Stereoselective renal tubular secretion of an organic anion in the isolated perfused rat kidney

Kazutaka Higaki, K. Kadono, S. Goto, M. Nakano

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

To clarify the stereoselective renal tubular secretion of an organic anion, renal excretion of 5-dimethylsulfamoyl-6,7-dichloro-2,3- dihydrobenzofuran-2-carboxylic acid (DBCA), a racemic compound, was studied with a single-pass perfused rat kidney preparation under constant perfusion pressure (ca. 120 mm Hg). The steady-state renal extraction ratio of (R)- (+)-DBCA (0.134) was 10 times higher than that of (S)-(-)-DBCA (0.015), indicating high selectivity for (R)-(+)-DBCA. The urinary excretion rate and renal excretory clearance (CLr(ex)) were 4 times larger for (R)-(+)-DBCA, and the unbound fraction in the perfusate also was higher for (R)-(+)-DBCA (R/S = 1.58). Fractional excretion (FE) and intrinsic clearance for tubular secretion (CLr(sec,int)) were about 3 times larger for (R)-(+)-DBCA than the antipode, showing the stereoselectively predominant secretion of (R)-(+)- DBCA. The N-monodemethylated metabolite, M-1, was found only for the R-(+)- enantiomer in the perfusate and urine, revealing highly stereoselective N- monodemethylation in the kidney. The CLr(sec,int) value for (R)-(+)-M-1 was 2.5 times larger than that for (R)-(+)-DBCA. The perfusion study using each enantiomer decreased R/S ratios of the extraction ratio (9.9), urinary excretion rate (3.9) and excretory clearance (3.9) in the perfusion of the racemate to 3.9, 2.1 and 2.1, respectively. No significant difference was found between (R)-(+)- and (S)-(-)-DBCA in FE and CLr(sec,int). The declined stereoselectivity in renal excretion parameters may be due to competitive inhibition of the tubular secretion of (R)-(+)-DBCA by the (R)-(+)-M-1 formed which possessed greater secretion ability in the (R)-(+)-DBCA perfusion study, whereas (S)-(-)-DBCA was secreted without great inhibition by (S)-(- )-M-1 in the (S)-(-)-DBCA perfusion because of a small amount of generated metabolite. Plotting of FE ratios of DBCA enantiomers to (R)-(+)-M-1 against FE of (R)-(+)-M-1 suggests that the actual FE for (R)-(+)-DBCA was 2 times larger than that for (S)-(-)-DBCA, and that (S)-(-)-DBCA secretion was inhibited more easily by (R)-(+)-M-1.

Original languageEnglish
Pages (from-to)329-335
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume270
Issue number1
Publication statusPublished - 1994
Externally publishedYes

Fingerprint

Carboxylic Acids
Anions
Kidney
Perfusion
S 8666

ASJC Scopus subject areas

  • Pharmacology

Cite this

Stereoselective renal tubular secretion of an organic anion in the isolated perfused rat kidney. / Higaki, Kazutaka; Kadono, K.; Goto, S.; Nakano, M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 270, No. 1, 1994, p. 329-335.

Research output: Contribution to journalArticle

@article{05bbdf442a1f4c2f9438f32068c63674,
title = "Stereoselective renal tubular secretion of an organic anion in the isolated perfused rat kidney",
abstract = "To clarify the stereoselective renal tubular secretion of an organic anion, renal excretion of 5-dimethylsulfamoyl-6,7-dichloro-2,3- dihydrobenzofuran-2-carboxylic acid (DBCA), a racemic compound, was studied with a single-pass perfused rat kidney preparation under constant perfusion pressure (ca. 120 mm Hg). The steady-state renal extraction ratio of (R)- (+)-DBCA (0.134) was 10 times higher than that of (S)-(-)-DBCA (0.015), indicating high selectivity for (R)-(+)-DBCA. The urinary excretion rate and renal excretory clearance (CLr(ex)) were 4 times larger for (R)-(+)-DBCA, and the unbound fraction in the perfusate also was higher for (R)-(+)-DBCA (R/S = 1.58). Fractional excretion (FE) and intrinsic clearance for tubular secretion (CLr(sec,int)) were about 3 times larger for (R)-(+)-DBCA than the antipode, showing the stereoselectively predominant secretion of (R)-(+)- DBCA. The N-monodemethylated metabolite, M-1, was found only for the R-(+)- enantiomer in the perfusate and urine, revealing highly stereoselective N- monodemethylation in the kidney. The CLr(sec,int) value for (R)-(+)-M-1 was 2.5 times larger than that for (R)-(+)-DBCA. The perfusion study using each enantiomer decreased R/S ratios of the extraction ratio (9.9), urinary excretion rate (3.9) and excretory clearance (3.9) in the perfusion of the racemate to 3.9, 2.1 and 2.1, respectively. No significant difference was found between (R)-(+)- and (S)-(-)-DBCA in FE and CLr(sec,int). The declined stereoselectivity in renal excretion parameters may be due to competitive inhibition of the tubular secretion of (R)-(+)-DBCA by the (R)-(+)-M-1 formed which possessed greater secretion ability in the (R)-(+)-DBCA perfusion study, whereas (S)-(-)-DBCA was secreted without great inhibition by (S)-(- )-M-1 in the (S)-(-)-DBCA perfusion because of a small amount of generated metabolite. Plotting of FE ratios of DBCA enantiomers to (R)-(+)-M-1 against FE of (R)-(+)-M-1 suggests that the actual FE for (R)-(+)-DBCA was 2 times larger than that for (S)-(-)-DBCA, and that (S)-(-)-DBCA secretion was inhibited more easily by (R)-(+)-M-1.",
author = "Kazutaka Higaki and K. Kadono and S. Goto and M. Nakano",
year = "1994",
language = "English",
volume = "270",
pages = "329--335",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Stereoselective renal tubular secretion of an organic anion in the isolated perfused rat kidney

AU - Higaki, Kazutaka

AU - Kadono, K.

