他汀类药物致肝损伤的生化特征
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摘要
目的利用大鼠实验复制他汀类药物肝损伤模型,分析并比较阿托伐他汀、辛伐他汀、洛伐他汀类药物致药物性肝损伤的生化特点,为促进临床合理用药提供理论依据.方法 SPF级8周龄SD大鼠80只,雌雄各半,随机分成4组:空白对照组、辛伐他汀组、洛伐他汀组、阿托伐他汀组,按人和大鼠间药物剂量换算,分别给予相应的药物灌胃给药,于10 d、35 d、55 d处死大鼠,处死前股动脉放血检测肝功能指标:总胆红素(TBIL)、直接胆红素(DBIL)、间接胆红素(IBIL)、谷草转氨酶(AST)、谷丙转氨酶(ALT)、碱性磷酸酶(ALP).结果(1)用药组TBIL、DBIL、IBIL、AST、ALT较空白对照组升高差异有统计学意义(P<0.01);(2)AST在给药第10天时,阿托伐他汀组较其他3组升高,差异有统计学意义(P<0.05);(3)ALT在给药55 d时,辛伐他汀组较洛伐他汀组和阿托伐他汀组比较差异有统计学意义(P<0.01),且以阿托伐组升高为主;(4)ALP在给药35 d、55 d时,阿托伐他汀组较辛伐组和洛伐组升高,差异有统计学意义(P<0.01)并以阿托伐组升高为主.结论 3组实验组大鼠的肝损伤均为轻中度型损伤,主要为胆汁淤积型,由此推测该损伤可能与肝内胆汁转运障碍密切相关.
Objectives To provide theoretical basis for the clinical rational using of drugs,biochemical characteristics of the liver injuries induced by the atorvastatin,simvastatin and lovastatin were analyzed and compared by replicating the rats model of liver injuries induced by statins,Methods 80 SPF SD rats(8 weeks of age),half male and half female, were divided into four groups randomly: control group, simvastatin group, lovastatin group, atorvastatin group. Human equivalent doses were administered to the latter three groups of rats which were sacrificed to draw blood on the 10 th,35 th and 55 th day respectively(via the femoral artery) for testing liver function index, including total bilirubin(TBIL), direct bilirubin(DBIL), indirect bilirubin(IBIL), aspartateaminotransferase(AST),alanineaminotransferase(ALT),alkalinephosphatase(ALP). Results(1)The increases in TBIL,DBIL,IBIL for treatment group in comparison with control group had statistical significance(P<0.01).2) At the 55 th day of administration, there was a significant statistical difference between the simvastatin group and the lovastatin group in AST(P<0.05);3)Meanwhile, there was great statistical difference between the atorvastatin group and lovastatin group in ALP(P<0.01). Conclusion The rats in the three experimental groups suffered from minor to moderate liver injuries, most of which being cholestasis type. It is speculated that this kind of liver injuries are closely related to the obstacle of transfering bile.
Objectives To provide theoretical basis for the clinical rational using of drugs,biochemical characteristics of the liver injuries induced by the atorvastatin,simvastatin and lovastatin were analyzed and compared by replicating the rats model of liver injuries induced by statins,Methods 80 SPF SD rats(8 weeks of age),half male and half female, were divided into four groups randomly: control group, simvastatin group, lovastatin group, atorvastatin group. Human equivalent doses were administered to the latter three groups of rats which were sacrificed to draw blood on the 10 th,35 th and 55 th day respectively(via the femoral artery) for testing liver function index, including total bilirubin(TBIL), direct bilirubin(DBIL), indirect bilirubin(IBIL), aspartateaminotransferase(AST),alanineaminotransferase(ALT),alkalinephosphatase(ALP). Results(1)The increases in TBIL,DBIL,IBIL for treatment group in comparison with control group had statistical significance(P<0.01).2) At the 55 th day of administration, there was a significant statistical difference between the simvastatin group and the lovastatin group in AST(P<0.05);3)Meanwhile, there was great statistical difference between the atorvastatin group and lovastatin group in ALP(P<0.01). Conclusion The rats in the three experimental groups suffered from minor to moderate liver injuries, most of which being cholestasis type. It is speculated that this kind of liver injuries are closely related to the obstacle of transfering bile.
