In Vitro Comparison of the Role of P-Glycoprotein and Breast Cancer Resistance Protein on Direct Oral Anticoagulants Disposition

Abstract

Background: Pharmacokinetics of direct oral anticoagulants (DOACs) are influenced by ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).

Objectives: To better understand the role of transporters in DOAC disposition, we evaluated and compared the permeabilities and transport properties of these drugs.

Methods: Bidirectional permeabilities of DOACs were investigated across Caco-2 cells monolayer. Transport assays were performed using different concentrations of DOAC and specific inhibitors of ABC transporters. Cell model functionality was evaluated by transport assay of two positive control substrates.

Results: The results of transport assays suggest a concentration-dependent efflux of apixaban, dabigatran etexilate and edoxaban, whereas the efflux transport of rivaroxaban did not seem to depend on concentration. Verapamil, a strong inhibitor of P-gp, decreased DOAC efflux in the Caco-2 cell model by 12-87%, depending on the drug tested. Ko143 reduced BCRP-mediated DOAC efflux in Caco-2 cells by 46-76%.

Conclusion: This study allowed identification of three different profiles of ABC carrier-mediated transport: predominantly P-gp-dependent transport (dabigatran), preferential BCRP-dependent transport (apixaban) and approximately equivalent P-gp and BCRP-mediated transport (edoxaban and rivaroxaban).