他汀类药物联合抗结核病药导致大鼠肝损伤
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摘要
目的:研究不同他汀类药物联合抗结核病药异烟肼、利福平、吡嗪酰胺致大鼠肝损伤的特点和机制,为临床合理用药提供理论依据。方法:80只SD大鼠,按随机数字表法分为空白对照组、阿托伐他汀+联合抗结核病药(异烟肼、利福平、吡嗪酰胺)组、辛伐他汀+联合抗结核病药组、洛伐他汀+联合抗结核病药组,每组20只。空白对照组灌胃生理盐水,联合用药组按照人-鼠间药物剂量换算表分别灌胃给予相应的药物。于给药第10、35、55天(d 55)采血,检测肝功能生化指标天冬氨酸氨基转移酶(AST)、谷氨酸氨基转移酶(ALT)、总胆红素(TBil)、直接胆红素(DBil)、间接胆红素(IBil)、碱性磷酸酶(ALP),同时取肝组织于电镜下观察肝细胞亚显微结构并分析细胞器的损伤情况。结果:在给药d 10、d 35、d 55,与空白对照组比较,各联合用药组的肝功能生化指标TBil、DBil、IBil显著升高(P<0.01)。AST在给药d 10、d 35,d 55,ALT在给药d 35,ALP在给药d 35、d 55,辛伐他汀+联合抗结核病药组和阿托伐他汀+联合抗结核病药组与空白对照组比较显著升高(P<0.01)。随着用药时间的延长,仅ALP在给药d 35、d 55,辛伐他汀+联合抗结核病药组及洛伐他汀+联合抗结核病药组分别与阿托伐他汀+联合抗结核病药组比较显著升高(P<0.01),其他各组进行组间两两比较差异均无统计学意义。电镜观察发现,随着用药时间延长,他汀类药物联合抗结核病药组大鼠均显示出不同程度的肝细胞损伤。结论:阿托伐他汀、辛伐他汀、洛伐他汀分别联合抗结核病药后均出现不同程度的肝损伤,以胆汁淤积型为主,且随着用药时间延长,肝损伤有加重趋势。
Objective: To study the characteristics and mechanism of liver injury induced by statins combined with anti-tuberculosis drugs(isoniazid,rifampicin,pyrazinamide),so as to provide theoretical basis for clinical rational use of drugs. Methods:Eighty SD rats were randomly divided into 4 groups by random cluster method: the blank control group,the atorvastatin combined with anti-tuberculosis drugs(isoniazid,rifampicin,pyrazinamide,IRP) group,the simvastatins+IRP group,the lovastatins+IRP group,each consisting 20 rats.The rats in the blank control group were gavaged with normal saline and the rats in the other groups were gavaged with statins combined with anti-tuberculosis drugs according to the dosage conversion table between humans and rats.Blood samples were taken at days 10,35,55 of medication to determine biochemical indexes of liver functions such as aspartate aminotransferase(AST),glutamate aminotransferase(ALT),total bilirubin(TBil),direct bilirubin(DBil),indirect bilirubin(IBil) and alkaline phosphatase(ALP).Meanwhile,hepatic tissues were taken to observe the ultrastructure of hepatic cells under electron microscopy and to analyze the damage of organelles.Results:Compared with the blank control group,the levels of biochemical indexes of liver functions, such as TBil,DBil,IBil in the combination treatment groups increased significantly(P<0.01).In the simvastatin+IRP group and the atorvastatin+IRP group,the levels of AST at 10,35,55 days,the level of ALT at 35 days,the levels of ALP at 35,55 days increased significantly compared with those of the blank control group(P<0.01).With the lengthening of medication time,only the levels of ALP at 35 and 55 days increased significantly(P<0.01) in the simvastatin+IRP group and the lovastatin+IRP group,compared with those of the atorvastatin+IRP group.No statistical significance could be seen, when comparisons were made between the two in the other groups.Electron microscopic observation showed that with the lengthening of medication time,the rats in the statins combined with anti-tuberculosis drugs groups displayed different degrees of hepatic cell damage.Conclusion:Atorvastatin,simvastatin and lovastatin combined with anti-tuberculosis drugs could respectively induce different degrees of liver injury in rats,with cholestasis as the main type,and liver injury tended to be aggravated with the lengthening of medication time.
