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目的研究新型桂皮酰胺类抗癫痫化合物氯桂丁胺体内代谢的CYP450同工酶亚型及其对6种主要CYP450同工酶活性的影响。方法超高速离心法制备大鼠肝微粒体,高效液相色谱法定量分析氯桂丁胺原型药、代谢物、6种CYP450同工酶探针药(CYP1A2/非那西汀、CYP2E1/氯唑沙宗、CYP3A/硝苯地平、CYP2C9/甲苯磺丁脲、CYP2C19/S-美芬妥英、CYP2D6/右美沙芬)代谢物,在大鼠肝微粒体、6种重组人源CYP450同工酶孵育模型中浓度的变化。结果 6种重组人源CYP450同工酶分别与氯桂丁胺共孵育,以及6种特异性CYP450同工酶抑制剂(α-奈黄酮/CYP1A2、磺胺苯吡唑/CYP2C9、奥美拉唑/CYP2C19、奎尼丁/CYP2D6、二乙基二硫氨甲酸/CYP2E1、酮康唑/CYP3A)分别与氯桂丁胺及大鼠肝微粒体共孵育结果显示,参与氯桂丁胺生物转化的主要代谢酶亚型包括代谢物M1(CYP2D6),M2(CYP1A2),M3(CYP2C19和CYP3A4)。氯桂丁胺在0.1~16μg·m L-1浓度范围内对CYP1A2,CYP2E1和CYP3A酶活性无显著性影响。在2~16μg·m L-1浓度范围内显著性抑制CYP2C9酶活性(抑制率60.45%~97.64%)、CYP2C19酶活性(抑制率50.44%~77.44%)、CYP2D6酶活性(抑制率35.92%~71.43%)。结论本研究结果提示氯桂丁胺可经多酶代谢,其自身的代谢清除可能不易受单一CYP450亚型遗传因素所干扰,但由于其抑制CYP2C9,CYP2C19及CYP3A的活性,如与相应底物类药物合用时应注意药物-药物间相互作用。
Objective To study the metabolism of CYP450 isoforms and their effects on the activities of six major CYP450 isoenzymes in vivo by a new cinnamic amide antiepileptic compound. Methods The rat liver microsomes were prepared by ultra-high speed centrifugation. High performance liquid chromatography (HPLC) was used for the quantitative analysis of the drugs, metabolites, six CYP450 isozyme probes (CYP1A2 / phenacetin, CYP2E1 / CYP3A / nifedipine, CYP2C9 / tolbutamide, CYP2C19 / S-mephenytoin, CYP2D6 / dextromethorphan) metabolites in rat liver microsomes, 6 recombinant human CYP450 isozymes Changes in concentration in the incubation model. Results Six kinds of recombinant human CYP450 isoenzymes were incubated with clofibrate respectively, and six specific CYP450 isoenzyme inhibitors (α-neferonin / CYP1A2, sulfapazole / CYP2C9, omeprazole / CYP2C19, quinidine / CYP2D6, diethyldithiocarbamate / CYP2E1, ketoconazole / CYP3A) were incubated with clofibrate and rat liver microsomes, respectively. The results showed that the main involved in the biological conversion of clofibrate Metabolic enzyme subtypes include metabolites M1 (CYP2D6), M2 (CYP1A2), M3 (CYP2C19 and CYP3A4). Chloropinine had no significant effect on the activities of CYP1A2, CYP2E1 and CYP3A in the concentration range of 0.1 ~ 16μg · m L-1. CYP2C9 (60.45% -97.64%), CYP2C19 (50.44% -77.44%) and CYP2D6 (35.92% ~ (-1)) were significantly inhibited in the concentration range of 2 ~ 16μg · m L- 71.43%). Conclusions The results of this study suggest that clofibrate may be metabolized by multiple enzymes and its own metabolic clearance may not be easily interfered by genetic factors of a single CYP450 subtype but due to its inhibitory activity on CYP2C9, CYP2C19 and CYP3A, Drugs should pay attention to drug-drug interactions.