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目的:建立同时测定大鼠全血中6种CYP450探针药物,即茶碱(CYP1A2)、甲苯磺丁脲(CYP2C9)、奥美拉唑(CYP2C19)、右美沙芬(CYP2D6)、氯唑沙宗(CYP2E1)和咪达唑仑(CYP3A4)的方法,并采用Cocktail法快速评价消癌平注射液CYP45同工酶的影响。方法:8只大鼠连续10 d给予消癌平注射液(临床剂量,10 mL·kg-1)前后,均同时灌胃给予6个探针底物(甲苯磺丁脲20 mg·kg-1、氯唑沙宗30 mg·kg-1、茶碱30 mg·kg-1、咪达唑仑20 mg·kg-1、奥美拉唑40 mg·kg-1、右美莎芬30 mg·kg-1),采血测定。用LC-MS/MS法同时测定大鼠体内各探针的血药浓度,DAS 1.0软件计算药动学参数,并以配对t检验对大鼠前后两轮主要药动学参数进行比较。结果:临床剂量组大鼠给药后,与给药前相比,茶碱的药动学参数无显著性变化(P>0.05);甲苯磺丁脲的AUC0-24h与给药前相比,有降低趋势(P<0.05);氯唑沙宗、咪达唑仑、奥美拉唑、右美莎芬的AUC0-24h与给药前相比,有升高趋势(P<0.05)。结论:连续给药14 d临床剂量消癌平注射液对大鼠CYP1A2活性无显著性影响;而临床剂量消癌平注射液对大鼠CYP3A4、CYP2D6有抑制作用;对CYP2C19、CYP2E1有一定的抑制作用;对CYP2C9有诱导作用。
OBJECTIVE: To establish a method for the simultaneous determination of six CYP450 probe drugs in whole blood of rats, namely theophylline (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6) (CYP2E1) and midazolam (CYP3A4). The method of Cocktail was used to evaluate the effect of CYP45 isoenzyme in Xiaojianping injection. Methods: Eight rats were treated with Xiaofanping injection (10 mL · kg-1, 10 mL · kg-1) for 10 consecutive days. Six probe substrates (tolbutamide 20 mg · kg-1 , Chlorzoxazone 30 mg · kg -1, theophylline 30 mg · kg -1, midazolam 20 mg · kg -1, omeprazole 40 mg · kg -1, dextromethorphan 30 mg · kg-1), blood test. The plasma concentration of each probe in rats was determined by LC-MS / MS simultaneously. The pharmacokinetic parameters were calculated by DAS 1.0 software and the main pharmacokinetic parameters were compared by paired t-test. Results: Compared with the pretreatment, the pharmacokinetic parameters of theophylline in the clinical dose group did not change significantly (P> 0.05) (P <0.05). AUC0-24h of chlorzoxazone, midazolam, omeprazole and dextromethorphan showed a trend of increase (P <0.05) compared with that before administration. Conclusions: The 14-day clinical dose of Xiao-Jin-Ping injection has no significant effect on the activity of CYP1A2 in rats. However, the clinical dose of Xiao-Jin-Ping Injection can inhibit the expression of CYP3A4 and CYP2D6 in rats and CYP2C19 and CYP2E1 Role; CYP2C9 induction.