Competitive tight-binding inhibition of VKORC1 underlies warfarin dosage variation and antidotal efficacy.

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-b

SUBMITTER: Li S 

PROVIDER: S-EPMC7252542 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature