blank tissue collection,and the remaining 84 rabbits were randomly divided into a single-dose group(36 rabbits)and a multiple-dose group(48 rabbits)equally between males and females using a random number table.The left eye was taken as the experimental eye.The single-dose group was given one drop of 0.3%gatifloxacin eye gel into the left eyes,and the rabbits were divided evenly into six subgroups.In each subgroup,tear specimens and blood specimens were collected at 0.5,1,3,5,7,10 hours after gel application,then cardiac blood samples were taken,after which animals were sacrificed immediately to collect ocular tissue including aqueous humor,conjunctiva,cornea,sclera,iris-ciliary body,lens,vitreous body,retina,and choroid.The multiple-dose group was given 1 drop of gatifloxacin ophthalmic gel in the left eye three times a day.At 0.5 hour after the first administration days 4 and 6,and 0.5,1,3,5,7,and 10 hours after the first administration on day 7,the cardiac blood sampling and ocular tissue collection were performed.The methanol precipitation protein method was used to pretreat samples,and the concentration of gatifloxacin in rabbit plasma and eye tissue was measured and calculated by high-performance liquid chromatography-tandem mass spectrometry method to obtain pharmacokinetic-related parameters such as peak concentration(C_(max)),peak time(T_(max)),and area under curve(AUC).The mobile phase was a methanol-0.1%acetic acid aqueous solution(volume ratio=70∶30),and a positive ion multiple reaction detection mode was used.Ciprofloxacin was used as the internal standard,the selectivity,standard curve and lower limit of quantification,accuracy and precision,extra

关 键 词：加替沙星 眼用凝胶 高效液相色谱串联质谱法 兔 药代动力学 

分 类 号：R969.1[医药卫生—药理学]