The Effect of α-Mangostin on the Pharmacokinetic Profile of Tofacitinib in Rats Both In Vitro and In Vivo.

This study investigated the effects of α-mangostin (α-MG) on the pharmacokinetics of tofacitinib in vitro and in vivo, aiming to recommend its appropriate application in clinical practice. To investigate the values of IC and inhibition of α-MG in vitro, rat liver microsomes were incubated with tofacitinib. In this study, Sprague-Dawley rats were randomly assigned to three groups: a control group, a single-dose group (50 mg/kg of α-MG), and a multiple-dose group (50 mg/(kg/d) of α-MG for 7 days). Tofacitinib (10 mg/kg) was administered 30 min after the intervention of α-MG to each group. The plasma was collected from the caudal vein at different time points and in heparinized tubes. Tofacitinib metabolites in the plasma were determined by UPLC-MS/MS. Further analyses were conducted utilizing Pymol molecular docking simulation to evaluate the effect of α-MG on tofacitinib. Our results showed that MG inhibited the metabolism of tofacitinib in vitro by exhibiting both competitive and noncompetitive inhibition. More importantly, we found that multiple-dose administration of α-MG significantly increased the AUC, AUC and C, prolonged the t and shortened the MRT and MRT of tofacitinib. At the same time, the CL was decreased, which was consistent with the results of in vitro experiments. Furthermore, we observed no significant difference between single-dose and multiple-dose groups. Intriguingly, α-MG and tofacitinib were close at the CYP3A4 spatial location. In summary, our investigation demonstrated that α-MG significantly impacts the metabolism of tofacitinib both in vitro and in vivo, suggesting potential herb-drug interactions (HDIs). The use of tofacitinib with herbs containing MG should be monitored clinically.