Characterization of the uptake mechanism for a novel loop diuretic, M17055, in Caco-2 cells: Involvement of organic anion transporting polypeptide (OATP)-B

Tomohiro Nishimura, Yoshiyuki Kubo, Yukio Kato, Yoshimichi Sai, Takuo Ogihara, Akira Tsuji

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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 K m 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.

Original languageEnglish
Pages (from-to)90-98
Number of pages9
JournalPharmaceutical Research
Volume24
Issue number1
DOIs
Publication statusPublished - 2007 Jan
Externally publishedYes

Fingerprint

Sodium Potassium Chloride Symporter Inhibitors
Caco-2 Cells
Anions
Peptides
Cells
B-Lymphocytes
Membranes
7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid
HEK293 Cells
Bile Acids and Salts
Oral Administration
Epithelial Cells
Cell Line

Keywords

  • Caco-2
  • Intestinal absorption
  • Loop diuretics
  • Membrane transport
  • OATP-B
  • Transporter

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

Cite this

Characterization of the uptake mechanism for a novel loop diuretic, M17055, in Caco-2 cells : Involvement of organic anion transporting polypeptide (OATP)-B. / Nishimura, Tomohiro; Kubo, Yoshiyuki; Kato, Yukio; Sai, Yoshimichi; Ogihara, Takuo; Tsuji, Akira.

In: Pharmaceutical Research, Vol. 24, No. 1, 01.2007, p. 90-98.

Research output: Contribution to journalArticle

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abstract = "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 K m 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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N2 - 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 K m 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.

AB - 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 K m 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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