Sophie Hodin1,2, Thierry Basset1,2,3, Elodie Jacqueroux1,2, Olivier Delezay1,2, Anthony Clotagatide4, Nathalie Perek1,2, Patrick Mismetti1,2,5, Xavier Delavenne6,7,8. 1. INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Étienne, France. 2. Université de Lyon, 42023, Saint-Étienne, France. 3. Laboratoire de Pharmacologie-Toxicologie-Gaz du sang, Plateau de Biologie-Hôpital Nord, CHU de Saint-Etienne, 42055, Saint-Étienne, France. 4. Service de Radiopharmacie, CHU de Saint-Etienne, 42055, Saint-Étienne, France. 5. Unité de Recherche Clinique Innovation et Pharmacologie, CHU de Saint-Etienne, 42055, Saint-Étienne, France. 6. INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Étienne, France. xavier.delavenne@chu-st-etienne.fr. 7. Université de Lyon, 42023, Saint-Étienne, France. xavier.delavenne@chu-st-etienne.fr. 8. Laboratoire de Pharmacologie-Toxicologie-Gaz du sang, Plateau de Biologie-Hôpital Nord, CHU de Saint-Etienne, 42055, Saint-Étienne, France. xavier.delavenne@chu-st-etienne.fr.
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).
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).
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