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目的建立同时测定大鼠血浆中4种CYP450探针药物,即甲苯磺丁脲(CYP2C9)、奥美拉唑(CYP2C19)、安非他酮(CYP2B6)和咪达唑仑(CYP3A4)的方法,采用cocktail法快速评价辣椒碱对CYP450同工酶的影响。方法大鼠分设试验组和空白组,分别给予体重30 mg/kg剂量的辣椒碱溶液和空白溶剂7 d诱导后,于腹腔注射4种探针混合物药物,再于一系列时间点尾静脉取血,采用LC-MS法对血浆探针药物浓度进行测定,通过对试验组和空白组探针药物药代动力学参数的比较,间接反映辣椒碱对上述CYP450酶亚型的影响。结果实验结果表明辣椒碱显著降低甲苯磺丁脲AUC(0-t)和AUC(0-∞)(P<0.05),显著增加其Clz/F(P<0.05),显著减少其Cmax(P<0.01),对t1/2、Tmax无显著影响;可显著降低咪达唑仑AUC(0-t)和AUC(0-∞)(P<0.01),显著增加其Clz/F(P<0.01),对t1/2、Tmax和Cmax无显著影响;显著增加奥美拉唑的AUC(0-t)和AUC(0-∞)(P<0.05),显著减少其Clz/F(P<0.05),对t1/2、Tmax和Cmax无显著影响;对安非他酮在大鼠体内的代谢无显著影响。结论辣椒碱对大鼠的CYP2C9、CYP3A4有诱导作用,对大鼠的CYP2C19有抑制作用,对CYP2B6没有显著的影响。
Objective To establish a method for simultaneous determination of 4 CYP450 probe drugs in rat plasma, namely, CYP2C9, omeprazole (CYP2C19), bupropion (CYP2B6) and midazolam (CYP3A4) Rapid evaluation of the effect of capsaicin on CYP450 isoenzyme by cocktail method. Methods Rats were randomly divided into test group and blank group. Capsaicin (30 mg / kg) and blank solvent (7 mg / kg) were given to the rats in the experimental group and the control group, respectively. Four kinds of probe mixture drugs were injected into the peritoneal cavity. , The concentration of plasma probe drug was determined by LC-MS method. The pharmacokinetic parameters of test drug and blank group probe indirectly reflected the effect of capsaicin on the CYP450 enzyme subtype. Results The experimental results showed that capsaicin significantly reduced the tolbutamide AUC (0-t) and AUC (0-∞) (P <0.05), significantly increased Clz / F (P < (P <0.01), and had no significant effect on t1 / 2 and Tmax. It significantly decreased midazolam AUC (0-t) and AUC (0-∞) (P <0.05), but no significant effect on t1 / 2, Tmax and Cmax; AUC (0-t) and AUC , No significant effect on t1 / 2, Tmax and Cmax; no significant effect on the metabolism of bupropion in rats. Conclusion Capsaicin can induce CYP2C9 and CYP3A4 in rats and inhibit CYP2C19 in rats, but not CYP2B6 in rats.