STUDIES ON THE REACTIVITY OF ACYL GLUCURONIDES .7. SALICYLIC ACYL GLUCURONIDE REACTIVITY IN-VITRO AND COVALENT BINDING OF SALICYLIC-ACID TOPLASMA-PROTEIN OF HUMANS TAKING ASPIRIN

Salicyl acyl glucuronide (SAG) is a significant metabolite of salicyli c acid (SA) and aspirin. We have shown that, under physiological condi tions in vitro, SAG undergoes rearrangement in a manner consistent wit h acyl migration to its 2-, 3- and 4-O-acyl positional isomers as the predominant pathway (T1/2 values were 1.4-1.7 hr in buffer at pH 7.4 a nd 37 degrees). Incubation of SAG or a mixture of its rearrangement is omers (be-SAG) (each at similar to 50 mu g SA equivalents/mL) with hum an serum albumin (HSA, at similar to 40 mg/mL) revealed the formation of covalent adducts with the protein, with peak concentrations of 1-2 mu g SA equivalents/mL. The data support a role for the rearrangement/ glycation mechanism of adduct formation. Covalent adducts of SA were a lso detected in the plasma of humans taking aspirin (at greater than o r equal to 1200 mg/day), but the concentrations were low (much less th an 100 ng SA equivalents/mL). Reactivity of SAG thus provides a mechan ism (though of uncertain quantitative importance) of covalent attachme nt of the salicyl moiety of aspirin to tissue macromolecules, which is in addition to its well-known acetylating capacity.