Involvement of Concentrative Nucleoside Transporter 1 in Intestinal Absorption of Trifluridine Using Human Small Intestinal Epithelial Cells. Issue 9 (21st April 2015)

• Record Type: Journal Article
• Authors: Takahashi, Koichi; Yoshisue, Kunihiro; Chiba, Masato; Nakanishi, Takeo; Tamai, Ikumi; Donovan, Maureen D.; Langguth, Peter; Polli, James E.; Tamai, Ikumi; Vig, Balvinder; Yu, Lawrence X.
• Is Part Of: Journal of pharmaceutical sciences. Volume 104:Issue 9(2015:Sep.)
• Page Start: 3146
• Page End: 3153
• Publication Date: 2015-04-21
• Subjects: Pharmacy -- Periodicals; 615.1
• DOI: 10.1002/jps.24455
• Languages: English
• ISSNs: 0022-3549

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <p>TAS‐102, which is effective for refractory metastatic colorectal cancer, is a combination drug of anticancer trifluridine (FTD; which is derived from pyrimidine nucleoside) and FTD‐metabolizing enzyme inhibitor tipiracil hydrochloride (TPI) at a molecular ratio of 1:0.5. To evaluate the intestinal absorption mechanism of FTD, the uptake and transcellular transport of FTD by human small intestinal epithelial cell (HIEC) monolayer as a model of human intestinal epithelial cells was investigated. The uptake and membrane permeability of FTD by HIEC monolayers were saturable, Na<sup>+</sup>‐dependent, and inhibited by nucleosides. These transport characteristics are mostly comparable with those of concentrative nucleoside transporters (CNTs). Moreover, the uptake of FTD by CNT1‐expressing <italic>Xenopus</italic> oocytes was the highest among human CNT transporters. The obtained <italic>K</italic><sub>m</sub> and <italic>V</italic><sub>max</sub> values of FTD by CNT1 were 69.0 μM and 516 pmol/oocyte/30 min, respectively. The transcellular transport of FTD by Caco‐2 cells, where CNT1 is heterologously expressed, from apical to basolateral side was greater than that by Mock cells. In conclusion, these results demonstrated that FTD exhibits high oral absorption by the contribution of human CNT1. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3146–3153, 2015</p> </abstract>