Dabigatran and its acylglucuronide metabolites

Dabigatran is a direct, competitive, and reversible thrombin inhibitor that prevents the conversion of fibrinogen into fibrin during the coagulation cascade (Pradaxa FDA Label). Following oral administration of the prodrug dabigatran etexilate, dabigatran is formed and subsequently conjugated into four isomeric acylglucuronides; the 1-O-acylglucuronide is the primary metabolite and possesses pharmacological activity equivalent to dabigatran (Glund et al., 2015). These molecules are the specific targets of the reversal agent idarucizumab, a humanized monoclonal antibody fragment (Fab). Idarucizumab binds to dabigatran and its metabolites with an affinity approximately 350 times higher than that of dabigatran for thrombin, effectively sequestering the drug and its active metabolites to rapidly reverse anticoagulation (Pollack et al., 2017, NEJM). This target-antagonist relationship is utilized clinically to manage life-threatening bleeding or to prepare patients for emergency surgery when they are under the effect of dabigatran therapy. The neutralization of dabigatran and its acylglucuronide metabolites is monitored using coagulation assays such as diluted thrombin time or ecarin clotting time (FDA Label for Praxbind).

Other names

DabigatranDabigatran glucuronides1-O-acylglucuronide of dabigatranDabigatran metabolites

Idarucizumab binds specifically to dabigatran and its acylglucuronide metabolites with high affinity, neutralizing their anticoagulant effect by preventing them from binding to thrombin (Pollack et al., 2015, NEJM; FDA Label for Praxbind).