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