万古霉素用药时间对小鼠肾脏及转运体的影响  

Effects of Vancomycin on Kidney and Transporters in Mice with Different Administration Time

作　　者：李泓静 杨巧玲 尹雪冬 孙华君[1] 李志玲[1] Li Hongjing;Yang Qiaoling;Yin Xuedong;Sun Huajun;Li Zhiling(Children’s Hospital of Shanghai,Children’s Hospital of Shanghai Jiao Tong University,Shanghai 200062,China;Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China)

机构地区：[1]上海市儿童医院,上海交通大学附属儿童医院,上海200062 [2]上海交通大学医学院,上海200025 [3]上海中医药大学中药研究所,上海201203

出　　处：《儿科药学杂志》2022年第3期1-5,共5页Journal of Pediatric Pharmacy

基　　金：国家自然科学基金青年科学基金资助项目,编号81603199;吴阶平医学基金会临床科研专项资助基金,编号320.6750.19090-1。

摘　　要：目的:探讨万古霉素(VCM)用药时间与小鼠肾毒性的相关性及其作用机制。方法:选取25只雄性C57BL/6小鼠随机分为VCM给药(600 mg/kg,腹腔注射,qd)1 d组、3 d组、7 d组、10 d组和空白对照组(生理盐水)各5只。末次给药后24 h,称取小鼠肾脏质量;采用全自动生化分析仪检测小鼠血清肌酐、尿素氮含量;苏木精-伊红染色观察小鼠肾脏组织形态学变化;液相色谱质谱联用技术(LC-MS)检测小鼠血清和肾脏中VCM浓度;实时荧光定量聚合酶链式反应(PCR)分析肾脏中转运体相关基因的mRNA表达情况。结果:与空白对照组相比,VCM能明显增加肾脏质量,引起肾功能损伤和肾脏病理结构变化,且有时间依赖性。VCM给药3 d后,在肾脏轻度蓄积;给药7 d后,在肾脏和血清中高度蓄积。VCM腹腔注射给药后,早期肾脏中有机阳离子转运体2(Oct2)、多药耐药相关蛋白2(Mrp2)mRNA水平上升,而在中后期肾脏中Oct1、Oct2、多药和毒素排泄蛋白1(Mate1)、有机阴离子转运体1(Oat1)、Oat3、Mrp2 mRNA水平下降,而Mrp4 mRNA水平无明显变化。结论:VCM腹腔注射给药3 d后开始造成肾脏损伤,且有药物蓄积在肾脏,其作用机制可能与影响肾脏转运体表达有关。Objective:To probe into the correlation between nephrotoxicity of vancomycin(VCM)in mice and administration time and its mechanism of action.Methods:Twenty-five male C57BL/6 mice were randomly divided into the VCM(600 mg/kg,intraperitoneal injection,qd)1 d group,VCM 3 d group,VCM 7 d group,VCM 10 d group and blank control group(normal saline),with 5 mice in each group.The kidney weight of each group was weighed after the last administration of 24 h.The levels of creatinine and urea nitrogen in serum of mice were determined by the automatic biochemical analyzer.The morphological and structural changes of kidney tissues were observed by hematoxylin-eosin staining.The concentrations of VCM in serum and kidney of mice were determined by liquid chromatography-mass spectrometer(LC-MS).The mRNA expression of transporter-related genes in kidney was analyzed by real-time polymerase chain reaction(PCR).Results:Compared with the blank control group,VCM significantly increased the kidney weight,induced the kidney function damage and kidney pathological changes in a time dependent manner.After 3 d of VCM administration,there was slight accumulation in the kidney.After 7 d of VCM administration,VCM was highly accumulated in the kidney and serum.After intraperitoneal injection of VCM,the mRNA levels of organic cation transporter 2(Oct2)and multidrug resistance associated protein 2(Mrp2)in the early kidney were up-regulated,the mRNA levels of Oct1,Oct2,multidrug and toxin-excreting protein 1(Mate1),organic anion transporter 1(Oat1),Oat3 and mRNA of Mrp2 in the middle and late kidney decreased significantly,while the mRNA levels of Mrp4 were not significantly changed.Conclusion:The mechanism of action of VCM may be related to the effects on kidney transporter expression as it starts to induce kidney damage 3 d after intraperitoneal administration,and there is drug accumulation in the kidney.

关 键 词：万古霉素 用药时间 肾毒性 药物浓度 转运体 

分 类 号：R965.3[医药卫生—药理学]