Objective: To study the characteristics and mechanism of liver injury induced by statins combined with anti-tuberculosis drugs(isoniazid,rifampicin,pyrazinamide),so as to provide theoretical basis for clinical rational use of drugs. Methods:Eighty SD rats were randomly divided into 4 groups by random cluster method: the blank control group,the atorvastatin combined with anti-tuberculosis drugs(isoniazid,rifampicin,pyrazinamide,IRP) group,the simvastatins+IRP group,the lovastatins+IRP group,each consisting 20 rats.The rats in the blank control group were gavaged with normal saline and the rats in the other groups were gavaged with statins combined with anti-tuberculosis drugs according to the dosage conversion table between humans and rats.Blood samples were taken at days 10,35,55 of medication to determine biochemical indexes of liver functions such as aspartate aminotransferase(AST),glutamate aminotransferase(ALT),total bilirubin(TBil),direct bilirubin(DBil),indirect bilirubin(IBil) and alkaline phosphatase(ALP).Meanwhile,hepatic tissues were taken to observe the ultrastructure of hepatic cells under electron microscopy and to analyze the damage of organelles.Results:Compared with the blank control group,the levels of biochemical indexes of liver functions, such as TBil,DBil,IBil in the combination treatment groups increased significantly(P<0.01).In the simvastatin+IRP group and the atorvastatin+IRP group,the levels of AST at 10,35,55 days,the level of ALT at 35 days,the levels of ALP at 35,55 days increased significantly compared with those of the blank control group(P<0.01).With the lengthening of medication time,only the levels of ALP at 35 and 55 days increased significantly(P<0.01) in the simvastatin+IRP group and the lovastatin+IRP group,compared with those of the atorvastatin+IRP group.No statistical significance could be seen, when comparisons were made between the two in the other groups.Electron microscopic observation showed that with the lengthening of medication time,the rats in the statins combined with anti-tuberculosis drugs groups displayed different degrees of hepatic cell damage.Conclusion:Atorvastatin,simvastatin and lovastatin combined with anti-tuberculosis drugs could respectively induce different degrees of liver injury in rats,with cholestasis as the main type,and liver injury tended to be aggravated with the lengthening of medication time.
引文
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[2] 中华医学会肝病学分会药物性肝病学组.药物性肝损伤诊治指南[J].临床肝胆病杂志,2015,31(11):1752-1769.Drug-induced Liver Disease Study Group,Chinese Society of Hepatology,Chinese Medical Association.Guidelines for the management of drug-induced liver injury[J].J Clin Hepatol,2015,31(11):1752-1769.In Chinese with English abstract.
[3] 张守堂,万国靖,李璐.药物性肝损伤机制的研究进展[J].药学服务与研究,2017,17(1):39-42.ZHANG Shoutang,WAN Guojing,LI Lu.Research advances in the machanism of drug-induced liver injury[J].Pharm Care Res,2017,17(1):39-42.In Chinese with English abstract.
[4] 彭江丽,马国伟,喻明丽,等.洛伐他汀联合异烟肼、利福平、吡嗪酰胺致大鼠肝损伤的实验研究[J].安徽医药,2017,21(12):2157-2163.PENG Jiangli,MA Guowei,YU Mingli,et al.Experimental study of liver injury caused by lovastatin combined with isoniazid,rifampicin and pyrazinamide in rats[J].Anhui Med Pharm J,2017,21(12):2157-2163.In Chinese with English abstract.
[5] 陈洁,王俊龙,马国伟.抗结核病药与辛伐他汀联用致肝损伤的特征及其机制研究[J].抗感染药学,2016,13(4):729-735.CHEN Jie,WANG Junlong,MA Guowei.Study on the characteristics and mechanism of liver injury damaged by the use of simvastatin combined with HRZ[J].Anti Infect Pharm,2016,13(4):729-735.In Chinese with English abstract.
[6] 罗季,陈永刚,喻明丽,等.抗结核药与阿托伐他汀联用致肝损伤的特征及其机制研究[J].抗感染药学,2016,13(5):978-985.LUO Ji,CHEN Yonggang,YU Mingli,et al.Study on characteristics and mechanism of liver injury impaired by the use of anti-tuberculotic(HRZ) combined with atorvastatin[J].Anti Infect Pharm,2016,13(5):978-985.In Chinese with English abstract.
[7] 郭瑶雪,邓晔,李春,等.异烟肼致线粒体损伤引起药物性肝损伤研究进展[J].中国临床药理学与治疗学,2015,20(3):356-360.GUO Yaoxue,DENG Ye,LI Chun,et al.Mitochondria dysfunction is involved in the pathogenesis of isoniazid-induced hepatotoxicity[J].Chin J Clin Pharmacol Ther,2015,20(3):356-360.In Chinese with English abstract.
[8] 牛国超,尹凤荣,张晓岚.他汀类药物致肝损伤的临床特征及其防治[J].临床荟萃,2018,33(6):478-481.NIU Guochao,YIN Fengrong,ZHANG Xiaolan.Clinical features and treatment of stains-induced liver injury[J].Clin Focus,2018,33(6):478-481.In Chinese with English abstract.
[9] 卫生部合理用药专家委员会.中国医师、药师临床用药指南[M].2版.重庆:重庆出版集团,重庆出版社,2009:615-617.Expert Committee of Rational Drug Use of Chinese Ministry of Health.Guidelines of clinical drug use for Chinese physicians and pharmacists[M].2nd ed.Chongqing:Chongqing Publishing Group,Chongqing Publishing House,2009:615-617.In Chinese.