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

Takada, Tappei; Yamanashi, Yoshihide; Kentaro, Konishi; Yamamoto, Takehito; Toyoda, Yu; Masuo, Yusuke; Yamamoto, Hideaki; Suzuki, Hiroshi

doi:10.1126/scitranslmed.3010329

Cited by 86 publications

(85 citation statements)

References 28 publications

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“…The Abcg2 KO mice (Ichida et al, 2012) had been maintained in our laboratory as described previously. All the animals were housed in temperature- and humidity-controlled animal cages with a 12-h dark-light cycle, and free access to water and standard animal chow (MF, Oriental Yeast Company, Tokyo, Japan) as described previously (Ito et al, 2014; Takada et al, 2015). In the present study, all the in vivo experiments were conducted with 6–8-week-old male mice.…”

Section: Methodsmentioning

confidence: 99%

Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations

et al. 2016

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ATP-binding cassette transporter G2 (ABCG2) is a plasma membrane protein that regulates the pharmacokinetics of a variety of drugs and serum uric acid (SUA) levels in humans. Despite the pharmacological and physiological importance of this transporter, there is no clinically available drug that modulates ABCG2 function. Therefore, to identify such drugs, we investigated the effect of drugs that affect SUA levels on ABCG2 function. This strategy was based on the hypothesis that the changes of SUA levels might caused by interaction with ABCG2 since it is a physiologically important urate transporter. The results of the in vitro screening showed that 10 of 25 drugs investigated strongly inhibited the urate transport activity of ABCG2. Moreover, febuxostat was revealed to be the most promising candidate of all the potential ABCG2 inhibitors based on its potent inhibition at clinical concentrations; the half-maximal inhibitory concentration of febuxostat was lower than its maximum plasma unbound concentrations reported. Indeed, our in vivo study demonstrated that orally administered febuxostat inhibited the intestinal Abcg2 and, thereby, increased the intestinal absorption of an ABCG2 substrate sulfasalazine in wild-type mice, but not in Abcg2 knockout mice. These results suggest that febuxostat might inhibit human ABCG2 at a clinical dose. Furthermore, the results of this study lead to a proposed new application of febuxostat for enhancing the bioavailability of ABCG2 substrate drugs, named febuxostat-boosted therapy, and also imply the potential risk of adverse effects by drug-drug interactions that could occur between febuxostat and ABCG2 substrate drugs.

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Section: Methodsmentioning

confidence: 99%

Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations

et al. 2016

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“…In addition, we also revealed that ezetimibe can inhibit the intestinal absorption of these fat-soluble vitamins in mice and rats. 56,58) Our findings suggest that intestinal absorption of vitamin E and vitamin K 1 is mediated by ezetimibe-sensitive NPC1L1-dependent pathway (Fig. 2).…”

Section: Physiological Substrates Of Npc1l1 Other Than Sterols and Pomentioning

confidence: 91%

“…Interestingly, it has been reported that anticoagulant activity of warfarin is enhanced by combination with ezetimibe. 58,63,64) Figure 4A shows typical cases of the ezetimibe-warfarin interaction found by our retrospective survey of clinical records at the University of Tokyo Hospital. 58) Although the mechanism of this drug-drug interaction was not clear, we recently demonstrated that ezetimibe-related vitamin K 1 malabsorption causes reduction in hepatic vitamin K 1 amounts, resulting in an unintentional enhancement of anticoagulant activity in almost all (more than 85%) patients taking both warfarin and ezetimibe simultaneously 58) (Fig.…”

Section: )mentioning

confidence: 99%

“…However, our recent studies demonstrated that NPC1L1 has ability to transport several fat-soluble nutrients such as vitamin E (α-tocopherol and other isoforms) 56,57) (Fig. 1C) and vitamin K 1 (phylloquinone: a major component of dietary vitamin K) 58) (Fig. 1D).…”

Section: Physiological Substrates Of Npc1l1 Other Than Sterols and Pomentioning

confidence: 99%

“…It should be noted, however, that such an unintentional effect of ezetimibe on blood coagulation was hardly observed in patients not taking warfarin, which was consistent with pharmacological studies with rats. 58) In the liver, the recycling of vitamin K via the vitamin K cycle regulates hepatic vitamin K robustness. Therefore if the vitamin K cycle is functional, inhibition of intestinal vitamin K 1 absorption should not directly affect blood coagulation.…”

Section: )mentioning

confidence: 99%

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Associations between Lifestyle-Related Diseases and Transporters Involved in Intestinal Absorption and Biliary Excretion of Cholesterol

Yamanashi

Takada

Suzuki

2018

Biological & Pharmaceutical Bulletin

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Westernization of dietary habits leads to an increase in lipid intake and is thought to be responsible for an increase in patients with dyslipidemia. It is a well-known fact that the impaired cholesterol homeostasis is closely related to the development of various lifestyle-related diseases such as fatty liver, diabetes, and gallstone as well as dyslipidemia leading to atherosclerosis and cardiovascular diseases such as heart attack and stroke. Therefore, appropriate management of cholesterol levels in the body is considered important in prevention and treatments of these lifestyle-related diseases and in addition, molecular mechanisms controlling plasma (and/or hepatic) cholesterol levels have been intensively studied. Due to its hydrophobicity, cholesterol was long believed to pass through cell membranes by passive diffusion. However, recent studies have identified a number of plasma membrane transporters that are responsible for the cellular uptake or efflux of cholesterol and involved in developments of lifestyle-related diseases. In this review, we focus on Niemann-Pick C1 Like 1 (NPC1L1) and a heterodimer of ATP-binding cassette transporter G5 and G8 (ABCG5/G8), both of which are responsible for intestinal cholesterol absorption and biliary cholesterol secretion, and discuss the relationship between these cholesterol transporters and lifestyle-related diseases. In addition, we also discuss the related uncertainties that need to be explored in future studies.

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Inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h between α‐tocopherol and ezetimibe

Nashimoto

Sato

Takekuma

et al. 2017

Biopharm & Drug Disp

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Tocopherol is used not only as an ethical drug but also as a supplement. In 2008, it was reported that α-tocopherol is partly transported via an intestinal cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1). Ezetimibe, a selective inhibitor of NPC1L1, is administered for a long time to inhibit cholesterol absorption and there is a possibility that the absorption of α-tocopherol is also inhibited by ezetimibe. This study investigated the influence of ezetimibe on the absorption of α-tocopherol with single administration and long-term administration. An approach to avoid its undesirable consequence was also examined. α-Tocopherol (10 mg/kg) and ezetimibe (0.1 mg/kg) were administered to rats, and the plasma concentration profiles of α-tocopherol and tissue concentrations were investigated. The plasma concentration of α-tocopherol was decreased by the combination use of ezetimibe in the case of concurrent single administration. On the other hand, inhibition of the absorption of α-tocopherol was prevented by an administration interval of 4 h. In a group of rats administered for 2 months with a 4 h interval, not only the plasma concentration but also the liver concentration was increased compared with those in a group with concurrent combination intake of α-tocopherol and ezetimibe. The absorption of α-tocopherol was inhibited by ezetimibe. The inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h, although ezetimibe is a medicine of enterohepatic circulation. Attention should be paid to the use of ezetimibe and components of NPC1L1 substrates such as α-tocopherol. Copyright © 2016 John Wiley & Sons, Ltd.

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

Cited by 86 publications

References 28 publications

Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations

Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations

Associations between Lifestyle-Related Diseases and Transporters Involved in Intestinal Absorption and Biliary Excretion of Cholesterol

Inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h between α‐tocopherol and ezetimibe

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