Role of ABC transporters in trans‐epithelial transport of vitamin K antagonists

Abstract

Vitamin K antagonists (VKAs) remain the oral anticoagulant of choice in venous thromboembolic disease. These drugs are characterized by a large inter-individual variability requiring frequent dose tailoring. Genetic polymorphisms for cytochrome CYP2C9 and VKORC1 explain some of the variability, especially in warfarin and acenocoumarol responses. The aim of this study was to assess, in cell models, the role of ABC transporters in the intestinal transfer of the main coumarin derivatives (warfarin, acenocoumarol) and indanedione derivatives (phenindione, fluindione). The results show a basal to apical polarized transport for fluindione, phenindione and acenocoumarol only. Experimental studies using specific inhibitors of transport protein demonstrate the implication of MRPs and BCRP proteins and to a lesser extent P-gp. Warfarin and acenocoumarol seem to be poor inhibitors of MRPs protein, whereas fluindione and phenindione have a slight or no effect. The regulation of the expression of ABC transporters by exposure to VKAs was also investigated in Caco-2 cells. The expression of mRNA P-gp, MRP1, MRP2 and BCRP was weakly or not modified after 24 h of VKAs exposure. In conclusion, the intestinal transfer of indanedione derivatives and acenocoumarol could be influenced by transport proteins of the ABC superfamily. Coumarin derivatives are poor inhibitors of these proteins and AVKs have a slight effect on the mRNA ABC transporter expression level. Copyright © 2016 John Wiley & Sons, Ltd.

Differences in teratogenicity of some vitamin K antagonist substances used as human therapeutic or rodenticide are due to major differences in their fate after an oral administration

“…Plasma concentrations of bromadiolone never exceeded 0.1 µg/ml and 72 hours after initial administration, they dropped below 0.02 µg/ml with a plasma half-life of bromadiolone in the same order of magnitude as that of warfarin. The high hepatic extraction of bromadiolone could be explained: 1/ by its high partition coefficient (log P = 3.8-4.1, pH 6-7) (European Chem Agency, 2012), higher than that of warfarin (log P = 2.7, pH unspecified) [30] or coumatetralyl (log P = 3.46, pH unspecified), , or 2/ by a different active transport among vitamin K antagonists, which has already been suggested by recent studies [31]. Considering the first hypothesis, the higher lipophilicity of bromadiolone could lead to greater association to lipoproteins in the enterocytes.…”