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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。
The effects of FZHY on 5 isoenzymes of cytochrome P450 (CYP450) in normal and hepatic fibrosis rats were studied using Cocktail probe method. Normal and dimethylnitrosamine (DMN) induced by intraperitoneal injection of liver fibrosis model rats, FZHY extract powder for 2 weeks after continuous gavage, a single dose of tail vein injection of CYP450 specific isoenzyme Cocktail probe configured for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 After the solution was prepared, the concentrations of five probe drugs in plasma were simultaneously detected by LC-MS / MS. The data were processed with PK solution 2TM and the main pharmacokinetic parameters were calculated. After FZHY was given to normal rats, the AUC0-t of phenacetin, tolbutamide, omeprazole and dextromethorphan hydrobromide all increased to some extent, and CL also decreased, suggesting that FZHY could Significantly inhibited the activity of CYP1A2, CYP2C9, CYP2C19 and CYP2D6 in normal rats, but had no obvious effect on the activity of CYP3A4. After FZHY administration, the AUC0-t of tolbutamide increased significantly and the Vd decreased significantly The pharmacokinetic parameters of four kinds of probe drugs showed no significant changes, suggesting that FZHY only inhibited CYP2C9 in liver fibrosis rats, but had no obvious effect on CYP1A2, CYP2C19, CYP2D6 and CYP3A4 activities. The change of activity of CYP450 in liver fibrosis may be the reason that FZHY has different effect on CYP450 enzyme in normal and hepatic fibrosis rats.