Clinical Importance of Drug-Drug Interaction Between Warfarin and Prednisolone and Its Potential Mechanism in Relation to the Niemann-Pick C1-Like 1-Mediated Pathway

Background: Warfarin is an anticoagulant drug used to prevent thromboembolic disorders, but its pharmacological effect is affected by co-administered drugs. Therefore, careful management of warfarin-related drug-drug interactions (DDIs) is necessary for its safety and effectiveness. Recently, intestinal vitamin K-1 absorption through the Niemann-Pick C1-like 1 (NPC1L1)-mediated pathway was found to affect the pharmacological effect of warfarin. This study aimed to identify high-frequency warfarin-related DDIs in a clinical setting and elucidate their mechanism(s) in terms of changes in NPC1L1 expression and/or activity. Methods and Results: Prednisolone was the most frequently suspected drug in retrospective surveys of medical records of patients who experienced warfarin-related DDIs. Prednisolone significantly increased the international normalized ratio of prothrombin time (PT-INR) values in warfarin-treated patients. To demonstrate the involvement of NPC1L1 in warfarin-prednisolone DDI, we conducted an in vitro vitamin K-1 uptake assay using NPC1L1-overexpressing cells and found that prednisolone inhibited NPC1L1-mediated vitamin K-1 uptake. Additionally, we found that prednisolone downregulates NPC1L1 in a glucocorticoid receptor alpha-dependent manner. Conclusions: Co-administration of warfarin and prednisolone frequently enhanced the anticoagulant effect of warfarin in a clinical setting. Prednisolone-mediated suppression of NPC1L1 expression and activity could be the mechanism of DDI between warfarin and prednisolone. To manage warfarin therapy, the potential of concomitant drugs to change its anticoagulant effect through NPC1L1-related mechanisms merits consideration.