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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 α-dependent manner.

circulation journal

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