ArticleBlood advances2020
Competitive tight-binding inhibition of VKORC1 underlies warfarin dosage variation and antidotal efficacy.
Article in Blood advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 19 citations in OpenAlex.
- Isomer-Dependent Pharmacokinetic Behavior and VKOR Interactions of Second-Generation Anticoagulant Rodenticides: An Integrated In Vivo-In Vitro-In Silico Investigation.International journal of molecular sciences · 2026Article
- A Prediction Model of Stable Warfarin Doses in Patients After Mechanical Heart Valve Replacement Based on a Machine Learning Algorithm.Reviews in cardiovascular medicine · 2025Article
- Association between gene polymorphisms and initial warfarin therapy in patients after heart valve surgery.Pharmacological reports : PR · 2024Article
- Acute kidney injury interacts with VKORC1 genotype on initiative warfarin dose among heart surgery recipients: a real-world research.Scientific reports · 2023Article
- Missense VKOR mutants exhibit severe warfarin resistance but lack VKCFD via shifting to an aberrantly reduced state.Blood advances · 2023Article
- Structural features determining the vitamin K epoxide reduction activity in the VKOR family of membrane oxidoreductases.The FEBS journal · 2022Article
- Vitamin K-Dependent Protein Activation: Normal Gamma-Glutamyl Carboxylation and Disruption in Disease.International journal of molecular sciences · 2022Review
- Stabilization and structure determination of integral membrane proteins by termini restraining.Nature protocols · 2022Review
- Illustrated State-of-the-Art Capsules of the ISTH 2020 Congress.Research and practice in thrombosis and haemostasis · 2021Review
- Targeting multiple enzymes in vitamin K metabolism for anticoagulation.Journal of thrombosis and haemostasis : JTH · 2021Article
- The catalytic mechanism of vitamin K epoxide reduction in a cellular environment.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Dose control of warfarin is a major complication in anticoagulation therapy and overdose is reversed by the vitamin K antidote. Improving the dosage management and antidotal efficacy requires mechanistic understanding. Here we find that effects of the major predictor of warfarin dosage, SNP -1639 G>A, follow a general correlation that warfarin 50% inhibitory concentration decreases with cellular level of vitamin K epoxide reductase (VKORC1), suggesting stoichiometric inhibition. Characterization of the inhibition kinetics required the use of microsomal VKORC1 with a native reductant, glutathione, that enables effective warfarin inhibition in vitro. The kinetics data can be fitted with the Morrison equation, giving a nanomolar inhibition constant and demonstrating that warfarin is a tight-binding inhibitor. However, warfarin is released from purified VKORC1-warfarin complex with increasing amount of vitamin K, indicating competitive inhibition. The competition occurs also in cells, resulting in rescued VKORC1 activity that augments the antidotal effects of vitamin K. Taken together, warfarin is a competitive inhibitor that binds VKORC1 tightly and inhibits at a stoichiometric (1:1) concentration, whereas exceeding the VKORC1 level results in warfarin overdose. Thus, warfarin dosage control should use VKORC1 level as a major indicator, and improved antidotes may be designed based on their competition with warfarin.
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Registered trials
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