Covalent protein modifications by electrophilic acyl glucuronide (AG) metabolites are hypothetical causes of hypersensitivity reactions associated with certain carboxylate drugs. The complex rearrangements and reactivities of drug AG have been defined in great detail, and protein adducts of carboxylate drugs, such as diclofenac, have been found in the liver and plasma of animals and humans. This study targeted mass spectrometric analyses of human serum albumin (HSA) isolated from diclofenac patients to characterize drug-derived structures, and thereby have deconstructed conclusively the pathways of adduct formation from a drug AG and its isomeric rearrangement products in vivo. Results demonstrate that HSA modifications by diclofenac in vivo are complicated and variable; that at least a fraction of the modifications are derived from the drug’s AG metabolite; and that albumin adduction is not inevitably a causation of hypersensitivity to carboxylate drugs or a coincidental association.
See article at J Pharmacol Exp Ther 2014, 350:387–402.
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