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-∞) , Tmax and Cmax of buspirone and 6-OH buspirone increased significantly while co-administering with apatinib, but Vz/F and CLz/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.