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- Title
Characterization of the Uptake Mechanism for a Novel Loop Diuretic, M17055, in Caco-2 Cells: Involvement of Organic Anion Transporting Polypeptide (OATP)-B.
- Authors
Tomohiro Nishimura; Yoshiyuki Kubo; Yukio Kato; Yoshimichi Sai; Takuo Ogihara; Akira Tsuji
- Abstract
AbstractPurpose??M17055 is under development as a novel loop diuretic for oral administration. To investigate the molecular mechanism of its gastrointestinal absorption, we initially aimed to clarify the mechanism of uptake of M17055 by Caco-2 cells, focusing on possible involvement of OATP-B (SLCO2B1), which is localized in the apical membranes of human intestinal epithelial cells.Materials and Methods??The uptake of [14C]M17055 by Caco-2 cells cultured on multi-well dishes was measured after cultivation for 14?days. Uptake of [14C]M17055 by HEK293 cells stably expressing OATP-B (HEK293/OATP-B cells) was also examined.Results??M17055 uptake by Caco-2 cells was saturable, and was inhibited by various organic anions, including other loop diuretics, and several bile acids. Uptake of M17055 by HEK293/OATP-B cells was much higher than that by mock cells. The inhibitory profiles of various organic anions and the estimatedKmvalues for M17055 uptake were similar in Caco-2 and HEK293/OATP-B cells. Moreover, the values of inhibition constants of several inhibitors for M17055 uptake were comparable in the two cell lines.Conclusion??Our data suggest that OATP-B plays a major role in the uptake of the novel loop diuretic M17055 from apical membranes in Caco-2 cells.
- Subjects
DIURETICS; GASTROINTESTINAL function tests; EPITHELIAL cells; BILE acids
- Publication
Pharmaceutical Research, 2007, Vol 24, Issue 1, p90
- ISSN
0724-8741
- Publication type
Article
- DOI
10.1007/s11095-006-9127-x