Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Sci Transl Med. 2015 Feb 18;7(275):275ra23. doi: 10.1126/scitranslmed.3010329.
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.
维生素 K（VK）是一种促进血液凝结的微量营养素。VK 拮抗剂，如华法林，临床上用于预防血栓栓塞。由于 VK 不能在体内合成，其肠道吸收对维持全身 VK 水平至关重要。然而，这种吸收的分子机制尚不清楚。我们证明，胆固醇转运蛋白 Niemann-Pick C1 样 1（NPC1L1）蛋白在肠道 VK 摄取中起核心作用，并调节华法林的抗凝作用。使用 NPC1L1 过表达的肠细胞进行的体外研究和 Npc1l1 敲除小鼠的体内研究表明，肠道 VK 吸收依赖于 NPC1L1，并被临床用于治疗血脂异常的 NPC1L1 选择性抑制剂依折麦布抑制。此外，体内药理研究表明，依折麦布和华法林的联合给药导致肝 VK 水平降低，并增强华法林的药理作用。依折麦布和华法林联合给药引起的不良反应通过口服 VK 补充得到挽救，这表明观察到的药物相互作用是依折麦布介导的 VK 吸收不良的结果。这一机制得到了临床数据回顾性评估的支持，该评估表明，在超过 85%的接受华法林治疗的患者中，依折麦布联合治疗增强了抗凝活性。我们的发现为 VK 吸收的分子机制提供了深入了解。依折麦布（胆固醇转运抑制剂）和华法林（VK 拮抗剂和抗凝剂）之间的这种新的药物相互作用机制可以为这些药物的患者的临床护理提供信息，例如通过改变必需的脂溶性维生素的动力学。
