Document Detail

Characterization of the uptake mechanism for a novel loop diuretic, M17055, in Caco-2 cells: involvement of organic anion transporting polypeptide (OATP)-B.
MedLine Citation:
PMID:  17103337     Owner:  NLM     Status:  MEDLINE    
PURPOSE: 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 estimated Km values 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.
Tomohiro Nishimura; Yoshiyuki Kubo; Yukio Kato; Yoshimichi Sai; Takuo Ogihara; Akira Tsuji
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-11-14
Journal Detail:
Title:  Pharmaceutical research     Volume:  24     ISSN:  0724-8741     ISO Abbreviation:  Pharm. Res.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2006-12-06     Completed Date:  2007-01-26     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  90-8     Citation Subset:  IM    
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
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MeSH Terms
Bile Acids and Salts / pharmacology
Caco-2 Cells
Data Interpretation, Statistical
Diuretics / metabolism*
Hydrogen-Ion Concentration
Organic Anion Transporters / metabolism*
Oximes / metabolism*
Quinolones / metabolism*
Sodium / physiology
Sulfates / metabolism
Reg. No./Substance:
0/Bile Acids and Salts; 0/Diuretics; 0/Organic Anion Transporters; 0/Oximes; 0/Quinolones; 0/SLCO2B1 protein, human; 0/Sulfates; 114417-20-8/M 17055; 7440-23-5/Sodium

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