新型抗肿瘤微管抑制剂IG-105的体外代谢及药物相互作用的研究

发布时间：2018-02-14 13:46

本文关键词： IG- 抗肿瘤体外代谢药物相互作用　出处：《药学学报》2017年06期 　论文类型：期刊论文

【摘要】：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。
[Abstract]:N-dimethoxy pyridine -3- substituted pyridine-3-methoxycarbazole-3-sulfonamide (IG-105) is a new structure of microtubule depolymerization agent. To understand the metabolic properties of IG-105 and evaluate the possibility of metabolic drug interaction, HPLC-Orbitrap-MS was used to identify possible metabolites of human liver microsomes (HLMs) and recombinant CYP450 isoenzyme rP450s, which were used to study the metabolic enzymes involved in the biotransformation of IG-105, and HPLC-Orbitrap-MSwere used to identify the possible metabolites of HPLC-Orbitrap-MS.HPLC-Orbitrap-MS. The inhibitory effects of IG-105 on five major CYP450 enzymes were evaluated. The results showed that IG-105 could be metabolized by various P450 enzymes including CYP1A2CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5, among which IG-105 metabolism was most likely mediated by CYP1A2CYP2B6CYP2C19 and CYP3A, and demethylation was the most important phase I metabolic reaction of IG-105. At the same time, the inhibitory effects of IG-105 on CYP2C9, CYP2C9, CYP2D6 and CYP3A were identified, and the IC50 values of CYP2C19, CYP2C9, CYP2D6 and CYP2C19, CYP2D6 and CYP3A, were 6. 4, 23. 64, 0. 391.4 and 3. 14 渭 mol 路L ~ (-1), respectively. The results showed that biotransformation of IG-105 involved multiple enzyme pathways, and when combined with other drugs, the biotransformation of IG-105 involved several enzyme pathways, and its IC50 was 6. 4 渭 mol 路L ~ (-1) and 3.14 渭 mol 路L ~ (-1) respectively. Because other drugs inhibit the activity of some P450 enzyme, the metabolism of IG-105 is blocked and the risk of side effects is lower, while IG-105 has moderate inhibitory effect on CYP1A2CY CYP2D6 and CYP3A, and strong inhibitory effect on CYP2C19. Therefore, drug interaction should be paid more attention to when combined with drugs metabolized mainly by these enzymes to avoid side effects.
【作者单位】：中国医学科学院北京协和医学院医药生物技术研究所抗感染药物研究北京市重点实验室;中国医学科学院北京协和医学院药物研究所;
【基金】：国家自然科学基金委创新群体(81621064) 北京市科技专项(Z141102004414065,Z151100000315029)
【分类号】：R96

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