氢溴酸樟柳碱注射液Beagle犬重复给药毒性试验及伴随毒代动力学试验  

Repeat doses toxicity study and accompanied toxicokinetic study of anisodine hydrobromide injection in Beagle dogs

作　　者：李勇 王峥屹 蒋文燕[1,2] 易勇 刘韵璐[1,2] 杨锋 杨娟[1,2] 兰明 万峰[3,4] LI Yong;WANG Zeng-yi;JIANG Wen-yan;YI Yong;LIU Yun-lu;YANG Feng;YANG Juan;LAN Ming;WAN Feng(Institute of Laboratory Animal Sciences,Sichuan Academy of Medical Sciences&Sichuan Provincial People′s Hospital,Chengdu Sichuan 610212,China;Department of Pharmacy,Sichuan Academy of Medical Sciences&Sichuan Provincial People′s Hospital,Chengdu Sichuan 610072,China;Chengdu First Pharmaceutical Co.Ltd.,Chengdu Sichuan 611930,China;Basic Medical College,Chengdu University of TCM,Chengdu Sichuan 610075,China)

机构地区：[1]四川省医学科学院四川省人民医院实验动物研究所,四川成都610212 [2]四川省医学科学院四川省人民医院药学部,四川成都610072 [3]成都第一制药有限公司,四川成都611930 [4]成都中医药大学基础医学院,四川成都610075

出　　处：《毒理学杂志》2021年第5期415-420,共6页Journal of Toxicology

基　　金：四川省科技支撑项目(2016sz0027)。

摘　　要：目的通过Beagle犬静脉注射重复给药毒性试验及伴随毒代动力学试验,评价氢溴酸樟柳碱注射液的安全性。方法将Beagle犬随机分为溶媒对照组和氢溴酸樟柳碱注射液2、6和20 mg/kg·bw剂量组,每组10只,静脉注射给药,连续26周,停药恢复6周。在给药第1、91和182天,静脉采血进行毒代动力学试验,测定不同时间点的血浆氢溴酸樟柳碱浓度,统计矩法计算氢溴酸樟柳碱在犬体内的毒代动力学参数。结果给药期间,无动物死亡,动物体重增长正常,各给药组均出现了瞳孔散大,鼻端、口唇、齿龈干燥,昏睡,心率加快和体温下降等症状,均为药物药理作用表现,其中,瞳孔散大、昏睡具有一定的剂量反应关系,20 mg/kg·bw剂量组甚至出现瞳孔对光反射消失。另外,20 mg/kg·bw剂量组动物血清Cl-水平升高,停药后恢复正常。在2~20 mg/kg·bw剂量范围内,氢溴酸樟柳碱犬体内暴露量未见性别差异,血浆消除较快,暴露量增加比例略高于剂量增加比例,多次用药蓄积分析表明其在犬体内无蓄积。结论氢溴酸樟柳碱注射液Beagle犬静脉注射重复给药毒性试验未见明显毒性反应剂量(NOAEL)为6 mg/kg·bw,约相当于临床剂量的36倍。并且,在伴随毒代动力学试验中,氢溴酸樟柳碱犬体内暴露量无性别差异,血浆消除较快,无蓄积性。提示氢溴酸樟柳碱注射液在临床剂量下使用具有较高的安全性。Objective To evaluate the safety of anisodine hydrobromide injection by repeated-dose toxicity study and accompanied toxicokinetic study in Beagle dogs.Methods Beagle dogs were randomly divided into solvent control group and the dose groups of 2,6 and 20 mg/kg·bw of anisodine hydrobromide injection,with 10 dogs in each group.The dogs were administered intravenously for 26 consecutive weeks and the drug withdrawal was resumed for 6 weeks.On day 1,91 and 182 of administration,the venous blood was collected for the toxicokinetic study,and the plasma concentration of anisodine hydrobromide at different time points was determined.The toxicokinetic parameters of anisodine hydrobromide in dogs were calculated by the statistical moment method.Results During the administration period,there was no animal death and the body weight of animals increased normally.Symptoms such as pupil dilation,dry nose,lips and gums,drowsiness,accelerated heart rate,and decreased body temperature appeared in each administration group,which were all pharmacological effects of the drug.Among them,pupil dilation and drowsiness had a certain dose-response relationship,in 20 mg/kg·bw group,the papillary light reflex disappeared even.In addition,the serum Cl-level increased in 20 mg/kg·bw group and returned to normal after drug withdrawal.In the dose range of 2-20 mg/kg·bw,there were no gender difference in the exposure of anisodine hydrobromide in dogs.The plasma elimination was rapid,and the proportion of internal exposure increase was slightly higher than that of extermal exposure increase.Multiple drug accumulation analysis showed that there was no accumulation in dogs.Conclusion The no observed adverse effect level(NOAEL)was found in repeated doses toxicity study of anisodine hydrobromide injection in Beagle dogs,which was 6 mg/kg·bw,about 36 times the clinical dose.In addition,in the accompanied toxicokinetic study,there was no gender difference in the exposure of anisodine hydrobromide in dogs,and the plasma elimination was rapid withou

关 键 词：氢溴酸樟柳碱 BEAGLE犬 重复给药毒性试验 毒代动力学试验 安全性 

分 类 号：R965.3[医药卫生—药理学] R99[医药卫生—药学]