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

Abstract

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 K1 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 K1 uptake assay using NPC1L1-overexpressing cells and found that prednisolone inhibited NPC1L1-mediated vitamin K1 uptake. Additionally, we found that prednisolone downregulates NPC1L1 in a glucocorticoid receptor α-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.

Elevated INR in a COVID-19 patient after concomitant administration of azvudine and anticoagulants

“…Although warfarin was associated with piperacillin sodium and tazobactam sodium, imipenem and cilastatin sodium, the INR continued to increase 1 or 2 days after discontinuation of the two drugs, so the interaction between warfarin and the two drugs was not considered. INR increase has been reported when high-dose dexamethasone (>40 mg/day) and warfarin are concomitantly administered (Sellam et al, 2007), which may be due to the action of highdose synthetic glucocorticoids on Niemann-Pick C1-like 1 protein (Ito et al, 2019). However, the dose of dexamethasone in this patient was 5.0 mg once a day, which was too low to cause any DDIs.…”

Elevated INR in a COVID‐19 patient after concomitant administration of favipiravir and warfarin: A case report

“…13 The underlying mechanism for DDIs involves the action of high-dose synthetic glucocorticoids on Niemann-Pick C1like 1 protein. 14 However, the dose of dexamethasone in this patient was 6.6 mg, which was too low to cause any DDIs. Ciclesonide, an inhaled drug, has a low transferability (<1%) of active metabolites into the blood; therefore, it carries little to no risk of causing DDIs.…”

In Silico Analysis to Identify Molecular Targets for Chemicals of Concern: The Case Study of Flocoumafen, an Anticoagulant Pesticide

“…Another target, the glucocorticoid receptor, has a long history of pharmacological interaction with warfarin‐like molecules. Prednisolone and dexamethasone, potent glucocorticoid receptor agonists, are frequently associated with drug–drug interactions in patients treated with warfarin (Sellam et al 2007; Ito et al 2019). Moreover, it has been shown that warfarin induces vascular calcification (Jiang et al 2016), a process that is also facilitated by glucocorticoids, although the evidence points to a mechanism involving the mineralocorticoid receptor (Zhu et al 2016).…”