Computational and Experimental Investigation of Antidiabetic Drugs on Tofacitinib Metabolism: Molecular Docking, in vitro, and in vivo Studies.

Background: Tofacitinib is an orally administered Janus kinase (JAK) inhibitor that has demonstrated significant efficacy in the treatment of rheumatoid arthritis. This study aimed to investigate the effects of gliquidone and linagliptin, two hypoglycemic agents on the pharmacokinetics of tofacitinib in vitro and in vivo.

Methods: The mechanism of drug-drug interaction was studied in vitro using a murine liver microsome incubation system and in vivo by administering gliquidone and linagliptin orally to rats pretreated with various concentrations of tofacitinib. This study used waters ACQUITY UPLC I-Class/Xevo TQD ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometer. Furthermore, molecular docking was performed to simulate the interaction using computer simulations.

Results: Gliquidone and linagliptin inhibited the metabolism of tofacitinib by heparanase in vitro with IC₅₀ values of 1.140 μM and 4.064 μM, respectively. Co-administration of gliquidone significantly increased the AUC_(0-t) of tofacitinib by approximately 43.3%, accompanied by a 45.1% increase in C_max and a 27.5% reduction in clearance (CLz/F). In contrast, linagliptin exhibited a more potent inhibitory effect, raising the AUC_(0-t) approximately 4.4-fold, enhancing the C_max by 2.86-fold, and decreasing clearance to 25.8% of the control level. These findings suggest that while both gliquidone and linagliptin significantly enhance the systemic exposure of tofacitinib, linagliptin demonstrates a markedly more significant inhibitory effect on tofacitinib's metabolism and elimination.

Conclusion: Gliquidone and linagliptin significantly altered the pharmacokinetics of tofacitinib in vitro and in vivo. This study demonstrated the drug-drug interactions between linagliptin, gliquidone, and tofacitinib, highlighting the need for clinical attention to this possibility.