Vitamin K (VK) is a fat-soluble vitamin involved in the regulation of blood coagulation. Mammals do not synthesize VK and must therefore obtain this vitamin by intestinal absorption. The molecular mechanism(s) of the VK absorption process are not clear. Based on the known role of the NPC1L1 protein in the intestinal absorption of fat-soluble compounds such as cholesterol and vitamin E, the possible uptake of VK via an NPC1L1-mediated pathway was examined. In vitro studies using NPC1L1-overexpressing cells and in vivo studies revealed that intestinal VK absorption is NPC1L1-dependent and inhibited by ezetimibe, an NPC1L1-selective inhibitor. In addition, in vivo pharmacological studies demonstrated that the co-administration of ezetimibe and warfarin, a VK antagonist used as an anticoagulant drug, caused a reduction in hepatic VK level and enhanced the pharmacological effect of warfarin. These adverse events caused by the co-administration were rescued by oral VK supplementation, suggesting that the drug interaction effects observed were the consequence of ezetimibe-mediated VK malabsorption. This non-idiosyncratic drug interaction mechanism was supported by clinical results showing that in the majority of warfarin-treated patients, anticoagulant activity was enhanced by co-treatment with ezetimibe. These findings suggest a novel mechanism of drug-drug interaction mediated by the alteration of the kinetics of essential vitamins. In the presentation, we are going to introduce the physiologically, pharmacologically, and clinically important topic with recent progress.
1) Takada T, et al., Science Translational Medicine. 7:275ra23, 2015.
2) M Ito S, et al., Circulation Journal. accepted.