Inhibition of Axitinib on Buspirone Metabolism in vitro and in vivo.

Objective: 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 IC 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 (C ) 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.