血府逐瘀汤功效配伍对大鼠CYP450代谢酶的影响  

Effect of Compatibility of Xuefuzhuyu Decoction(血府逐瘀汤)on CYP450 Metabolic Enzyme in Rats

作　　者：刘兆悦 彭勍[1] 任常英 孙明谦[1] 张颖[1] 苗兰[1] 林力[1] LIU Zhaoyue;PENG Qing;REN Changying;SUN Mingqian;ZHANG Ying;MIAO Lan;LIN Li(Xiyuan Hospital of China Academy of Chinese Medical Sciences,Institute of Basic Medicine,Beijing Key Laboratory of Traditional Chinese Medicine Pharmacology,Beijing 100091,China)

机构地区：[1]中国中医科学院西苑医院基础医学研究所,中药药理北京市重点实验室,北京100091

出　　处：《中华中医药学刊》2024年第12期52-57,I0035-I0039,共11页Chinese Archives of Traditional Chinese Medicine

基　　金：国家自然科学基金项目(81872992);中国中医科学院科技创新工程项目(C12021A04508,C12021A05022)。

摘　　要：目的明晰血府逐瘀汤(XFZY)合并用药隐患,探究血府逐瘀汤及其活血组(桃红四物汤)和理气组(四逆散)药物对大鼠体内5种酶亚型细胞色素P450酶1A2(CYP1A2)、细胞色素P450酶2C11(CYP2C11)、细胞色素P450酶2D2(CYP2D2)、细胞色素P450酶3A1/2(CYP3A1/2)和细胞色素P450酶2C6(CYP2C6)的影响。方法24只SD大鼠随机分为空白对照组、理气组、活血组及复方组,连续灌胃给药14d后给予混合探针药:咖啡因(CAF)、奥美拉唑(OMP)、右美沙芬(DM)、咪达唑仑(MDZ)及氯沙坦钾(LK)。大鼠体内相应的代谢物分别为1,7-二甲基黄嘌呤(PXT)、5-羟基奥美拉唑(HOMP)、去甲右美沙芬(DP)、1-羟基咪达唑仑(HMDZ)、羰基氯沙坦(LC)。使用在线固相萃取液质联用法(OnlineSPE-LC-MS/MS)检测探针药及特异代谢物不同时间点的血药浓度,比较探针药及代谢物的药代参数及代谢率的变化,评价重复给予XFZY及其功效配伍组对大鼠CYP450酶活性的影响。结果重复给予XFZY及各功效配伍组对大鼠CYP2C11、CYP3A1/2代谢酶活性没有显著影响;XFZY对CYP1A2代谢酶的活性没有显著影响,而活血组对CYP1A2代谢酶活性呈现出一定诱导作用(P<0.05);XFZY对CYP2D2具有显著抑制作用(P<0.01),其抑制作用可能来自于活血药;XFZY对大鼠CYP2C6的活性具有诱导的趋势,但无统计学意义。结论重复给予XFZY对大鼠CYP2D2(人体CYP2D6)具有一定抑制作用,该作用可能来自活血药,XFZY大鼠对CYP1A2、CYP2C11、CYP3A1/2和CYP2C6酶活性均无显著影响,初步提示临床上应用血府逐瘀汤时应避免与经CYP2D6代谢的药物合并使用。Objective To clarify the hidden dangers of concomitant medication of Xuefu Zhuyu Decoction(血府逐瘀汤,XFZY).To investigate the effects of Xuefu Zhuyu Decoction,blood-activating group[Taohong Siwu Decoction(桃红四物汤)]and Qi-regulating group[Sini Powder(四逆散)]on 5 enzyme subtypes cytochrome P450 enzyme 1A2(CYP1A2),cytochrome P450 enzyme 2C11(CYP2C11),cytochrome P450 enzyme 2D2(CYP2D2),cytochrome P450 enzyme 3A1/2(CYP3A1/2)and cytochrome P450 enzyme 2C6(CYP2C6).Methods Twenty-four SD rats were randomly divided into blank control group,Qi-regulating group,blood-activating group and compound group.After continuous intragastric administration for 14 days,the mixed probe drugs including caffeine(CAF),omeprazole(OMP),dextromethorphan(DM),midazolam(MDZ)and losartan potassium(LK)were given.The corresponding metabolites in rats were 1,7-dimethylxanthine(PXT),5-hydroxyomeprazole(HOMP),nordextromethorphan(DP),1-hydroxymidazolam(HMDZ)and carbonyl losartan(LC).Online SPE-LC-MS/MS was used to detect the plasma concentrations of probe drugs and specific metabolites at different time points.The pharmacokinetic parameters and metabolic rates of probe drugs and metabolites were compare and the effects of repeated administration of XFZY and its effi-cacy combination group on the activity of CYP450 enzyme in rats were evaluated.Results Repeated administration of XFZY and each efficacy combination group had no significant effect on the activities of CYP2C11 and CYP3A1/2 metabolic enzymes in rats.XFZY had no significant effect on the activity of CYP1A2 metabolic enzyme,while blood-activating group showed certain induc-tion effect on the activity of CYP1A2 metabolic enzyme(P<0.05).XFZY had a significant inhibitory effect on CYP2D2(P<0.01),and the inhibitory effect may come from blood-activating drugs.XFZY showed a tendency to induce CYP2C6 activity in rats,but there was no statistical significance.Conclusion Repeated administration of XFZY has a certain inhibitory effect on hu-man CYP2D6 in rats,which may be attributed t

关 键 词：血府逐瘀汤 CYP450s 代谢酶活性 药代动力学 OnlineSPE-LC-MS/MS法 

分 类 号：R289.5[医药卫生—方剂学]