阿哌沙班是一种口服抗凝剂，可直接抑制目标因子 Xa (FXa)。在本研究中，我们重点关注阿达格拉西和阿西米尼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）并探讨其抑制机制。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数抑制浓度（IC50）分别为7.99 μM和117.40 μM。阿西米尼在 RLM 和 HLM 中针对阿哌沙班的 IC50 值分别为 4.28 μM 和 18.42 μM。抑制机制分析结果表明，阿达格拉西通过非竞争性机制抑制阿哌沙班的代谢，而阿西米尼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阿达格拉西和阿西米尼在 Sprague-Dawley (SD) 大鼠中的相互作用。结果发现，阿哌沙班与这两种抗肿瘤药合用时，药代动力学特征发生显着改变，AUC(0-t)、AUC(0-∞)、t1/2、Tmax、Cmax增加，而CLz/F增加。明显减少。但这两种药物似乎都没有显着影响 M2 的代谢。体外和体内的一致结果表明阿达格拉西和阿西米尼均抑制阿哌沙班的代谢。为未来阿哌沙班的临床个体化提供参考数据。版权所有©2024。Elsevier B.V.出版。

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 (IC50) of adagrasib in rat liver microsomes (RLM) and human liver microsomes (HLM) against apixaban was 7.99 μM and 117.40 μM, respectively. The IC50 value of asciminib against apixaban in RLM and HLM was 4.28 μM and 18.42 μM, respectively. The results of the 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(0-t), AUC(0-∞), t1/2, Tmax, and Cmax were increased, while CLz/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.Copyright © 2024. Published by Elsevier B.V.