| Stereoselective renal tubular secretion of an organic anion in the isolated perfused rat kidney. | |
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MedLine Citation:
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PMID: 8035328 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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To clarify the stereoselective renal tubular secretion of an organic anion, renal excretion of 5-dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carbox yli c 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 (CLrex) 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 (CLrsec,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 CLrsec,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 Clrsec,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. |
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Authors:
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K Higaki; K Kadono; S Goto; M Nakano |
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Publication Detail:
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Type: In Vitro; Journal Article |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 270 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 1994 Jul |
Date Detail:
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Created Date: 1994-08-15 Completed Date: 1994-08-15 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 329-35 Citation Subset: IM |
Affiliation:
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Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Diuretics / pharmacokinetics* Drug Interactions Kidney / metabolism, secretion Kidney Tubules / metabolism, secretion* Male Perfusion Rats Rats, Sprague-Dawley Stereoisomerism Sulfonamides / pharmacokinetics* |
| Chemical | |
Reg. No./Substance:
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0/Diuretics; 0/Sulfonamides; 103968-87-2/S 8666 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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