The Effect of <i>α</i> ‐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 IC₅₀ 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_(0-12h), AUC_(0-∞), and C_max, prolonged the t_1/2 and shortened the MRT_(0-12h) and MRT_(0-∞) of tofacitinib. At the same time, the CL_z/F 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.