Department of Pharmacy, Ouhai District, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Wenzhou City, 325000, China.
Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Cancer Chemother Pharmacol. 2021 Jan;87(1):43-52. doi: 10.1007/s00280-020-04191-0. Epub 2020 Nov 10.
The objective of present work is to evaluate possible interactions among four clinically-used vascular epidermal growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKIs), including apatinib, cabozantinib, sorafenib, and sunitinib, with epidermal growth factor receptor (EGFR)-TKI gefitinib. This may advance knowledge regarding possible dual-target suppression strategies for advanced NSCLC, including VEGFR-TKI plus EGFR-TKI. The in vitro metabolism study demonstrated that apatinib inhibited the formation of metabolite M537194 with moderate effect, and inhibited another metabolite formation of M523595 with strong effect, in both human and rat liver microsomes. Sorafenib, cabozantinib, and sunitinib had no significant inhibitory effect on gefitinib metabolism. The results of the in vivo pharmacokinetics study were consistent with the in vitro metabolism study: the AUC, AUC and C of gefitinib increased significantly when co-administered with apatinib by 26.8, 28.7, and 19.8%, respectively. Cabozantinib, sorafenib, and sunitinib exhibited no effect on gefitinib pharmacokinetics. Molecular docking was applied to investigate the binding mode between TKIs and CYP2D6. The docking results illustrated that binding characteristics of apatinib and gefitinib with CYP2D6 were similar, which accounts for competitive mechanism of apatinib-inhibited gefitinib metabolism. In summary, apatinib inhibited the metabolism of gefitinib in vitro and in vivo that were mediated by CYP2D6 and CYP3A4. In addition, cabozantinib, sorafenib, and sunitinib expressed no interaction with gefitinib. The results of the present study may provide a basis and valuable information for the development of treatment strategies.
本工作旨在评估四种临床应用的血管表皮生长因子受体（VEGFR）-酪氨酸激酶抑制剂（TKI），包括阿帕替尼、卡博替尼、索拉非尼和舒尼替尼，与表皮生长因子受体（EGFR）-TKI 吉非替尼之间可能存在的相互作用。这可能有助于深入了解晚期 NSCLC 中可能的双重靶向抑制策略，包括 VEGFR-TKI 加 EGFR-TKI。体外代谢研究表明，阿帕替尼对人肝微粒体和大鼠肝微粒体中 M537194 代谢物的形成具有中等抑制作用，对 M523595 代谢物的形成具有较强抑制作用。索拉非尼、卡博替尼和舒尼替尼对吉非替尼代谢无明显抑制作用。体内药代动力学研究结果与体外代谢研究一致：当与阿帕替尼合用时，吉非替尼的 AUC、AUC 和 C 分别显著增加 26.8%、28.7%和 19.8%。卡博替尼、索拉非尼和舒尼替尼对吉非替尼的药代动力学无影响。应用分子对接研究了 TKI 与 CYP2D6 的结合模式。对接结果表明，阿帕替尼和吉非替尼与 CYP2D6 的结合特征相似，这解释了阿帕替尼抑制吉非替尼代谢的竞争机制。综上所述，阿帕替尼在体外和体内抑制了由 CYP2D6 和 CYP3A4 介导的吉非替尼代谢。此外，卡博替尼、索拉非尼和舒尼替尼与吉非替尼无相互作用。本研究结果可为治疗策略的制定提供依据和有价值的信息。
