title: Role of P-glycoprotein in the uptake/efflux transport of oral vitamin K antagonists and rivaroxaban through the Caco-2 cell model.
abstract: Vitamin K antagonists (VKAs) are prescribed worldwide and remain the oral anticoagulant of choice. These drugs are characterized by a narrow therapeutic index and a large inter- and intra-individual variability. P-glycoprotein could contribute to this variability. The aim of this study was to investigate the involvement of P-gp in the transport of acenocoumarol, phenprocoumon and warfarin using an in vitro Caco-2 cell monolayer model. These results were compared with those obtained with rivaroxaban, a new oral anticoagulant known to be a P-gp substrate. The transport of these four drugs was assessed at pH conditions 6.8/7.4 in the presence or absence of the P-gp inhibitor cyclosporine A (10 μM) and the more potent and specific P-gp inhibitor valspodar (5 μM). Analytical quantification was performed by LC/MS. With an efflux ratio of 1.7 and a significant decrease in the efflux (Papp B-A), in the presence of P-gp inhibitors at a concentration of 50 μM, acenocoumarol can be considered as a weak P-gp substrate. Concerning phenprocoumon, the results suggest that this molecule is a poor P-gp substrate. The P-gp inhibitors did not affect significantly the transport of warfarin. The efflux of rivaroxaban was strongly inhibited by the two P-gp inhibitors. In conclusion, none of the three VKAs tested are strong P-gp substrates. However, acenocoumarol can be considered as a weak P-gp substrate and phenprocoumon as a poor P-gp substrate.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospitals of Geneva, Geneva, Switzerland; School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Liliane
authors.initials: L
authors.lastname: Gschwind
authors.forename: Victoria
authors.initials: V
authors.lastname: Rollason
authors.forename: Youssef
authors.initials: Y
authors.lastname: Daali
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonnabry
authors.forename: Pierre
authors.initials: P
authors.lastname: Dayer
authors.forename: Jules Alexandre
authors.initials: JA
authors.lastname: Desmeules
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000074:Acenocoumarol / Q000493:pharmacokinetics; D000925:Anticoagulants / Q000493:pharmacokinetics*; D001692:Biological Transport; D018938:Caco-2 Cells; D006801:Humans; D046529:Microscopy, Electron, Transmission; D009025:Morpholines / Q000493:pharmacokinetics*; D000069552:Rivaroxaban; D013876:Thiophenes / Q000493:pharmacokinetics*; D014812:Vitamin K / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D014859:Warfarin / Q000493:pharmacokinetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000925:Anticoagulants; D009025:Morpholines; D013876:Thiophenes; D014812:Vitamin K; D014859:Warfarin; D000069552:Rivaroxaban; D000074:Acenocoumarol