PubMed · 7182898
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J R Azanza Perea, J M Honorato Pérez, R Cuena Boy. 1982. [Diflunisal].. https://pubmed.ncbi.nlm.nih.gov/7182898/
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Acyl glucuronide conjugates are chemically reactive metabolites which can undergo hydrolysis, rearrangement (isomerization via acyl migration) and covalent binding reactions with protein. The present study was undertaken to identify factors modulating the reactivity of diflunisal acyl glucuronide (DAG) with human serum albumin (HSA) in vitro, by comprehensively evaluating the interplay of the three pathways above when DAG and a mixture of its 2-, 3- and 4-isomers (iso-DAG) were incubated with protein. Buffer, plasma, fraction V HSA, fatty acid-free HSA, globulin-free HSA and fatty acid- and globulin-free HSA were investigated at pH 7.4 and 37 degrees, each in the absence and presence of warfarin, diazepam and diflunisal (DF) as reversible binding competitors. DAG and iso-DAG were highly reversibly bound (ca. 98-99.5%) in plasma and HSA solutions. The binding was primarily at the benzodiazepine site, since displacement occurred in the presence of diazepam and fatty acids but not warfarin. DAG degradation, via rearrangement, hydrolysis and covalent adduct formation (in that order of quantitative importance), was retarded in plasma and HSA solutions compared to buffer. The protective effect of protein was afforded by the high reversible binding to the (non-catalytic) benzodiazepine site. The warfarin site appeared to be catalytic for DAG hydrolysis, whereas rearrangement appeared to be hydroxide ion-catalysed only. In contrast to DAG, iso-DAG degradation was greatly accelerated in the presence of protein, through both covalent binding and catalysis of hydrolysis. Covalent binding via DAG was increased in the presence of warfarin but decreased in the presence of diazepam, DF and fatty acids. The opposite effects were found for covalent binding via iso-DAG. The data suggest that covalent binding of DF to HSA via DAG and iso-DAG occurs by different mechanisms (presumably transacylation and glycation, respectively) at different sites (benzodiazepine and warfarin, respectively) whereas reversible binding occurs primarily at the same site (benzodiazepine).
Diflunisal is frequently used for management of postoperative dental pain as it has some advantages over other commonly used non-steroidal anti-inflammatory drugs including improved analgesia, a prolonged duration of action lasting up to 12 hours, and a low incidence of side effects. The aim of this paper is to review the relevant pharmacologic actions of the drug including its mechanism of action in suppressing the inflammatory response, and indications for its use in dentistry. Diflunisal can be safely recommended for the dental patient following oral surgery and exodontia, periodontal surgery and endodontic surgery.
A major metabolite of diflunisal (DF) is its reactive acyl glucuronide conjugate (DAG) which can undergo hydrolysis (regeneration of DF), intramolecular rearrangement (isomerization via acyl migration) and intermolecular reactions with nucleophiles. We have compared the fate of DAG and its individual 2-, 3- and 4-O-acyl positional isomers (at ca. 55 micrograms DF equivalents/mL) after incubation with human serum albumin (HSA, 40 mg/mL) at pH 7.4 and 37 degrees. Initial half-lives (T1/2) for DAG and its 2-, 3- and 4-isomers were 53, 75, 61 and 26 min, respectively. DAG was more labile to hydrolysis than any of its isomers but the latter, in particular the 4-isomer, were much better substrates for formation of covalent DF-HSA adducts. After a 2-hr incubation, 2.4, 8.2, 13.7 and 36.6% of substrate DAG and its 2-, 3- and 4-isomers (respectively) were present as DF-HSA adducts. With long term incubation, the concentrations of adducts so generated in situ declined in a biphasic manner, with apparent terminal T1/2 values of ca. 28 days. DAG was much more labile to transacylation with methanol (i.e. formation of DF methyl ester) than an equimolar mixture of its isomers after incubation in a 1:1 methanol:pH 7.4 buffer solution at 37 degrees (T1/2 values of 5 and 70 min, respectively). The data do not support direct transacylation with nucleophilic groups on protein as the predominant mechanism of formation of covalent DF-HSA adducts in vitro.