iv盐酸左氧氟沙星注射液Beagle犬毒动学及毒性研究  

Toxicokinetics and toxicity study of Levofloxacin Hydrochloride Injection administered intravenously in Beagle dogs

作　　者：张娜 房城 刘永武 朴成玉 董婉茹 安柏松 吴修红 ZHANG Na;FANG Cheng;LIU Yongwu;PIAO Chengyu;DONG Wanru;AN Baisong;WU Xiuhong(Drug Safety Evaluation Center,Heilongjiang University of Chinese Medicine,Harbin 150040,China)

机构地区：[1]黑龙江中医药大学药物安全性评价中心,黑龙江哈尔滨150040

出　　处：《药物评价研究》2021年第5期964-970,983,共8页Drug Evaluation Research

基　　金：国家自然科学基金(81803995,82004243);黑龙江省博士后资助(LBH-Z16196);黑龙江中医药大学博士创新科研基金项目(051761);黑龙江省中医药学会青年科技创新基金(ZHY19-013);黑龙江省自然科学基金(LH2020H081)。

摘　　要：目的评价盐酸左氧氟沙星注射液在Beagle犬体内的暴露情况及其对动物的长期毒性研究。方法建立Beagle犬血浆样品中左氧氟沙星的高效液相色谱(HPLC)检测方法;Beagle犬按分层随机法分为对照组和盐酸左氧氟沙星注射液低、高剂量(20、40 mg/kg,分别为人临床拟用剂量的2.33、4.67倍)组,每组8只。iv给药,对照组iv生理盐水,1次/d,给药期4周,恢复期4周。对Beagle犬首、末次给药后血浆样品进行分析测定,采用Winnolin 6.2.1采用非房室模型法(NCA)判定盐酸左氧氟沙星注射液对受试动物体内毒动学的影响。观察动物一般状态;采用生物机能实验系统,以Ⅱ导联记录Beagle犬给药前、给药期结束、恢复期结束Beagle犬在清醒状态下的心电图。结果首次给药后,雄性Beagle犬低、高剂量组C_(max)、AUC_(0-t)比值分别为1∶1.86和1∶2.19,MRT比值为1∶1.16,CL_F比值为1∶0.77,t_(1/2)比值为1∶1.44;末次给药后,低、高剂量组C_(max)、AUC_(0-t)比值分别为1∶3.73和1∶2.24,MRT比值为1∶0.87,CLF比值为1∶0.92,t_(1/2)比值为1∶0.94。首次给药后,雌性Beagle犬低、高剂量组C_(max)、AUC_(0-t)比值分别为1∶2.10和1∶2.12,MRT比值为1∶1.02,CL_F比值为1∶0.63,t_(1/2)比值为1∶1.05;末次给药后,低、高剂量组C_(max)、AUC_(0-t)比值分别为1∶1.88和1∶1.53,MRT比值为1∶0.67,CLF比值为1∶1.47,t_(1/2)比值为1∶0.66。盐酸左氧氟沙星注射液低剂量组动物给药第1周内出现困倦(2/8),皮肤水肿、发红(2/8),上睑松弛(1/8),唾液分泌过多(1/8),呕吐(1/8);给药第2~4周出现皮肤水肿(1/8)、发红(1/8);恢复期症状消失;高剂量组动物给药第1、2天出现上睑松弛(1/8),部分动物出现短期或长期的皮肤水肿(4/8)、困倦(5/8)、呕吐或干呕(6/8)、唾液分泌过多(7/8)、鼻有分泌物(2/8)、皮肤发红(2/8);给药第2、3周开始出现肌张力降低(2/8),偶尔出现大小便失禁(4/8);恢复期症状消失。给药前各组�Objective To analyze and determine plasma samples of Levofloxacin Hydrochloride Injection administered iv around Beagle dogs in order to evaluate its exposure in Beagle dogs and to provide reference for clinical studies on the toxicity of the donor to animals.Method An HPLC method was established for the determination of levofloxacin in plasma samples of Beagle dogs.Beagle dogs were randomly divided into control group and levofloxacin hydrochloride injection low and high dose(20 and 40 mg/kg,respectively,2.33 and 4.67 times of human clinical dose)groups,with eight dogs in each group.The control group was given normal saline,once a day,seven days a week.The administration period was four weeks and the recovery period was four weeks.Plasma samples were analyzed and measured after the first and last iv injections of levofloxacin hydrochloride injection in Beagle dogs,and Winnolin 6.2.1 was used to determine the effect of levofloxacin hydrochloride injection on the body of the test animals using the non-compartmental model(NCA)method.The general state of the animals was observed,and the ECG of beagle dogs in awake state was recorded with lead Ⅱ before administration,at the beging and end of administration period and at the end of recovery period.Results After the first administration,the C_(max) and AUC_(0-t) ratios of male Beagle dogs in the low and medium dose groups were 1:1.86 and 1:2.19 respectively,the MRT ratios was 1:1.16,the CLF ratio was 1:0.77,The t_(1/2) ratio was 1:1.44;After the last administration,the C_(max) and AUC_(0-t) ratio of low and medium dose groups were 1:3.73 and 1:2.24 respectively.the MRT ratio was1:0.87,the CLF ratio was 1:0.92,the t_(1/2) ratio was 1:0.94;After the first administration,the C_(max) and AUC_(0-t) ratios of female Beagle dogs were 1:2.10 and 1:2.12,respectively between the low and medium dose group.The MRT ratio was 1:1.02,the ratio of CLF was 1:0.63,the t_(1/2) ratio was 1:1.05;After the last administration,the C_(max) and AUC_(0-t) ratios of low and medium dose groups w

关 键 词：左氧氟沙星 毒动学 毒性 一般状态 心电图 

分 类 号：R969.1[医药卫生—药理学]