扶正化瘀方对正常及肝纤维化大鼠体内CYP450酶的影响

Effect of Fuzheng Huayu recipe on CYP450 isozymes in normal and liver fibrosis rats

使用Cocktail探针药物法,研究扶正化瘀方(FZHY)对正常和肝纤维化大鼠细胞色素P450(CYP450)5种同工酶的影响。正常和二甲基亚硝胺(dimethylnitrosamine,DMN)腹腔注射诱导的肝纤维化模型大鼠,以FZHY浸膏粉连续灌胃2周后,单剂量尾静脉注射由CYP450 5种同工酶的特异性探针底物非那西丁(CYP1A2)、甲苯磺丁脲(CYP2C9)、奥美拉唑(CYP2C19)、氢溴酸右美沙芬(CYP2D6)和咪达唑仑(CYP3A4)配置的Cocktail探针溶液后,通过建立的LC-MS/MS法同时检测血浆中5种探针药物的浓度,采用PK solution 2TM对数据进行处理,并计算主要药动学参数。正常大鼠灌胃FZHY后,非那西丁、甲苯磺丁脲、奥美拉唑和氢溴酸右美沙芬的AUC0-t均出现不同程度的增加,CL也均出现降低趋势,提示FZHY能明显抑制正常大鼠CYP1A2,CYP2C9,CYP2C19,CYP2D6的活性,但对CYP3A4的活性影响不明显;肝纤维化大鼠灌胃FZHY后,甲苯磺丁脲的AUC0-t显著增加,Vd显著降低,其他4种探针药物的药动学参数未见显著改变,提示在肝纤维化大鼠体内FZHY仅对CYP2C9有抑制作用,对CYP1A2,CYP2C19,CYP2D6,CYP3A4活性影响不明显。CYP450酶在肝纤维化条件下活性的改变可能是FZHY对正常和肝纤维化大鼠CYP450酶影响不同的原因。

To study the effect of Fuzheng Huayu recipe（ FZHY） on five types of isozymes of cytochrome P450（ CYP450） of normal and liver fibrosis rats by using the cocktail probe method. Dimethylnitrosamine（ DMN） was injected to induce the liver fibrosis model. After the tail vein injection with Cocktail probe solutions prepared with five CYP450 s probe substrates（ phenacetin-CYP1A2,omeprazole-CYP2C9,tolbutamide-CYP2C19,dextromethorphan-CYP2D6,midazolam-CYP3A4）,the plasma concentrations of the five probe substrates were determined by LC-MS / MS,and the pharmacokinetic parameters were calculated by PK solutions 2. After the oral administration with FZHY,normal rats given phenacetin,omeprazole,tolbutamide and dextromethorphan showed increase in AUC0-tand decrease in CL to varying degrees,indicating that FZHY obviously inhibited the activities of CYP1A2,CYP2C9,CYP2C19 and CYP2D6 in normal rats,but with no obvious effect on the activity of CYP3A4. After the oral administration with FZHY,liver fibrosis rats treated with CYP2C9 showed the significant increase in AUC0-tand significant decrease in Vd,but with no obvious changes in the pharmacokinetic parameters of other four types of prove substances,suggesting that FZHY could significantly inhibit the activity of CYP2C9 in rats but had no effect on the activities of CYP1A2,CYP2C19,CYP2D6 and CYP3A4. The changes in the activity of CYP450 isozymes in liver fibrosis rats may be the reason for FZHY＇s different effects on CYP450 isozymes in normal and liver fibrosis rats.