灯盏花素注射液对大鼠体外肝微粒体细胞色素P450酶活性的影响
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摘要
目的:研究灯盏花素注射液对大鼠肝微粒体CYP1A2、CYP2C9、CYP2D6、CYP2E1和CYP3A1/2五个亚型酶活性的影响。方法:采用大鼠肝微粒体体外孵育法,选用非那西丁(CYP1A2)、甲苯磺丁脲(CYP2C9)、右美沙芬(CYP2D6)、氯唑沙宗(CYP2E1)和睾酮(CYP3A1/2)作为5个亚型酶的探针药物,孵育系统中加入不同浓度的灯盏花素注射液,用HPLC法测定5个亚型酶探针药物代谢产物的生成量,比较空白对照组与不同浓度灯盏花素注射液给药组探针药物的活性,反映灯盏花素注射液对5个亚型酶活性的影响。结果:大鼠肝微粒体体外孵育系统中,灯盏花素注射液对大鼠CYP3A1/2的.IC_(50)为29.40μg·ml~(-1),K_i为37.78μg·ml~(-1);对CYP1A2、CYP2C9、CYP2D6和CYP2E1的IC_(50)>200μg·ml~(-1)。结论:灯盏花素注射液对大鼠体外肝微粒体CYP3A1/2有弱的抑制作用,对CYP1A2、CYP2C9、CYP2D6和CYP2E1活性无明显影响。
Objective:To study the effects of breviscapine injections on the activities of CYP1A2,CYP2C9,CYP2D6,CYP2E1 and CYP3A1/2 enzymes in rat liver microsomes in vitro.Method:Phenacetin(CYP1A2),tolbutamide(CYP2C9),dextromethorphan (CYP2D6),chlorzoxazone(CYP2E1) and testosterone(CYP3 A1/2) were selected as the five probe drugs of the enzymes in the microsomal incubation system.An HPLC method was used to determine the metabolites of the probe drugs in the blank control group and breviscapine injections groups with different concentrations of breviscapine to investigate the effects of the injections on the activities of CYP1A2,CYP2C9,CYP2D6,CYP2E1 and CYP3A1/2.Result:The IC_(50) of breviscapine injection on rat CYP3A1/2 enzyme was 29.40μg·ml~(-1) and the K_i was 37.78μg·ml~(-1).The IC_(50) of CYP1A2,CYP2C9,CYP2D6 and CYP2E1 were more than 200μg ? ml~(-1) in rat liver microsomal incubation systems.Conclusion:Mild inhibition effect of breviscapine injections on rat CYP3A1/2 enzyme in rat liver microsomal.incubation system in vitro is observed without effects on CYP1A2,CYP2C9,CYP2D6 and CYP2E1.
Objective:To study the effects of breviscapine injections on the activities of CYP1A2,CYP2C9,CYP2D6,CYP2E1 and CYP3A1/2 enzymes in rat liver microsomes in vitro.Method:Phenacetin(CYP1A2),tolbutamide(CYP2C9),dextromethorphan (CYP2D6),chlorzoxazone(CYP2E1) and testosterone(CYP3 A1/2) were selected as the five probe drugs of the enzymes in the microsomal incubation system.An HPLC method was used to determine the metabolites of the probe drugs in the blank control group and breviscapine injections groups with different concentrations of breviscapine to investigate the effects of the injections on the activities of CYP1A2,CYP2C9,CYP2D6,CYP2E1 and CYP3A1/2.Result:The IC_(50) of breviscapine injection on rat CYP3A1/2 enzyme was 29.40μg·ml~(-1) and the K_i was 37.78μg·ml~(-1).The IC_(50) of CYP1A2,CYP2C9,CYP2D6 and CYP2E1 were more than 200μg ? ml~(-1) in rat liver microsomal incubation systems.Conclusion:Mild inhibition effect of breviscapine injections on rat CYP3A1/2 enzyme in rat liver microsomal.incubation system in vitro is observed without effects on CYP1A2,CYP2C9,CYP2D6 and CYP2E1.
