Characterization of renal excretion mechanism for a novel diuretic, M17055, in rats

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

M17055 was developed as a novel diuretic that inhibits both Na+, K+, and 2Cl- cotransport at the thick ascending Henle's loop and Na+ reuptake at the distal tubule. It is secreted at the renal proximal tubules. The purpose of the present study was to characterize the renal excretion mechanism of M17055. We used the renal cortical slices and brush border membrane vesicles (BBMVs) to investigate the transport mechanisms across the basolateral and brush border membranes, respectively. M17055 uptake by rat renal slices increased with time and was saturable. Several organic anions including probenecid, para-aminohippurate (PAH), and estrone-3-sulfate, decreased M17055 uptake. The uptake of M17055 was also observed into HEK293 cells expressing rat OAT1, and was inhibited by PAH. M17055 uptake by BBMVs was time-dependent, saturable, osmolarity-sensitive, and inhibited by several organic anions, but not by PAH. These results suggest that plural organic anion transport systems are involved in M17055 transport via both basolateral and brush border membranes of proximal tubule epithelial cells, a part of the renal uptake being mediated by OAT1.

Original languageEnglish
Pages (from-to)2558-2566
Number of pages9
JournalJournal of Pharmaceutical Sciences
Volume93
Issue number10
DOIs
Publication statusPublished - 2004 Oct
Externally publishedYes

Fingerprint

Diuretics
Rats
Brushes
Microvilli
Membranes
Anions
Kidney
Loop of Henle
Probenecid
Proximal Kidney Tubule
HEK293 Cells
7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid
Renal Elimination
Osmolar Concentration
Epithelial Cells
Cells

Keywords

  • BBMVs
  • Gender
  • Loop diuretics
  • M17055
  • Organic anion transporters
  • Renal excretion

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science

Cite this

Characterization of renal excretion mechanism for a novel diuretic, M17055, in rats. / Nishimura, Tomohiro; Kato, Yukio; Sai, Yoshimichi; Ogihara, Takuo; Tsuji, Akira.

In: Journal of Pharmaceutical Sciences, Vol. 93, No. 10, 10.2004, p. 2558-2566.

Research output: Contribution to journalArticle

Nishimura, Tomohiro ; Kato, Yukio ; Sai, Yoshimichi ; Ogihara, Takuo ; Tsuji, Akira. / Characterization of renal excretion mechanism for a novel diuretic, M17055, in rats. In: Journal of Pharmaceutical Sciences. 2004 ; Vol. 93, No. 10. pp. 2558-2566.
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