Acyl glucuronidation is a common metabolic fate for acidic drugs and
their metabolites and, because these metabolites are reactive, they have
been linked to adverse drug reactions (ADRs) and drug withdrawals.
However, alternative routes of metabolism leading to reactive metabolites
(e.g., oxidations and acyl-CoA thioesters) mean that unambiguous proof
that acyl glucuronides are toxic is lacking. Here, we review the synthesis
and reactivity of these metabolites, and describe the use of molecular
modelling and in vitro and in vivo reactivity assessment of acyl glucuronide
reactivity. Based on the emerging structure-dependent differences in
reactivity and protein adduction methods for risk assessment for acyl
glucuronide-forming acid drugs or drug candidates in drug discovery/
development are suggested.