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标题：Intestinal Absorption of Alogliptin Is Mediated by a Fruit-Juice-Sensitive Transporter
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作者：Kaori Morimoto ; Momona Sasaki ; Erika Oikawa 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2021
卷号：44
期号：5
页码：653-658
DOI：10.1248/bpb.b20-00947
出版社：The Pharmaceutical Society of Japan
摘要：Alogliptin (ALG), an inhibitor of dipeptidylpeptidase-4, is used in the management of type 2 diabetes mellitus, and has a high absorption rate (>60–71%), despite its low lipophilicity (log P =−1.4). Here, we aimed to clarify the mechanism of its intestinal absorption. ALG uptake into Caco-2 cells was time-, temperature-, and concentration-dependent, but was not saturated at concentrations up to 10 mmol/L. The uptake was significantly inhibited by the organic anion transporting polypeptide (OATP) substrate fexofenadine and by the OATP inhibitor 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS), but was not inhibited by organic cation transporter (OCT)/organic cation/carnitine transporter (OCTN) or peptide transporter 1 (PEPT1) substrates. Grapefruit, orange, and apple juices and their constituents, which are known to strongly inhibit intestinal OATPs, significantly inhibited ALG uptake into Caco-2 cells. The pH dependence was bell-shaped, indicating the involvement of a pH-sensitive transporter. However, ALG uptake by HEK293 cells overexpressing OATP2B1, a key intestinal OATP transporter of amphiphilic drugs, was not different from that of mock cells. In a rat in vivo study, apple juice reduced systemic exposure to orally administered ALG without changing the terminal half-life. These observations suggest that intestinal absorption of ALG is carrier-mediated, and involves a fruit-juice-sensitive transporter other than OATP2B1.
关键词：alogliptin;absorption;drug–food interaction;transporter