Drug Design, Development and Therapy (Jun 2022)
Inhibition of Axitinib on Buspirone Metabolism in vitro and in vivo
Abstract
Bo-Wen Zhang,1 Ni-Hong Pang,2 Ren-Ai Xu,1 Gao-Er Qu,3 Cong-Rong Tang1 1Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Pharmacy, The Third Affiliated Hospital of Shanghai University (Wenzhou People’s Hospital), Wenzhou, People’s Republic of China; 3Department of Pharmacy, Health Service Community of Yueqing Third People’s Hospital, Wenzhou, People’s Republic of ChinaCorrespondence: Cong-Rong Tang, Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China, Tel +86 13867722688, Email [email protected]: To evaluate the effect of axitinib on buspirone metabolism in vitro and in vivo.Methods: A microsome incubation assay was performed to study the effect and mechanism of axitinib on buspirone metabolizing. In vivo, buspirone was administered with or without axitinib to Sprague–Dawley rats. Plasma samples were collected and subjected to ultra-performance liquid chromatography–tandem mass spectrometry.Results: In both human liver microsomes (HLMs) and rat liver microsomes (RLMs), axitinib (100 μM) decreased buspirone hydroxylation and N-dealkylation by > 85%. Axitinib inhibited buspirone hydroxylation and N-dealkylation, with an IC50 of 15.76 and 9.74 for RLMs, and 10.63 and 9.902 for HLMs. Axitinib showed noncompetitive inhibition of both 6′-hydroxylation and N-dealkylation. Moreover, coadministration of axitinib and buspirone led to an increase in the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of buspirone by 4.3- and 5.3-fold, respectively, compared with the control group.Conclusion: Axitinib inhibited buspirone metabolism in vivo and in vitro, which increases the risk of the side effects of buspirone in the clinic. When coadministered with axitinib, a lower dosage of buspirone should be defined to avoid a toxic response. Axitinib is suspected to function as an inhibitor of CYP3A4.Keywords: buspirone, axitinib, drug-drug interactions, liver microsomes, noncompetitive inhibition
