Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Chem Biol Interact. 2024 Aug 25;399:111146. doi: 10.1016/j.cbi.2024.111146. Epub 2024 Jul 14.
Apixaban is an oral anticoagulant that directly inhibits the target Factor Xa (FXa). In this study, we focused on the in vivo and in vitro effects of adagrasib and asciminib on apixaban metabolism, to discover potential drug-drug interactions (DDI) and explore their inhibitory mechanisms. The levels of apixaban and its metabolite, O-desmethyl-apixaban (M2), were determined by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In vitro evaluation, the maximum half inhibitory concentration (IC) of adagrasib in rat liver microsomes (RLM) and human liver microsomes (HLM) against apixaban was 7.99 μM and 117.40 μM, respectively. The IC value of asciminib against apixaban in RLM and HLM was 4.28 μM and 18.42 μM, respectively. The results of the analysis on inhibition mechanisms showed that adagrasib inhibited the metabolism of apixaban through a non-competitive mechanism, while asciminib inhibited the metabolism of apixaban through a mixed mechanism. Moreover, the interaction of apixaban with adagrasib and asciminib in Sprague-Dawley (SD) rats was also investigated. It was found that the pharmacokinetic characteristics of apixaban were significantly changed when combined with these two antitumor drugs, where AUC, AUC, t, T, and C were increased, while CL/F was significantly decreased. But both drugs did not appear to affect the metabolism of M2 in a significant way. Consistent results from in vitro and in vivo demonstrated that both adagrasib and asciminib inhibited the metabolism of apixaban. It provided reference data for the future clinical individualization of apixaban.
阿哌沙班是一种直接抑制靶向因子 Xa（FXa）的口服抗凝剂。在这项研究中，我们专注于阿达格拉西布和 ASC 抑制剂对阿哌沙班代谢的体内和体外影响，以发现潜在的药物相互作用（DDI）并探索其抑制机制。通过超高效液相色谱串联质谱法（UPLC-MS/MS）测定阿哌沙班及其代谢物 O-去甲基阿哌沙班（M2）的水平。体外评价，阿达格拉西布在大鼠肝微粒体（RLM）和人肝微粒体（HLM）中对阿哌沙班的最大半抑制浓度（IC）分别为 7.99μM 和 117.40μM。ASC 抑制剂在 RLM 和 HLM 中对阿哌沙班的 IC 值分别为 4.28μM 和 18.42μM。抑制机制分析结果表明，阿达格拉西布通过非竞争性机制抑制阿哌沙班的代谢，而 ASC 抑制剂通过混合机制抑制阿哌沙班的代谢。此外，还研究了阿哌沙班与 ADG 和 ASC 在 Sprague-Dawley（SD）大鼠中的相互作用。结果发现，当与这两种抗肿瘤药物联合使用时，阿哌沙班的药代动力学特征发生了显著变化，AUC、AUC、t、T 和 C 增加，而 CL/F 显著降低。但这两种药物均未明显影响 M2 的代谢。体内外的一致结果表明，阿达格拉西布和 ASC 抑制剂均抑制阿哌沙班的代谢。为阿哌沙班未来的个体化临床应用提供了参考数据。
