氘代沃替西汀氢溴酸盐对家兔胚胎-胎仔发育毒性的研究  

Embryo-fetal development toxicity of deuterated Vortioxetine hydrobromide on rabbit

作　　者：张玉堂 舒斌[1] 蔡鸣[1] 张逸民 邵卿[1] 袁艳娟 乔红群[2] 刘晶[1] ZHANG Yutang;SHU Bin;CAI Ming;ZHANG Yimin;SHAO Qing;YUAN Yanjuan;QIAO Hongqun;LIU Jing(Jiangsu Institute of Materia Medica,Nanjing,Jiangsu,210009 P.R.China;School of Pharmacy,Nanjing University of Technology,Nanjing,Jiangsu,211816 P.R.China)

机构地区：[1]江苏省药物研究所,江苏南京210009 [2]南京工业大学药学院,江苏南京211816

出　　处：《华西药学杂志》2021年第3期289-294,共6页West China Journal of Pharmaceutical Sciences

基　　金：江苏省政策引导类计划(产学研合作)—前瞻性联合研究项目(BY2016005-10)。

摘　　要：目的观察灌胃给予氘代沃替西汀氢溴酸盐(DVH)对家兔胚胎-胎仔发育的影响及其毒代动力学。方法将孕兔随机分为空白组(溶媒)、阳性对照组(10 mg·kg^(-1)注射用环磷酰胺)和低、中、高剂量DVH组(2.4、8、24 mg·kg^(-1)DVH),在妊娠GD 6~18时灌胃给药,GD 29时处死家兔,记录各项指标,并检测孕兔的血药浓度以及DVH在孕兔和胎兔体内的组织分布。结果高剂量DVH组孕兔GD 9时的耗食量小于空白组;高剂量DVH组胎兔体重低于空白组,顶臀长度明显较空白组短,高、中剂量DVH组胎兔产生的骨骼发育变异情况也较空白组有明显增加。在2.4~24 mg·kg^(-1)DVH剂量范围内,给予DVH后的原形药物及羧基代谢产物在孕兔血浆内Cmax呈非线性动力学特征。DVH及其羧基代谢产物可透过胎盘屏障,胎仔体内的脏器分布趋势与母体不同,DVH及其羧基代谢产物在胎免体内以肺脏含量最高。结论在试验条件下,24 mg·kg^(-1)及以下剂量的DVH未对孕兔母体产生明显毒性,2.4 mg·kg^(-1)DVH未对胎兔产生明显毒性。DVH可透过孕兔胎盘屏障,母体与胎仔的组织分布情况相似。OBJECTIVE To study embryo-fetal developmental toxcity of deuterated Vortexitin hydrobromide(DVH)and its toxicokinetics on rabbit.METHODS Pregnant rabbits were randomly divided into normal control(NC)group(vehicle),positive control group(cyclophosphamide for injection of 10 mg·kg^(-1))and DVH low,medium and high dose groups(2.4,8 and 24 mg·kg^(-1) DVH).Pregnant rabbits were administrated by gavage at GD 6-18 and sacrificed on GD 29.All indexes were recorded and plasma drug concentration of pregnant rabbits as well as tissue distribution of DVH in maternal and fetal rabbits were detected.RESULTS The food consumption on GD 9 of high dose group was less than that of NC group.The body weight of fetal rabbits in high dose group was lower than that in NC group,the crown-rump length was significantly shorter than that in NC group,and the skeletal development variation of fetal rabbits in high and medium dose groups was also significantly increased than that in NC group.Across the dose range of 2.4-24 mg·kg^(-1),the Cmax of the proto-drug and carboxyl metabolites after administration of DVH showed nonlinear dynamic characteristics in the plasma of pregnant rabbits.DVH and its carboxyl metabolites were able to pass through the placental barrier,and the distribution trend of organs in the fetus is different from that of the maternal.The DVH and its carboxyl metabolites have the highest content in lung of the fetus.CONCLUSION Under the experimental conditions,24 mg·kg^(-1) or less of DVH do not bring about obvious toxicity to pregnant rabbits,and 2.4 mg·kg^(-1) of it do not have obvious toxicity to fetal rabbits.TK study show that the DVH is able to pass through the placenta barrier,and the tissue distributions of both maternal and fetal rabbits are similar.

关 键 词：氘代沃替西汀氢溴酸盐 家兔 灌胃 胚胎-胎仔发育毒性 伴随毒动学 胎盘屏障 组织分布 代谢产物 

分 类 号：R96[医药卫生—药理学]