| Stereoselective disposition of S-8666, a novel uricosuric antihypertensive diuretic, and its N-monodemethylated metabolite in a perfused rat liver preparation. Effect of protein binding on the kinetics of S-8666. | |
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MedLine Citation:
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PMID: 1355707 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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S-8666 (5-dimethyl-sulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid), a novel uricosuric antihypertensive diuretic, and its N-monodemethylated metabolite (M-I) were studied in a single pass perfused rat liver preparation under constant perfusate flow (ca. 16 ml/min). During perfusion with 100 nmol/ml of racemic S-8666 not containing bovine serum albumin (BSA), the steady-state hepatic extraction ratio of R(+)-S-8666 was two times higher (0.65 +/- 0.08) than that of S(-)-S-8666 (0.34 +/- 0.08). R(+)- and S(-)-M-I in the effluent perfusate plasma accounted for 64 and 18% of the influx rate of each enantiomeric S-8666, respectively. The N-monodemethylation was found to be responsible for the hepatic extraction of S-8666 enantiomers. S(-)-S-8666 was excreted into bile at a more rapid rate than the R(+)-enantiomer. Biliary excretion of R(+)-M-I was faster than S(-)-M-I, although the excretion rates of M-I were slower than those of S-8666 for both enantiomers. The steady-state extractions of preformed R(+)- and S(-)-M-I were low and a significant difference [S(-) greater than R(+)] was observed during the perfusion of 100 nmol/ml preformed racemic M-I without BSA. Increasing the concentration of BSA in the perfusate led to decreases in the extraction ratios of S-8666 enantiomers and biliary excretion rates of all chemicals, which was due to the decreases in the free fractions of S-8666 and M-I enantiomers. The binding of S-8666 and M-I enantiomers to BSA also showed stereoselectivity [R(+) less than S(-)].(ABSTRACT TRUNCATED AT 250 WORDS) |
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Authors:
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K Higaki; M Nakano |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 20 ISSN: 0090-9556 ISO Abbreviation: Drug Metab. Dispos. Publication Date: 1992 May-Jun |
Date Detail:
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Created Date: 1992-10-15 Completed Date: 1992-10-15 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 350-5 Citation Subset: IM |
Affiliation:
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Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Diuretics / metabolism, pharmacokinetics* Kinetics Liver / metabolism* Male Methylation Protein Binding Rats Rats, Inbred Strains Serum Albumin, Bovine / metabolism, pharmacology Statistics as Topic Stereoisomerism Sulfonamides / metabolism, pharmacokinetics* Uricosuric Agents / metabolism, pharmacokinetics* |
| Chemical | |
Reg. No./Substance:
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0/Diuretics; 0/Serum Albumin, Bovine; 0/Sulfonamides; 0/Uricosuric Agents; 103968-87-2/S 8666 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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