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Studies on the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in rats.

Studies on the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in rats. Research Abstract Details 

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  • Studies on the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in rats. Abstract Text:

     olsen Olsen,chunze liChunze Li,christian skonbergChristian Skonberg,inga Inga ,ulrik sideniusUlrik Sidenius,leslie z benetLeslie Z Benet, hansen Hansen,

    Carboxylic acids may be metabolized to acyl glucuronides and acyl-coenzyme A thioesters (acyl-CoAs), which are reactive metabolites capable of reacting with proteins in vivo. In this study, the metabolic activation of tolmetin (Tol) to reactive metabolites and the subsequent formation of Tol-protein adducts in the liver were studied in rats. Two hours after dose administration (100 mg/kg i.p.), tolmetin acyl-CoA (Tol-CoA) was identified by liquid chromatography-tandem mass spectrometry in liver homogenates. Similarly, the acyl-CoA-dependent metabolites tolmetin-taurine conjugate (Tol-Tau) and tolmetin-acyl carnitine ester (Tol-Car) were identified in rat livers. In a rat bile study (100 mg/kg i.p.), the S-acyl glutathione thioester conjugate was identified, providing further evidence of the formation of reactive metabolites such as Tol-CoA or Tol-acyl glucuronide (Tol-O-G), capable of acylating nucleophilic functional groups. Three rats were treated with clofibric acid (150 mg/kg/day i.p. for 7 days) before dose administration of Tol. This resulted in an increase in covalent binding to liver proteins from 0.9 nmol/g liver in control rats to 4.2 nmol/g liver in clofibric acid-treated rats. Similarly, levels of Tol-CoA increased from 0.6 nmol/g to 4.4 nmol/g liver after pretreatment with clofibric acid, whereas the formation of Tol-O-G and Tol-Tau was unaffected by clofibric acid treatment. However, Tol-Car levels increased from 0.08 to 0.64 nmol/g after clofibric acid treatment. Collectively, these results confirm that Tol-CoA is formed in vivo in the rat and that this metabolite can have important consequences in terms of covalent binding to liver proteins.

    Studies on the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in rats. Publishing Authors By Initials

    j olsenJ Olsen,c liC Li,c skonbergC Skonberg,i I ,u sideniusU Sidenius,lz benetLZ Benet,sh hansenSH Hansen,

    For similar heterocyclic compounds: heterocyclic compounds, 1-ring: azoles: pyrroles: tolmetin research abstracts see: heterocyclic compounds: heterocyclic compounds, 1-ring: azoles: pyrroles: tolmetin research

    PUBMED ID PMID:

    MEDLINE DATE:

    Studies on the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in rats. Journal Published:

    PUBLICATION TYPE: Research Support, Non-U.S. Gov

    Journal: Drug metabolism and disposition: the biological fa

    VOLUME: 35

    Page Numbers: 758-64

    Journal Abbreviation:

    ISSN: 0090-9556

    DAY: 15

    MONTH: 02

    YEAR: 2007

    Studies on the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in rats. Information

    Number of References:

    LANGUAGE: eng

    NlmUniqueID: 9421550

    Studies on the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in rats. Keywords Mesh Terms:

    KEYWORDS: Tolmetin

    MESH TERMS: pharmacology

    Chemical & Substance for Abstract: Studies on the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in rats. Information

    Substance Name: Clofibric Acid

    Registry Number: 882-09-7

    Grant and Affiliation Information for Studies on the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in rats.

    AFFILIATION: Department of Pharmaceutics and Analytical Chemistry, the Danish University of Pharmaceutical Sciences, Copenhagen, Denmark. jqgo@novonordisk.com

    Country: United States

    United States Research PublicationUnited States Research Publication

    AGENCY: United States NIGMS

    GRANT: GM 36633

    ACRONYM: GM

    MEDLINETA: Drug Metab Dispos

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