这项研究的目的是阐明aumolertinib的药物相互作用谱,CYP3A4基因多态性对aumolertinib代谢特征的影响。通过微粒体酶反应,我们筛选了153种药物,鉴定出15种显著抑制aumolertinib代谢的药物.其中,替米沙坦和卡维地洛在大鼠肝微粒体(RLM)和人肝微粒体(HLM)中表现出有效的抑制活性。在体内,奥莫替尼的药代动力学参数,包括AUC和Cmax,当与卡维地洛共同给药时,清除率CLz/F显着降低。有趣的是,代谢物HAS-719的药代动力学参数在共同给药时表现出与aumolertinib相似的趋势.机械上,替米沙坦和卡维地洛对aumolertinib的代谢均表现出混合型抑制作用.此外,我们使用杆状病毒-昆虫细胞表达系统制备了24个重组CYP3A4微粒体,并以aumolertinib为底物获得了酶动力学参数.酶动力学研究获得了各种CYP3A4变体介导的aumolertinib代谢的动力学参数。根据相对清除率,与野生型相比,CYP3A4.4、5、7、8、9、12、13、14、17、18、19、23、24、33和34显示出显著更低的清除率。在不同的CYP3A4变体中,替米沙坦和卡维地洛对奥莫替尼代谢的抑制作用也不同。替米沙坦和卡维地洛在CYP3A4.1中的IC50值分别为6.68±1.76μM和0.60±0.25μM,分别,而在CYP3A4.12中,IC50超过100μM。最后,我们利用腺相关病毒实现CYP3A4*1和CYP3A4*12的肝脏特异性高表达。在活性较低的CYP3A4*12的高表达组中,药物-药物相互作用的幅度显着减弱。总之,CYP3A4基因多态性不仅影响奥莫替尼的药代动力学特征,还有替米沙坦和卡维地洛对其的抑制作用。
The purpose of this study is to clarify the drug interaction profile of aumolertinib, and the influence of CYP3A4 genetic polymorphism on aumolertinib metabolic characteristics. Through microsomal enzyme reactions, we screened 153 drugs and identified 15 that significantly inhibited the metabolism of aumolertinib. Among them, telmisartan and carvedilol exhibited potent inhibitory activities in rat liver microsomes (RLM) and human liver microsomes (HLM). In vivo, the pharmacokinetic parameters of aumolertinib, including AUC and Cmax, were significantly altered when co-administered with carvedilol, with a notable decrease in the clearance rate CLz/F. Interestingly, the pharmacokinetic parameters of the metabolite HAS-719 exhibited a similar trend as aumolertinib when co-administered. Mechanistically, both telmisartan and carvedilol exhibited a mixed-type inhibition on the metabolism of aumolertinib. Additionally, we used a baculovirus-insect cell expression system to prepare 24 recombinant CYP3A4 microsomes and obtained enzymatic kinetic parameters using aumolertinib as a substrate. Enzyme kinetic studies obtained the kinetic parameters of various CYP3A4 variant-mediated metabolism of aumolertinib. Based on the relative clearance rates, CYP3A4.4, 5, 7, 8, 9, 12, 13, 14, 17, 18, 19, 23, 24, 33, and 34 showed significantly lower clearance rates compared to the wild-type. Among the different CYP3A4 variants, the inhibitory potency of telmisartan and carvedilol on the metabolism of aumolertinib also varied. The IC50 values of telmisartan and carvedilol in CYP3A4.1 were 6.68 ± 1.76 μM and 0.60 ± 0.25 μM, respectively, whereas in CYP3A4.12, the IC50 exceeded 100 μM. Finally, we utilized adeno-associated virus to achieve liver-specific high expression of CYP3A4*1 and CYP3A4*12. In the group with high expression of the less active CYP3A4*12, the magnitude of the drug-drug interaction was significantly attenuated. In conclusion, CYP3A4 genetic polymorphism not only influences the pharmacokinetic characteristics of aumolertinib, but also the inhibitory potency of telmisartan and carvedilol on it.