Cocktail探针药物法评价生、制黄柏对CYP450酶亚型的影响
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摘要
目的:用Cocktail探针药物法,研究黄柏不同炮制品对大鼠细胞色素P450酶(CYP450)4种亚型活性的影响并进行比较,探讨黄柏的炮制原理。方法:将SD大鼠随机分组,生、酒、盐黄柏组分别灌胃生、酒、盐黄柏水煎液(3.24 g/kg),空白对照组灌胃生理盐水,灌胃1 w,于第8天给予由茶碱、氨苯砜、氯唑沙宗、甲苯磺丁脲组成的混合探针药物,在不同时间点采集血样,利用HPLC检测探针药物在大鼠体内的代谢情况,通过DAS3.0软件计算各探针药物的药动学参数并进行统计分析,以评价生、制黄柏对CYP450酶的影响。结果:与空白对照组比较,生品组和盐品组茶碱的t_(1/2)均显著增加,生品组和酒品组的CL/F均显著降低,AUC_(0-t)、AUC_(0-∞)均显著增加;生品组、酒品组和盐品组氨苯砜的t_(1/2)、AUC_(0-t)、AUC_(0-∞)均显著降低,CL/F显著增加;生品组和盐品组氯唑沙宗的AUC_(0-t)显著增加,酒品组氯唑沙宗的t_(1/2)、AUC_(0-∞)、AUC_(0-t)均显著降低,CL/F显著增加;生品组、酒品组和盐品组甲苯磺丁脲的AUC0-t均显著降低。结论:生黄柏对CYP1A2具有抑制作用,对CYP3A4具有诱导作用,对CYP2C9、CYP2E1活性的影响有待进一步的研究,而经炮制成为酒黄柏和盐黄柏后可改变药物代谢酶的活性;酒黄柏可降低对CYP1A2的抑制作用和增强对CYP3A4的诱导作用,该研究可为解释酒制黄柏能缓和药性提供参考依据。
Objective: To research and compare the influences of raw and processed Phellodendri Cortex on the cytochrome P450 four isoforms by Cocktail probe drugs,and to explore the processing principle of Phellodendri Cortex.Methods: SD rats were randomly divided into raw group,processed with rice-wine group,processed with salt-water group and blank control group,which were given raw decoction,processed with rice-wine decoction,processed with salt-water decoction( 3.24 g / kg) and normal saline respectively for one week,then given the mixture of four probe drugs on the 8th day,and soon after the blood samples were obtained through the orbits at a series of time-points.HPLC method was used to determine the concentrations of probe drugs in rat plasma,and pharmacokinetic parameters were estimated by DAS3.0.The effect of raw and processed Phellodendri Cortex on cytochrome P450 were judged indirectly by the pharmacokinetic parameters.Results: Compared with the blank control group,the t_(1/2) significantly increased of theophylline in raw and processed with salt-water group.The CL/F significantly decreased and AUC_(0-t),AUC_(0-∞) significantly increased of theophylline in raw and processed with rice-wine groups.The t_(1/2),AUC_(0-t) and AUC_(0-∞) significantly decreased and CL/F significantly increased of dapsone in raw,processed with rice-wine and processed with salt-water group.The AUC0-tsignificantly increased of chlorzoxazone in raw and processed with salt-water group.The t_(1/2),AUC_(0-∞) and AUC_(0-t) significantly decreased and CL/F significantly increased of chlorzoxazone in processed with rice-wine group.The AUC_(0-t) significantly decreased of tolbutamide in raw,processed with rice-wine and processed with salt-water groups.Conclusion: The raw Phellodendri Cortex can inhibit CYP1A2,induce CYP3A4 and also is need to make a further research work on CYP2C9 and CYP2E1.Meanwhile,it also can change the activities of cytochrome P450 after processed with rice-wine and salt-water.The Phellodendri Cortex processed with rice-wine can reduce the inhibitory effect of CYP1A2 and enhance induction of CYP3A4,it provides reference and basis to make an interpretation about Phellodendri Cortex processed with rice-wine.
