An investigation into possible interactions among four vascular epidermal growth factor receptor-tyrosine kinase inhibit
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ORIGINAL ARTICLE
An investigation into possible interactions among four vascular epidermal growth factor receptor‑tyrosine kinase inhibitors with gefitinib Chenxiang Wang1 · Lili Ying2 · Mi Jin1 · Fangfang Zhang1 · Dawei Shi1 · Ying Dai1 · Ziye Zhou1 Received: 5 July 2020 / Accepted: 20 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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 AUC0–t, AUC0–∞ and Cmax 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. Keywords VEGFR-TKI · Gefitinib · Combination · Interaction · Advanced NSCLC
Introduction
Chenxiang Wang and Lili Ying contributed equally to this work. Electronic Supplementary Material The online version of this article (https://doi.org/10.1007/s00280-020-04191-0) contains supplementary material, which is available to authorized users. * Ziye Zhou [email protected] 1
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
2
Non-small cell lung cancer (NSCLC) is a malignant tumor with high morbidity and mortality rates. Patients with NSCLC usually present with epidermal growth factor receptor (EGFR) mutations, and tyrosine kinase inhibitors (TKIs) targeting EGFR mutations are currently the main medications for treatment of NSCLC. As a fir
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