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

In vitro metabolism and drug-drug interaction potential of IG-105,a novel antimicrotubule agent

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。

IG-105, N-（2,6-dimethoxypyridine-3-yl）-9-methylcarbazole-3-sulfonamide, a novel antimicrotubule agent, showed potent anticancer activity in a variety of human tumor cells in vitro and in vivo. In order to characterize the metabolism and the possible drug-drug interaction of IG-105, we carried out a series of experiments. Drug metabolizing enzymes involved in IG-105 metabolism were investigated by using pooled human liver microsomes （HLMs） and recombinant cytochrome P450 isoforms （rP450s） respectively. The possible metabolites were analyzed by liquid chromatography-orbitrap-mass spectrometry （LC-Orbitrap-MS）.The inhibitory effect of IG-105 on main P450 enzymes was also evaluated. The results showed that IG-105 can be metabolized by a series of rP450s, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5, with the major contribution enzymes being CYP1A2, CYP2B6, CYP2C19, and CYP3A. Three metabolites （M1-M3） were identified and demethylation was the major phase I metabolic reaction for IG-105. IG-105 moderately inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A enzyme activities with ICs0 values of 6.42, 23.64, 0.39, 1.4, and 3.14 μmol＇L 1, respectively. Since the biotransformation of IG-105 involves multiple enzymatic pathways, the compound is less likely to be a victim of a concomitantly used medicine which inhibits activity of one of the CYPs. However, as IG-105 showed medium to strong inhibition on CYP1A2, CYP2D6, CYP3A, and CYP2C19, caution is particularly needed when IG-105 is co-administrated with other anticancer drugs which are mainly metabolized by the above enzymes.