Objective: To research and compare the influences of raw and processed Phellodendri Cortex on the cytochrome P450 four isoforms by Cocktail probe drugs,and to explore the processing principle of Phellodendri Cortex.Methods: SD rats were randomly divided into raw group,processed with rice-wine group,processed with salt-water group and blank control group,which were given raw decoction,processed with rice-wine decoction,processed with salt-water decoction( 3.24 g / kg) and normal saline respectively for one week,then given the mixture of four probe drugs on the 8th day,and soon after the blood samples were obtained through the orbits at a series of time-points.HPLC method was used to determine the concentrations of probe drugs in rat plasma,and pharmacokinetic parameters were estimated by DAS3.0.The effect of raw and processed Phellodendri Cortex on cytochrome P450 were judged indirectly by the pharmacokinetic parameters.Results: Compared with the blank control group,the t_(1/2) significantly increased of theophylline in raw and processed with salt-water group.The CL/F significantly decreased and AUC_(0-t),AUC_(0-∞) significantly increased of theophylline in raw and processed with rice-wine groups.The t_(1/2),AUC_(0-t) and AUC_(0-∞) significantly decreased and CL/F significantly increased of dapsone in raw,processed with rice-wine and processed with salt-water group.The AUC0-tsignificantly increased of chlorzoxazone in raw and processed with salt-water group.The t_(1/2),AUC_(0-∞) and AUC_(0-t) significantly decreased and CL/F significantly increased of chlorzoxazone in processed with rice-wine group.The AUC_(0-t) significantly decreased of tolbutamide in raw,processed with rice-wine and processed with salt-water groups.Conclusion: The raw Phellodendri Cortex can inhibit CYP1A2,induce CYP3A4 and also is need to make a further research work on CYP2C9 and CYP2E1.Meanwhile,it also can change the activities of cytochrome P450 after processed with rice-wine and salt-water.The Phellodendri Cortex processed with rice-wine can reduce the inhibitory effect of CYP1A2 and enhance induction of CYP3A4,it provides reference and basis to make an interpretation about Phellodendri Cortex processed with rice-wine.
引文
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[8]王菊,陆兔林,毛春芹,等.Cocktail探针药物法评价生、醋莪术对CYP450酶亚型的影响[J].中国药理学通报,2012,28(11):1562-1565.
[9]李丹,韩永龙,余涛,等.黄连解毒汤对人细胞色素P450酶6个亚型的体外抑制作用研究[J].中国临床药理学与治疗学,2012,17(2):131-136.
[2]李丹丹,江培,杨书美,等.黄柏的化学成分、药理作用及临床应用研究进展[J].黑龙江医药,2014,27(3):601-605.
[3]孙加矿.黄柏炮制的历史沿革[J].中医药信息,1996,(5):29-30.
[4]Wienkers LC,Heath TG.Predicting in vivo drug interactions from in vitro drug discovery data[J].Nat Rev Drug Discov,2005,4(10):825-833.
[5]Guengerich FP.Cytochrome P450s and other enzymes in drug metabolism and toxicity[J].APPS J,2006,8(1):E101-111.
[6]Izzo AA,Emst E.Interactions between herbal medicines and prescribed drugs:an updated systematic review[J].Drugs,2009,69(13):1777-1798.
[7]赵文婷,张波,李湘晖,等.疏血通注射液对大鼠细胞色素P450酶6种亚型活性的影响[J].中药新药与临床药理,2012,23(4):445-449.
[8]王菊,陆兔林,毛春芹,等.Cocktail探针药物法评价生、醋莪术对CYP450酶亚型的影响[J].中国药理学通报,2012,28(11):1562-1565.
[9]李丹,韩永龙,余涛,等.黄连解毒汤对人细胞色素P450酶6个亚型的体外抑制作用研究[J].中国临床药理学与治疗学,2012,17(2):131-136.