引文
1毛睿.中国注射液的现状及安全性分析[J].中国药师,2009,12 (1):51-53
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6昊寿福.灯盏花注射液改善血液流变学的临床观察[J].深圳中西医结合杂志,2001,11(5):281
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9邱丽萍,王丽娟,崔红霞,等.灯盏花素联合用药对肾上腺素所致心律失常的预防作用[J].齐齐哈尔医学院学报,2002,23(8): 845-846
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11刘高峰,郭兴蕾,黄丽军.红花注射液对大鼠细胞色素P450 2D6亚型的抑制作用[J].中草药,2008,39(12):1829-1832
12石杰,陈安进,张芳,等.三七总皂苷对CYP450的影响及药物相互作用预测[J].药物流行病学杂志,2008,17(5):281-284
13 Bjornsson TD,Callaghan JT,Einolf HJ,et al.The conduct of in vitro and in vivo drug-drug interaction studies:a Pharmaceutical Research and Manufacturers of America(PhRMA)perspective[J]. Drug.Metab Dispos,2003,31(7):815-832
14刘治军,傅得兴,汤光.FDA药物相互作用研究指南(草案)2006版解读[J].国际药学研究杂志,2008,35(1):50-58
15 Nedeleheva V,Gut I.P450 in the rat and man:Methods of investigation, substrate specificities and relevance to cancer[J].Xenobiotica, 1994,24(12):1151-1175
16 Lee JI,Chaves G,Amico JA,et al.Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping[J].Clin Pharmacol Ther,2002,72(6):718-728
17中国国家处方集编委会.中国国家处方集[M].北京:人民军医出版社,2010.903
2 Pekthong D,Martin H,Abadie C,et al.Differential inhibition of rat and human hepatic cytochrome P450 by Andrographis paniculata extract and andrographolide[J].J Ethnopharmacol,2008,115(3): 432-440
3 Qiu F,Zhang R,Sun J,et al.Inhibitory effects of seven components of danshen extract on catalytic activity of cytochrome P450 enzyme in human liver microsomes[J].Drug Metab Dispos,2008,36(7): 1308-1314
4 Dostalek M,Pistovcakova J,Jurica J,et al.Effect of St John's wort (Hypericum perforatum)on cytochrome P450 activity in perfused rat liver[J].Life Sci,2005,78(3):239-244
5刘高峰,董凤.细胞色素P450药物代谢研究方法分析与评价[J].中国药师,2010,13(1):129-131
6昊寿福.灯盏花注射液改善血液流变学的临床观察[J].深圳中西医结合杂志,2001,11(5):281
7石森林,徐莲英,吕圭源.灯盏花的药理学研究进展[J].浙江中医学院学报,2004,28(4):87-89
8陈祖琨.灯盏花素注射液联合黄芪注射液治疗视网膜静脉阻塞31例疗效观察[J].云南中医中药杂志,2004,25(1):9
9邱丽萍,王丽娟,崔红霞,等.灯盏花素联合用药对肾上腺素所致心律失常的预防作用[J].齐齐哈尔医学院学报,2002,23(8): 845-846
10杜建军,刘淑娟.灯盏花素联合酚妥拉明治疗肺心病心力衰竭的临床观察[J].宁夏医学杂志,2002,24(12):734-735
11刘高峰,郭兴蕾,黄丽军.红花注射液对大鼠细胞色素P450 2D6亚型的抑制作用[J].中草药,2008,39(12):1829-1832
12石杰,陈安进,张芳,等.三七总皂苷对CYP450的影响及药物相互作用预测[J].药物流行病学杂志,2008,17(5):281-284
13 Bjornsson TD,Callaghan JT,Einolf HJ,et al.The conduct of in vitro and in vivo drug-drug interaction studies:a Pharmaceutical Research and Manufacturers of America(PhRMA)perspective[J]. Drug.Metab Dispos,2003,31(7):815-832
14刘治军,傅得兴,汤光.FDA药物相互作用研究指南(草案)2006版解读[J].国际药学研究杂志,2008,35(1):50-58
15 Nedeleheva V,Gut I.P450 in the rat and man:Methods of investigation, substrate specificities and relevance to cancer[J].Xenobiotica, 1994,24(12):1151-1175
16 Lee JI,Chaves G,Amico JA,et al.Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping[J].Clin Pharmacol Ther,2002,72(6):718-728
17中国国家处方集编委会.中国国家处方集[M].北京:人民军医出版社,2010.903