【摘要】 目的:考察延胡索乙素(tetrahydropalmatine,THP)对映体对小鼠肝脏主要CYP450酶的体外抑制及体内诱导作用,从而预测其在临床上可能发生的代谢性药物相互作用,为临床合理用药提供科学依据。方法:以探针底物法,考察左旋延胡索乙素[(-)-tetrahydropalmatine,(-)-THP]和右旋延胡索乙素[(+)-tetrahydropalmatine,(+)-THP]体外对小鼠肝微粒体主要Ⅰ相代谢酶CYP1A2、CYP2C、CYP2D22、CYP2E1、CYP3A11活性的影响;采用微粒体体外孵育"鸡尾酒"法(cocktail法),考察小鼠经高、低剂量(-)-THP和(+)-THP(240 mg/kg和60 mg/kg)连续灌胃7 d后,其肝微粒体中主要I相代谢酶活性的变化,以评价(-)-THP和(+)-THP对小鼠肝微粒体主要CYP450酶是否具诱导作用。结果:(-)-THP和(+)-THP体外对小鼠肝微粒体主要的CYP 450 I相代谢酶的抑制作用均不强,(+)-THP对CYP2C抑制的IC50为43.89μmol/L,两者对本研究考察的其它CYP亚型的IC50均大于100μmol/L;与溶剂处理组比较,小鼠经60 mg/kg和240 mg/kg的(-)-THP处理后,CYP1A2活性分别增加了68.7%和73.0%(P<0.05、P<0.01),经240 mg/kg的(-)-THP处理后,小鼠CYP2C37活性增加了80.4%(P<0.05),(-)-THP对其余CYP亚型活性未显示明显影响;(+)-THP对本研究考察的所有CYP亚型均未显示明显影响。结论:(-)-THP和(+)-THP体外对小鼠肝微粒体CYP主要亚型的抑制作用较弱;(-)-THP对小鼠肝微粒体CYP1A2、CYP2C37仅显示微弱的诱导作用,(+)-THP对小鼠肝微粒体主要CYP450酶亚型无明显诱导作用。更多还原

【Abstract】 Objective: To investigate the inhibitive and inductive effect of(-)-tetrahydropalmatine(THP) and(+)-THP on main CYP450 isoforms in mouse liver microsomes.Methods: The in vitro inhibitory effect was evaluated by incubating(-)-THP or(+)-THP with the probe substrates of main phase I metabolic enzymes in mouse liver microsomes,and the remaining substrates were determined by HPLC or LC-MS/MS method.Mice were administered with(-)-THP or(+)-THP at dosage of 240 mg/kg or 60 mg/kg by gastric lavage for successive 7 days,then the cocktail-LC-MS method was applied to assess the activities of main CYP450 isoforms in mouse liver microsomes.Results: The IC50 values of both(-)-THP and(+)-THP on isoforms studied were higher than 100 μmol/L except that IC50 value of(+)-THP on CYP2C was 43.89 μmol/L,indicating weak inhibition of(-)-THP and(+)-THP on CYP1A2,CYP2D22,CYP2E1 and CYP3A11 in vitro.Compared with the vehicle group,the activities of CYP2D22,CYP2E1 and CYP3A11 were not increased significantly in(-)-THP and(+)-THP treatment groups,while the activities of CYP1A2 in 60 mg/kg and 240 mg/kg(-)-THP groups were 68.7% and 73.0% higher,than that of the vehicle group(P<0.05,P<0.01,respectively),the activity of CYP2C37 in 240 mg/kg(-)-THP treatment group was 80.4%,higher than that of the vehicle group(P<0.05).Conclusions: There is negligible or weak inhibition on main CYP450 in mouse liver microsomes by(-)-THP and(+)-THP in vitro.(+)-THP does not induce main CYP450 in mouse liver microsomes while(-)-THP weakly induces CYP1A2 and CYP2C37.更多还原