Warfarin Metabolite Profiles Reveal the Importance of Factors on Patient Dose‐Responses to Anticoagulant Therapy

Abstract

Coumadin (R/S‐warfarin) anticoagulation therapy remains challenging due to a narrow therapeutic range and high inter‐individual variations in response. We hypothesize that plasma metabolite profiles capture clinically relevant variations in warfarin metabolism as a resource to improve therapeutic strategies to minimize risk. We profiled R‐ and S‐warfarin and ten oxidized metabolites from fifty‐nine patient plasma samples using a novel LC‐MS method. Profiles included R‐ and S‐6‐, 7‐, and 4′‐hydroxywarfarin plus four 10‐hydroxywarfarin diastereomers, yet neither R‐ nor S‐8‐hydroxywarfarin was detected. Profiles differed significantly from those generated by R‐ and S‐warfarin using human liver microsomes and thus indicate variations in secondary metabolism and/or transport contributing to metabolite levels and their impact on dose‐responses. Multi‐linear regression analysis of metabolite levels normalized to parent drugs identified the relative importance and factors influencing their contributions to R‐ and S‐warfarin metabolism as evidence of the ability of metabolite profiles to capture the metabolic phenotype. These seminal findings provide a promising foundation to identify metabolite patterns as predictors of patient dose‐response to warfarin during anticoagulant therapy. Work was supported by National Institutes of Health (5R25HL108825‐02), National Institutes of Health and UAMS Translational Research Institute (UL1RR029884), and American Heart Association (13GRNT1690043).