基于鸡尾酒法评价曲马多对大鼠CYP450同工酶活性的影响

Effect of tramadol on CYP450 isoforms activity in rats

目的研究曲马多对细胞色素P450(CYP)酶代谢能力的影响,采用鸡尾酒法评价CYP2B1、CYP2D1、CYP1A2、CYP3A2、CYP2C11的活性。方法将大鼠随机分为曲马多组(低、中、高)和对照组。曲马多组大鼠连续灌胃给药10 mg/kg、20 mg/kg、30 mg/kg(低、中、高)曲马多14 d。然后灌胃给予安非他酮、美托洛尔、非那西丁、咪唑安定和甲苯磺丁脲5种探针药物,UPLC-MS/MS测定血浆浓度。结果曲马多组与对照组比较,安非他酮和美托洛尔药代动力学参数差异有统计学意义(P <0. 05)。另外,与对照组相比,曲马多灌胃14 d后谷丙转氨酶(ALT)、碱性磷酸酶(ALP)、尿素、肌酐(Cr)、尿酸(UA)、谷草转氨酶(AST)差异无统计学意义(P> 0. 05)。结论曲马多连续14 d灌胃可抑制大鼠CYP2B1和CYP2D1的活性。生化检测结果显示连续14 d给予曲马多不会造成肝肾功能变化。

Objective In order to investigate the effects of tramadol on the metabolic capacity of cytochrome P450（ CYP）enzymes,a cocktail method was employed to evaluate the activities of CYP2 B1,CYP2 D1,CYP1 A2,CYP3 A2,CYP2 C11.Methods The rats were randomly divided into tramadol group（ Low,Medium,High） and control group. The tramadol group rats were given 10 mg/kg,20 mg/kg,30 mg/kg（ Low,Medium,High） tramadol by continuous intragastric administration for14 days. Five probe drugs including bupropion,metroprolol,phenacetin,midazolam and tolbutamide were given to rats through intragastric administration,and the plasma concentrations were determined by ultra performance liquid chromatography-tandem massspectrometry（ UPLC-MS/MS）. Results Statistical significance on the pharmacokinetics difference for bupropion and metroprolol in rats were observed by comparing tramadol group with control group（ P 0. 05）. And there was no statistical significance on the difference for alanine aminotransferase（ ALT）,alkaline phosphatase（ ALP）,urea,creatinine（ Cr）,uric acid（ UA） after 14 days of intragastric administration of tramadol（ P 0. 05）. Conclusion Continuous 14 days-intragastric administration of tramadol may inhibit the activities of CYP2 B1 and CYP2 D1 in rats. The biomedical test results showed continuous 14 days-intragastric administration of tramadol would not cause liver or kidney damage.