探针药物法评价大鼠体内甘草配伍大戟、甘遂和芫花对细胞色素CYP1A2活性的影响

Effects of Radix Glycyrrhizae co-administered with Radix Euphorbiae Pekinensis,Radix Euphorbiae Kansui and Flos Genkwa on the activity of hepatic CYP1A2 evaluated by probe drug in vivo

目的:研究甘草与大戟、甘遂和芫花配伍禁忌的CYP1A2酶活性机制。方法:大鼠随机分为8组,对照组(Ⅰ)、甘草组(Ⅱ)、大戟组(Ⅲ)、大戟+甘草组(Ⅳ)、甘遂组(Ⅴ)、甘遂+甘草组(Ⅵ)、芫花组(Ⅶ)和芫花+甘草组(Ⅷ),各组大鼠连续10 d灌胃上述提取液,于第11天灌胃给予大鼠探针药物非那西丁溶液(10 mg·kg-1)。用HPLC-MS/MS法测定大鼠血浆中的非那西丁,并对其药动学参数进行统计学分析。结果:甘草、甘遂对CYP1A2有诱导作用,大戟、芫花对CYP1A2无显著性影响,甘草与大戟、甘遂和芫花配伍后均表现出了对CYP1A2的诱导作用。结论:对酶活性的诱导作用可能会加速大戟、甘遂和芫花中有效成分的代谢,而使功效降低;或促使大戟、甘遂和芫花中所含前毒性成分转化成为毒性成分,导致对机体毒性作用的增强,揭示了其配伍增毒、减效的内在机制。

OBJECTIVE To investigate the possible incompatible mechanisms of Radix Glycyrrhizae with Radix Euphorbiae Pekinensis,Radix Euphorbiae Kansui and Flos Genkwa on enzyme activity of CYP1A2 in traditional Chinese medicine practice.METHODS 48 rats were randomly divided into 8 groups：control group（Ⅰ）,Radix Glycyrrhizae group（Ⅱ）,Radix Euphorbiae Pekinensis group（Ⅲ）,Radix Euphorbiae Pekinensis and Radix Glycyrrhizae group（Ⅳ）,Radix Euphorbiae Kansui group（Ⅴ）,Radix Euphorbiae Kansui and Radix Glycyrrhizae group（Ⅵ）,Flos Genkwa group（Ⅶ） and Flos Genkwa and Radix Glycyrrhizae group（Ⅷ）.The rats were administered with the above decoctions by i.g consecutively 10 days,and then in the eleventh day,a single oral dose of phenacetin was given to all rats.The plasma concentration of phenacetin was determined by HPLC-MS /MS assay,and the related pharmacokinetic parameters of phenacetin were statistically analyzed.RESULTS Radix Glycyrrhizae and Radix Euphorbiae Kansui could remarkably induce the activity of CYP1A2,meanwhile,Radix Euphorbiae Pekinensis and Flos Genkwa had no significant effect on CYP1A2.The combination of Radix Glycyrrhizae with Radix Euphorbiae Pekinensis,Radix Euphorbiae Kansui and Flos Genkwa showed the induction of CYP1A2.CONCLUSION The inducing effect on the enzyme activity might decrease the medicinal efficacy by accelerating the metabolism of the active ingredients of Radix Euphorbiae Pekinensis,Radix Euphorbiae Kansui and Flos Genkwa,and /or enhance in vivo toxicity by activating the toxic components.The results revealed the possible internal mechanisms under the toxicity increasing and efficacy reducing of these incompatible medicinal herbs.