title: Involvement of Concentrative Nucleoside Transporter 1 in Intestinal Absorption of Trifluridine Using Human Small Intestinal Epithelial Cells.
abstract: 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(+) -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 Xenopus oocytes was the highest among human CNT transporters. The obtained Km and Vmax 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.
authors.affiliation: Pharmacokinetics Research Laboratories, Tsukuba Research Center, Taiho Pharmaceutical Company, Ltd, Tsukuba, Ibaraki, Japan.|Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Pharmacokinetics Research Laboratories, Tsukuba Research Center, Taiho Pharmaceutical Company, Ltd, Tsukuba, Ibaraki, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yoshisue
authors.affiliation: Pharmacokinetics Research Laboratories, Tsukuba Research Center, Taiho Pharmaceutical Company, Ltd, Tsukuba, Ibaraki, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Chiba
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004338:Drug Combinations; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D033703:Nucleoside Transport Proteins / Q000378:metabolism*; D009705:Nucleosides / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D011759:Pyrrolidines; D013941:Thymine; D014271:Trifluridine / Q000378:metabolism* / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology; D014981:Xenopus / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004338:Drug Combinations; D026901:Membrane Transport Proteins; D033703:Nucleoside Transport Proteins; D009705:Nucleosides; D011759:Pyrrolidines; C065171:cif nucleoside transporter; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D013941:Thymine; D014271:Trifluridine
keywords: CNT1; FTD; cancer; intestinal absorption; intestinal epithelia; nucleoside transporters; transcellular transport; trifluridine