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.

酰基葡萄糖醛酸化是酸性药物及其代谢物的常见代谢结果，由于这些代谢物具有反应性，因此它们与药物不良反应 (ADR) 和停药有关。然而，导致反应性代谢物（例如，氧化和酰基辅酶 A 硫酯）的替代代谢途径意味着缺乏明确的证据证明酰基葡萄糖醛酸苷具有毒性。在这里，我们回顾了这些代谢物的合成和反应性，并描述了分子建模和体外和体内的使用酰基葡糖苷酸反应性的反应性评估。基于在反应性和蛋白质加成方法中出现的结构依赖性差异，建议在药物发现/开发中对形成酰基葡萄糖醛酸的酸性药物或候选药物进行风险评估。