A F McDonagh

TL;DR: Irreversible binding in vivo correlated with overall exposure to zomepirac glucuronide when exposure was expressed as the area under the plasma concentration vs. time curve, and the reaction may be general for other drugs that are metabolized to acyl glucuronides.

TL;DR: Evidence is presented for an alternative mechanism where irreversible binding occurs by isomerization of the glucuronide and formation of an imine linkage between the glucuronic acid moiety of the conjugate and a lysine or terminal amino group of the protein.

TL;DR: Results show unambiguously that the glucuronic acid moiety of acyl glucuronides can be retained within the structure when these reactive metabolites bind covalently to proteins, and suggest that acyl migration followed by Schiff base (imine) formation is a credible mechanism for the generation of covalent adducts in vivo.

TL;DR: The results establish that the binding of these reactive metabolites to nucleophilic sites of proteins occur via two different mechanisms: one involving imine (Schiff base) formation and the other involvingucleophilic displacement of glucuronic acid.

TL;DR: The correlation of Z covalent binding with AUC of ZG in the guinea pig is similar to that found in humans suggesting that the degree to which acyl glucuronides form covalENT adducts with proteins in humans may be predictable from studies in animals.