AU - Goto, S.

AU - Nakano, M.

PY - 1994

Y1 - 1994

N2 - To clarify the stereoselective renal tubular secretion of an organic anion, renal excretion of 5-dimethylsulfamoyl-6,7-dichloro-2,3- dihydrobenzofuran-2-carboxylic acid (DBCA), a racemic compound, was studied with a single-pass perfused rat kidney preparation under constant perfusion pressure (ca. 120 mm Hg). The steady-state renal extraction ratio of (R)- (+)-DBCA (0.134) was 10 times higher than that of (S)-(-)-DBCA (0.015), indicating high selectivity for (R)-(+)-DBCA. The urinary excretion rate and renal excretory clearance (CLr(ex)) were 4 times larger for (R)-(+)-DBCA, and the unbound fraction in the perfusate also was higher for (R)-(+)-DBCA (R/S = 1.58). Fractional excretion (FE) and intrinsic clearance for tubular secretion (CLr(sec,int)) were about 3 times larger for (R)-(+)-DBCA than the antipode, showing the stereoselectively predominant secretion of (R)-(+)- DBCA. The N-monodemethylated metabolite, M-1, was found only for the R-(+)- enantiomer in the perfusate and urine, revealing highly stereoselective N- monodemethylation in the kidney. The CLr(sec,int) value for (R)-(+)-M-1 was 2.5 times larger than that for (R)-(+)-DBCA. The perfusion study using each enantiomer decreased R/S ratios of the extraction ratio (9.9), urinary excretion rate (3.9) and excretory clearance (3.9) in the perfusion of the racemate to 3.9, 2.1 and 2.1, respectively. No significant difference was found between (R)-(+)- and (S)-(-)-DBCA in FE and CLr(sec,int). The declined stereoselectivity in renal excretion parameters may be due to competitive inhibition of the tubular secretion of (R)-(+)-DBCA by the (R)-(+)-M-1 formed which possessed greater secretion ability in the (R)-(+)-DBCA perfusion study, whereas (S)-(-)-DBCA was secreted without great inhibition by (S)-(- )-M-1 in the (S)-(-)-DBCA perfusion because of a small amount of generated metabolite. Plotting of FE ratios of DBCA enantiomers to (R)-(+)-M-1 against FE of (R)-(+)-M-1 suggests that the actual FE for (R)-(+)-DBCA was 2 times larger than that for (S)-(-)-DBCA, and that (S)-(-)-DBCA secretion was inhibited more easily by (R)-(+)-M-1.

AB - To clarify the stereoselective renal tubular secretion of an organic anion, renal excretion of 5-dimethylsulfamoyl-6,7-dichloro-2,3- dihydrobenzofuran-2-carboxylic acid (DBCA), a racemic compound, was studied with a single-pass perfused rat kidney preparation under constant perfusion pressure (ca. 120 mm Hg). The steady-state renal extraction ratio of (R)- (+)-DBCA (0.134) was 10 times higher than that of (S)-(-)-DBCA (0.015), indicating high selectivity for (R)-(+)-DBCA. The urinary excretion rate and renal excretory clearance (CLr(ex)) were 4 times larger for (R)-(+)-DBCA, and the unbound fraction in the perfusate also was higher for (R)-(+)-DBCA (R/S = 1.58). Fractional excretion (FE) and intrinsic clearance for tubular secretion (CLr(sec,int)) were about 3 times larger for (R)-(+)-DBCA than the antipode, showing the stereoselectively predominant secretion of (R)-(+)- DBCA. The N-monodemethylated metabolite, M-1, was found only for the R-(+)- enantiomer in the perfusate and urine, revealing highly stereoselective N- monodemethylation in the kidney. The CLr(sec,int) value for (R)-(+)-M-1 was 2.5 times larger than that for (R)-(+)-DBCA. The perfusion study using each enantiomer decreased R/S ratios of the extraction ratio (9.9), urinary excretion rate (3.9) and excretory clearance (3.9) in the perfusion of the racemate to 3.9, 2.1 and 2.1, respectively. No significant difference was found between (R)-(+)- and (S)-(-)-DBCA in FE and CLr(sec,int). The declined stereoselectivity in renal excretion parameters may be due to competitive inhibition of the tubular secretion of (R)-(+)-DBCA by the (R)-(+)-M-1 formed which possessed greater secretion ability in the (R)-(+)-DBCA perfusion study, whereas (S)-(-)-DBCA was secreted without great inhibition by (S)-(- )-M-1 in the (S)-(-)-DBCA perfusion because of a small amount of generated metabolite. Plotting of FE ratios of DBCA enantiomers to (R)-(+)-M-1 against FE of (R)-(+)-M-1 suggests that the actual FE for (R)-(+)-DBCA was 2 times larger than that for (S)-(-)-DBCA, and that (S)-(-)-DBCA secretion was inhibited more easily by (R)-(+)-M-1.

UR - http://www.scopus.com/inward/record.url?scp=0028309020&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028309020&partnerID=8YFLogxK

M3 - Article

C2 - 8035328

AN - SCOPUS:0028309020

VL - 270

SP - 329

EP - 335

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -