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N-(2,6-二甲氧基吡啶-3-取代)-9-甲基咔唑-3-磺酰胺(IG-105)是全新结构的小分子微管解聚合剂,在体外和动物实验中显示出较好的抗肿瘤活性。为了解IG-105的代谢性质并评价代谢性药物相互作用可能性,使用混合人肝微粒体(HLMs)和重组CYP450同工酶(r P450s)研究参与IG-105生物转化的药物代谢酶,利用液相色谱-静电场轨道阱质谱(HPLC-Orbitrap-MS)鉴定可能的代谢产物,并评估IG-105对5种主要CYP450酶的抑制作用。结果显示,IG-105可以被包括CYP1A2、CYP2B6、CYP2C9、CYP2C19、CYP2D6、CYP3A4和CYP3A5在内的多种P450酶代谢,其中IG-105的代谢最有可能是由CYP1A2、CYP2B6、CYP2C19和CYP3A介导的;脱甲基化是IG-105最主要的I相代谢反应,鉴定出3种代谢产物(M1~M3);同时IG-105对CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A具有一定的抑制作用,IC50值分别为6.4、23.64、0.39、1.4和3.14μmol·L~(-1)。结果表明,IG-105的生物转化涉及多个酶途径,当与其他药物合用时,由于其他药物抑制某种P450酶的活性而使IG-105代谢受阻从而引起毒副作用的风险较低;同时,IG-105对CYP1A2、CYP2D6和CYP3A具有中度抑制作用,对CYP2C19具有较强的抑制作用,因此与主要被这些酶代谢的药物合用时应格外注意药物相互作用,避免毒副作用。
N- (2,6-dimethoxypyridin-3-yl) -9-methylcarbazole-3-sulfonamide (IG-105) is a novel structure of a small molecule microtubule depolymerization agent in vitro and in animals Experiments showed good antitumor activity. To understand the metabolic properties of IG-105 and to evaluate the potential for metabolic drug interactions, drug-metabolizing enzymes involved in IG-105 biotransformation were studied using mixed human liver microsomes (HLMs) and recombinant CYP450 isoenzymes (rP450s) The possible metabolites were identified by HPLC-Orbitrap-MS and the inhibitory effect of IG-105 on five major CYP450 enzymes was evaluated. The results showed that IG-105 can be metabolized by a variety of P450 enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5. IG-105 is most likely metabolized by CYP1A2, CYP2B6, CYP2C19 and CYP3A Demethylation is the most important phase I metabolic reaction of IG-105, and three metabolites (M1 ~ M3) were identified. IG-105 also inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A The IC50 values were 6.4, 23.64, 0.39, 1.4 and 3.14 μmol·L -1, respectively. The results showed that the biotransformation of IG-105 involves multiple enzyme pathways. When combined with other drugs, IG-105 has a lower risk of toxic side effects due to the inhibition of the activity of certain P450 enzymes by other drugs. At the same time, IG-105 has a moderate inhibitory effect on CYP1A2, CYP2D6 and CYP3A, and has a strong inhibitory effect on CYP2C19. Therefore, IG-105 should pay special attention to drug interactions and avoid side effects when combined with drugs that are mainly metabolized by these enzymes.