Document Detail


Reactivity of mefenamic acid 1-o-acyl glucuronide with proteins in vitro and ex vivo.
MedLine Citation:
PMID:  8869817     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mefenamic acid is a nonsteroidal anti-inflammatory drug commonly used in analgesia. The use of this drug has been implicated in several cases of nephrotoxicity including acute renal failure and tubulointerstitial nephritis. One theory of drug-induced tubulointerstitial nephritis is that the drug or a derivative of the drug becomes irreversibly bound to certain sites in renal tissue and an immune response is directed against the hapten-host conjugate. Previous studies have shown that in humans the nonsteroidal anti-inflammatory drug mefenamic acid is metabolized by both phase I enzymes and the phase II enzyme family UDP-glucuronosyltransferase. Indeed, three glucuronides were identified and isolated from human urine by semipreparative HPLC after oral administration of mefenamic acid. This study focuses on mefenamic acid glucuronide and further characterizes this acyl glucuronide in terms of stability and its ability to bind irreversibly to proteins. Stability studies of mefenamic acid glucuronide in aqueous buffer highlighted the relative stability of this acyl glucuronide at physiological pH. The half-life at 37 degrees C, pH 7.4, was 16.5 +/- 3.1 hr, which is considerably longer than those reported for many acyl glucuronides. The degradation of mefenamic acid glucuronide was accelerated under alkaline conditions, decreasing the half-life to 5 +/- 1.6 hr at pH 8.0. Mefenamic acid glucuronide, although extremely stable in buffer at physiological pH, was found to bind irreversibly to human serum albumin in vitro. Irreversible binding to cellular proteins in culture was also evident with the addition of mefenamic acid to the heterologous Chinese hamster lung fibroblast cell line V79 expressing the human UDP-glucuronosyltransferase isoenzyme UGT1*02. This binding was directly related to glucuronide formation, because irreversible binding was not evident in the untransfected cell line V79.
Authors:
K A McGurk; R P Remmel; V P Hosagrahara; D Tosh; B Burchell
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  24     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  1996 Aug 
Date Detail:
Created Date:  1997-01-21     Completed Date:  1997-01-21     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  842-9     Citation Subset:  IM    
Affiliation:
Department of Biochemical Medicine, University of Dundee, Ninewells Hospital and Medical School, UK.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Inflammatory Agents, Non-Steroidal / metabolism*,  pharmacokinetics
Cell Line
Cricetinae
Cricetulus
Glucuronates / metabolism,  urine
Half-Life
Humans
Magnetic Resonance Spectroscopy
Mefenamic Acid / analogs & derivatives*,  metabolism*,  pharmacokinetics,  urine
Protein Binding
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Glucuronates; 102623-18-7/1-O-(2-(2,3-dimethylphenyl)aminobenzoyl)glucopyranuronic acid; 61-68-7/Mefenamic Acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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