Studies on the reactivity of acyl glucuronides-VII. Salicyl acyl glucuronide reactivity in vitro and covalent binding of salicylic acid to plasma protein of humans taking aspirin

Salicyl acyl glucuronide (SAG) is a significant metabolite of salicylic acid (SA) and aspirin. We have shown that, under physiological conditions in vitro, SAG undergoes rearrangement in a manner consistent with acyl migration to its 2-, 3- and 4-O-acyl positional isomers as the predominant pathway (T 1 2 values were 1.4-1.7 hr in buffer at pH 7.4 and 37°). Incubation of SAG or a mixture of its rearrangement isomers (iso-SAG) (each at ∼50 μg SA equivalents/mL) with human serum albumin (HSA, at ∼40 mg/mL) revealed the formation of covalent adducts with the protein, with peak concentrations of 1-2 μg SA equivalents/mL. The data support a role for the rearrangement/glycation mechanism of adduct formation. Covalent adducts of SA were also detected in the plasma of humans taking aspirin (at ≥1200 mg/day), but the concentrations were low (≪100ng SA equivalents/mL). Reactivity of SAG thus provides a mechanism (though of uncertain quantitative importance) of covalent attachment of the salicyl moiety of aspirin to tissue macromolecules, which is in addition to its well-known acetylating capacity