不同结构头孢菌素类药物引起双硫仑样反应机制研究  

A study on the mechanism of disulfiram-like reactions induced by cephalosporins with different structures

作　　者：李耀光 刘聪颖 章雯 张枫林 牛卫芬 曹洁[1,2,3] 尉志文 贠克明[1,2,3] 贾娟 Li Yaoguang;Liu Congying;hang Wen;Zhang Fenglin;Niu Weifen;Cao Jie;Wei Zhiwen;Yun Keming;Jia Juan(Shanxi Medical University,Jinzhong City,Shanxi Province,030600;Key Laboratory of Forensic Toxicology Analysis,Ministry of Public Security,Jinzhong City,Shanxi Province,030600;Key Laborary of forensic Medicine in Shanxi Province,Jinzhong Shanxi 030600)

机构地区：[1]山西医科大学法医学院,山西晋中030600 [2]法庭毒物分析公安部重点实验室,山西晋中030600 [3]法医学山西省重点实验室,山西晋中030600

出　　处：《中国法医学杂志》2024年第2期192-195,202,共5页Chinese Journal of Forensic Medicine

基　　金：国家自然科学基金重点资助项目(82130056)。

摘　　要：目的研究头孢哌酮和头孢他啶这两种具有不同结构的头孢菌素类药物与乙醇联合作用产生双硫仑样反应(disulfiram-ethanol reaction,DLR)的机制是否存在差异。方法建立头孢哌酮和头孢他啶给药后饮酒产生双硫仑样反应的中毒模型。检测血液中不同时间点乙醇、乙醛浓度,DAS3.2.8药代动力学软件计算毒物代谢动力学参数。测定肝脏乙醇脱氢酶(alcohol dehydrogenase,ADH)和乙醛脱氢酶(aldehyde dehydrogenase,ALDH)活性水平。结果头孢哌酮与乙醇联合使用后,会增大乙醇的最大血药浓度,引起乙醛在血液中的蓄积。在头孢哌酮用药0 d,3 d后都可以检测到肝脏ALDH活性被抑制。头孢他啶对乙醇和乙醛的代谢无明显影响,且肝脏ADH、ALDH活性未发生明显改变。结论通过头孢哌酮和头孢他啶给药后饮酒大鼠血液中乙醇、乙醛代谢数据,以及肝脏ADH、ALDH活性的变化,可表明头孢哌酮引起双硫仑样反应主要由于对肝脏ALDH活性的抑制,而头孢他啶无相同作用。结果显示不同结构的头孢菌素类药物与乙醇联合作用,产生双硫仑样反应的机制不同。Objective To investigate whether there is a difference in the mechanism of disulfiram-ethanol reaction(DLR)produced by the combination of cephalosporins with different structures,cefoperazone and ceftazidime,and ethanol.Methods A toxicity model for DLR induced by alcohol consumption was established after administration of cefoperazone or ceftazidime.The concentrations of ethanol and acetaldehyde in the blood were detected at various time points,and the toxic metabolic kinetic parameters were calculated using the DAS3.2.8 pharmacokinetic software.The activities of hepatic alcohol dehydrogenase(ADH)and aldehyde dehydrogenase(ALDH)were measured.Results The combination of cefoperazone and ethanol increased the maximum plasma concentration of ethanol and led to the accumulation of acetaldehyde in the blood.After 0 days and 3 days of cefoperazone administration,inhibition of hepatic ALDH activity could be detected.Ceftazidime had no significant effects on the metabolism of ethanol and acetaldehyde.Moreover,the activities of hepatic ADH and ALDH were not significantly changed after ceftazidime treatment.Conclusion Based on the data of ethanol and acetaldehyde metabolism in the blood of rats that consumed alcohol after administration of cefoperazone or ceftazidime,as well as the observed changes in hepatic ADH and ALDH activities,it can be concluded that the DLR induced by cefoperazone is mainly due to ALDH inhibition in the liver,whereas ceftazidime does not have similar effects.When combined with ethanol,cephalosporins with different structures induce DLR by distinct mechanisms.

关 键 词：双硫仑样反应 头孢哌酮 头孢他啶 乙醇 乙醛 

分 类 号：D918.93[政治法律—法学]