引文
[1]于乐成,茅益民,陈成伟,等.药物性肝损伤诊治指南[J].临床肝胆病杂志,2015,31(11):1752-1769.
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[5]马葵芬,谢先吉,刘莹,等.细胞色素P450酶基因多态性及其介导的药物性肝损伤研究进展[J].中国药理学与毒理学杂志,2013,27(5):889-892.
[6]曾含清,张琼,彭文兴,等.阿托伐他汀致肝损伤的机制[J].药物不良反应志,2012,14(4):232-235.
[7]刘敏惠,陈崇泽.阿托伐他汀致11例患者肝损伤及费用分析[J].海峡药学,2018,30(02):265-268.
[8]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.
[9]陈洁,王俊龙,马国伟,等.抗结核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(04):729-735.
[10]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(05):978-985.
[11]丁德云,张淑芳,马力,等.阿托伐他汀的药物专论[M].重庆:重庆出版社,2014:644-649.
[12]刘志军,熊玉卿.药代动力学/药效学模型研究进展及其在他汀类药物临床治疗的应用[J].中国临床药理学杂志,2015,31(15):1552-1554.
[13]BOELSTERLI U A,LIM P L.Mitochondrial abnormalitiesa link to idiosyncratic hepatotoxicity drug[J].Toxicol Appl Pharmacol,2007,220(1):92-107.
[14]AU J S,NAVARRO V J,ROSSI S.et al.Review article:drug-induced liver injure-its pathophysiology and evolving diagnostic tools[J].Aliment Pharmacol Ther,2011,34(1):11-20.
[15]范颖,赵红,药物性肝损伤防治指南[J],中华全科医师杂志,2016,15(6):416-420.
[2]CHALASANI N P,HAYASHI PH,BONKOVSKY H L,et al.ACG Clinical Guideline:the diagnosis and management of idiosyncratic drug-induced liver injury[J].Am J Gastroenterol,2014,109(7):950-966.
[3]HAYASHI P H,FONTANA R J.Clinical features,diagnosis,and natural history of drug-induced liver injury[J].Semin Liver Dis,2014,34(2):134-144.
[4]ROBLES-DIAZ M,LUCENA MI,KAPLOWITZ N,et al.Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury[J].Gastroenterology,2014,147(1):109-118.
[5]马葵芬,谢先吉,刘莹,等.细胞色素P450酶基因多态性及其介导的药物性肝损伤研究进展[J].中国药理学与毒理学杂志,2013,27(5):889-892.
[6]曾含清,张琼,彭文兴,等.阿托伐他汀致肝损伤的机制[J].药物不良反应志,2012,14(4):232-235.
[7]刘敏惠,陈崇泽.阿托伐他汀致11例患者肝损伤及费用分析[J].海峡药学,2018,30(02):265-268.
[8]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.
[9]陈洁,王俊龙,马国伟,等.抗结核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(04):729-735.
[10]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(05):978-985.
[11]丁德云,张淑芳,马力,等.阿托伐他汀的药物专论[M].重庆:重庆出版社,2014:644-649.
[12]刘志军,熊玉卿.药代动力学/药效学模型研究进展及其在他汀类药物临床治疗的应用[J].中国临床药理学杂志,2015,31(15):1552-1554.
[13]BOELSTERLI U A,LIM P L.Mitochondrial abnormalitiesa link to idiosyncratic hepatotoxicity drug[J].Toxicol Appl Pharmacol,2007,220(1):92-107.
[14]AU J S,NAVARRO V J,ROSSI S.et al.Review article:drug-induced liver injure-its pathophysiology and evolving diagnostic tools[J].Aliment Pharmacol Ther,2011,34(1):11-20.
[15]范颖,赵红,药物性肝损伤防治指南[J],中华全科医师杂志,2016,15(6):416-420.