NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy

NPC1L1, a cholesterol importer and a molecular target of ezetimibe, mediates the physiological absorption of vitamin K and therefore modulates the anticoagulant effect of warfarin. A tug of war: Two drugs modulate vitamin K function Kale was the superfood of 2014, with even soda-laden convenience stores like 7-Eleven adding kale juices to their inventories. But patients on warfarin—a commonly prescribed drug to prevent blood clotting—should avoid eating these healthy, leafy greens. Greens such as kale and spinach harbor loads of vitamin K (VK), which can interfere with the drug’s activity. The mechanism linking VK to warfarin action remains unclear; however, in a new study in rodent models, Takada et al. reveal that Niemann-Pick C1-like 1 (NPC1L1) protein, a cholesterol transporter, plays a key role in vitamin transport, too. The consequence of this interaction between VK and NPC1L1? Animals taking lipid-lowering drugs like ezetimibe, which act on NPC1L1, demonstrate heightened activity of warfarin, presumably because VK is not absorbed properly. When the animals were given oral VK supplementation, warfarin activity returned to normal, even if the animals were taking both drugs. Takada and colleagues retrospectively evaluated the medical records of patients taking warfarin alone or warfarin with ezetimibe and confirmed that the anticoagulant activity of warfarin was increased in more than 85% of patients also taking ezetimibe. This drug-drug interaction will be an important consideration when prescribing patients both warfarin and ezetimibe (or similar anticoagulant and cholesterol drugs), but lucky for those patients, this study further suggests that the interaction can be countered in part by a kale salad or, for those averse to this trendy roughage, a daily supplement of VK. Vitamin K (VK) is a micronutrient that facilitates blood coagulation. VK antagonists, such as warfarin, are used in the clinic to prevent thromboembolism. Because VK is not synthesized in the body, its intestinal absorption is crucial for maintaining whole-body VK levels. However, the molecular mechanism of this absorption is unclear. We demonstrate that Niemann-Pick C1-like 1 (NPC1L1) protein, a cholesterol transporter, plays a central role in intestinal VK uptake and modulates the anticoagulant effect of warfarin. In vitro studies using NPC1L1-overexpressing intestinal cells and in vivo studies with Npc1l1-knockout mice revealed that intestinal VK absorption is NPC1L1-dependent and inhibited by ezetimibe, an NPC1L1-selective inhibitor clinically used for dyslipidemia. In addition, in vivo pharmacological studies demonstrated that the coadministration of ezetimibe and warfarin caused a reduction in hepatic VK levels and enhanced the pharmacological effect of warfarin. Adverse events caused by the coadministration of ezetimibe and warfarin were rescued by oral VK supplementation, suggesting that the drug-drug interaction effects observed were the consequence of ezetimibe-mediated VK malabsorption. This mechanism was supported by a retrospective evaluation of clinical data showing that, in more than 85% of warfarin-treated patients, the anticoagulant activity was enhanced by cotreatment with ezetimibe. Our findings provide insight into the molecular mechanism of VK absorption. This new drug-drug interaction mechanism between ezetimibe (a cholesterol transport inhibitor) and warfarin (a VK antagonist and anticoagulant) could inform clinical care of patients on these medications, such as by altering the kinetics of essential, fat-soluble vitamins.