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目的建立“Cocktail”探针药物法分析辛硫磷对鲫鱼细胞色素P450不同亚型酶系代谢活性的影响,为探究辛硫磷在鲫鱼体内的残留代谢途径及毒理学评价奠定基础。方法将鲫鱼随机分为4组,即辛硫磷染毒组、空白对照组、抑制剂对照组和诱导剂对照组,连续给药1周后,利用液液萃取-高效液相色谱法检测鲫鱼血浆中各探针药物浓度及药动学参数。结果辛硫磷能够显著增加咖啡因在鲫鱼体内的半衰期t_(1/2)(P<05)、血药浓度与时间曲线下的面积AUC(P<0.01)以及平均驻留时间MRT(P<0.05);能够显著降低甲苯磺丁脲在鲫鱼体内的清除率CL(P<0.05)、AUC(P<0.01)以及MRT(P<0.05),氨苯砜在鲫鱼体内的t1/2(P<0.05)、AUC(P<0.05)以及MRT(P<0.01)。而对氯唑沙宗、奥美拉唑、美托洛尔3种探针药物在鲫鱼体内的药动学参数无显著影响。结论辛硫磷能够抑制鲫鱼体内CYP1A2的活性,诱导鲫鱼体内的CYP2C9、CYP3A4的活性,对鲫鱼体内CYP2E1、CYP2D6和CYP2C19的活性不具有明显的诱导或抑制作用。
OBJECTIVE To establish the “Cocktail” probe drug method to analyze the effect of phoxim on the metabolic activity of different subtypes of Carassius auratus CYP150 in Carassius auratus, and lay the foundation for the study of the metabolic pathway and the toxicological evaluation of phoxim in the carp. Methods Crucian carp were randomly divided into 4 groups: phoxim group, blank control group, inhibitor control group and inducer control group. After continuous administration for one week, the carp was detected by liquid-liquid extraction and high performance liquid chromatography Plasma concentrations of each probe and pharmacokinetic parameters. Results Phoxim could significantly increase the half-life (t 1/2) of caffeine in carp (P <0.05), AUC (P <0.01) and mean residence time (MRT) 0.05). The clearance rate of tolbutamide in crucian carp (P <0.05), AUC (P <0.01) and MRT (P <0.05) 0.05), AUC (P <0.05) and MRT (P <0.01). There was no significant effect on the pharmacokinetic parameters of the three probe drugs of chlorzoxazone, omeprazole and metoprolol in the crucian carp. Conclusion Phoxim can inhibit the activity of CYP1A2 in vivo and induce CYP2C9 and CYP3A4 activity in Carassius auratus, but not induce or inhibit the activity of CYP2E1, CYP2D6 and CYP2C19 in Carassius auratus.