Studies on the reactivity of acyl glucuronides--II. Interaction of diflunisal acyl glucuronide and its isomers with human serum albumin in vitro.
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.[1]References
- Studies on the reactivity of acyl glucuronides--II. Interaction of diflunisal acyl glucuronide and its isomers with human serum albumin in vitro. Dickinson, R.G., King, A.R. Biochem. Pharmacol. (1991) [Pubmed]
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