注射用伏立康唑前药的遗传及生殖毒性研究  

Genotoxicity and reproductive toxicity studies of Voriconazole prodrug for injection

作　　者：刘晶[1] 杨欢欢[1] 蔡鸣[2] 侯艳[2] 

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

出　　处：《华西药学杂志》2016年第4期378-381,共4页West China Journal of Pharmaceutical Sciences

摘　　要：目的研究注射用伏立康唑前药(Voriconazole prodrug,VP)的遗传及生殖毒性。方法分别采用Ames试验、中国仓鼠肺细胞(CHL)染色体畸变试验、小鼠骨髓微核试验,观察VP的遗传毒性,并通过伴随毒动学试验了解其血浆暴露量;生殖毒性研究了注射用VP对SD大鼠胚胎-胎仔发育毒性的影响,于SD大鼠妊娠第6~15天连续iv给药(30、60、120 mg·kg^(-1)·d-1),于妊娠第20天剖检,分析其生殖毒性。结果遗传毒性的Ames试验、CHL试验和微核试验中,结果均显示为阴性;伴随毒动学试验表明:受试物在小鼠体内呈线性消除;胚胎-胎仔发育毒性试验中,受试物高剂量组中胎鼠头颅骨和/或胸骨异常的数量与溶媒对照组相比显著增加。结论注射用VP未见明显遗传毒性;受试物在120 mg·kg^(-1)剂量下对胎鼠骨骼发育有一定的毒性作用,未见其他生殖毒性。OBJECTIVE To investigate the genotoxicity and reproductive toxicity of Voriconazole prodrug（VP） for injection and to provide toxicological information for further clinical application. METHODS Genotoxieity studies consisted of Ames test, chromosome aberration test of CHL and micronucleus test. In addition,the toxicokinetic test was used to analyze the concentration of drugs in mice. The reproductive toxicity study was mainly to investigate the effects of VP for injection on embryo - fetal development in Sprague - Dawley rats when administered by intravenous injection from gestation day（GD） 6 to 15 at the dosages of 30,60 and 120 mg·kg^-1·d^-1. Pregnant rats were subjected to necropsy and caesarean section on GD20 to evaluate the reproductive toxicity of VP. RESULTS The genotoxicity studies including Ames test, CHL test and micronucleus test,all indicated negative results;the toxicokinetic test showed that the elimination of VP and its metabolite in the mice were linear. In embryo - fetal development study, the number of abnormal fetal skull and/or sternum was significantly increased in high - dose group, compared with the vehicle control group. CONCLUSION The present data shows that VP for injection canproduce no significant genotoxic effects in the mice,but it has a certain toxicity on fetal bones at the dose of 120 mg·kg^-1·d^-1 ,and no other reproductive toxicity has been found.

关 键 词：伏立康唑 遗传毒性 生殖毒性 毒动学 代谢物 前体药物 

分 类 号：R96[医药卫生—药理学]