The effect of apatinib on pharmacokinetic profile of buspirone both in vivo and in vitro

Objective: In this study, we aimed to investigate the potential interaction of apatinib and buspirone and underlying mechanism.

Methods: UPLC-MS/MS assay was applied to determine the concentrations of buspirone and its main metabolites (1-PP and 6-OH buspirone) after incubated with liver microsomes. Moreover, the connection of in vitro and in vivo was further determined. Sprague Dawley rats were randomly divided into two groups: group A (20 mg/kg buspirone) and group B (buspirone vs 40 mg/kg apatinib). Tail vein blood was collected and subjected to the UPLC-MS/MS detection.

Key findings: Apatinib inhibited the generations of 1-PP and 6-OH buspirone dose-dependently with IC₅₀ of 1.76 and 2.23 μm in RLMs, and 1.51 and 1.48 μm in HLMs, respectively. There was a mixed mechanism underlying such an inhibition effect. In rat, AUC_{(0- t )} , AUC_(0-∞) , T_max and C_max of buspirone and 6-OH buspirone increased significantly while co-administering with apatinib, but V_z/F and CL_z/F decreased obviously while comparing group A with group B .

Conclusions: Apatinib suppresses the CYP450 based metabolism of buspirone in a mixed mechanism and boosted the blood exposure of prototype drug and 6-OH buspirone dramatically. Therefore, extra caution should be taken when combining apatinib with buspirone in clinic.

apatinib; buspirone; drug interaction; metabolism; pharmacokinetics.