Yang_2026_Drug.Metab.Dispos_54_100267

Immunosuppressants are a class of therapeutic agents that attenuate immune responses by modulating pathways involved in immune cell activation, proliferation, and signaling, and are widely used to prevent organ transplant rejection and to treat autoimmune diseases. The present study aimed to evaluate potential drug-drug interactions (DDIs) induced by immunosuppressants through inhibition of human carboxylesterases (CESs). Based on network pharmacology analysis, CESs were identified as potential targets of immunosuppressants and coadministered drugs. In vitro incubation experiments demonstrated that several immunosuppressants strongly inhibited the activities of CES1 and CES2, with inhibition ratios exceeding 70%. Kinetic studies and in vitro-in vivo extrapolation revealed that immunosuppressants might induce DDIs by inhibiting CESs in vivo. Molecular docking and molecular dynamics simulations indicated that hydrogen bonding contributed to the interactions between immunosuppressants and CESs. Furthermore, studies in human liver microsomes and HepG2 cells confirmed that the hydrolysis of aspirin and mycophenolate mofetil was significantly reduced by coadministration. These findings highlight the necessity of careful monitoring for potential DDIs when immunosuppressants are used concomitantly in clinical settings. SIGNIFICANT STATEMENT: This study reveals that immunosuppressants potently inhibit human carboxylesterases (CES1 and CES2), thereby disrupting the metabolic hydrolysis of coadministered drugs and highlighting a critical risk for clinically significant drug-drug interactions.