title: Inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h between α-tocopherol and ezetimibe.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, 060-0812, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nashimoto
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, 060-0812, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, 060-0812, Japan.
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takekuma
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, 060-0812, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sugawara
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D000975:Antioxidants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D000069438:Ezetimibe / Q000008:administration & dosage* / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D007408:Intestinal Absorption / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D024502:alpha-Tocopherol / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics
chemical_list: D000924:Anticholesteremic Agents; D000975:Antioxidants; D000069438:Ezetimibe; D024502:alpha-Tocopherol
keywords: NPC1L1; absorption; ezetimibe; intestine; α-tocopherol