MRC Centre for Drug Safety Science, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3GE, UK.
Biopharm Drug Dispos. 2010 Oct;31(7):367-95. doi: 10.1002/bdd.720.
Acyl glucuronidation is the major metabolic conjugation reaction of most carboxylic acid drugs in mammals. The physiological consequences of this biotransformation have been investigated incompletely but include effects on drug metabolism, protein binding, distribution and clearance that impact upon pharmacological and toxicological outcomes. In marked contrast, the exceptional but widely disparate chemical reactivity of acyl glucuronides has attracted far greater attention. Specifically, the complex transacylation and glycation reactions with proteins have provoked much inconclusive debate over the safety of drugs metabolised to acyl glucuronides. It has been hypothesised that these covalent modifications could initiate idiosyncratic adverse drug reactions. However, despite a large body of in vitro data on the reactions of acyl glucuronides with protein, evidence for adduct formation from acyl glucuronides in vivo is limited and potentially ambiguous. The causal connection of protein adduction to adverse drug reactions remains uncertain. This review has assessed the intrinsic reactivity, metabolic stability and pharmacokinetic properties of acyl glucuronides in the context of physiological, pharmacological and toxicological perspectives. Although numerous experiments have characterised the reactions of acyl glucuronides with proteins, these might be attenuated substantially in vivo by rapid clearance of the conjugates. Consequently, to delineate a relationship between acyl glucuronide formation and toxicological phenomena, detailed pharmacokinetic analysis of systemic exposure to the acyl glucuronide should be undertaken adjacent to determining protein adduct concentrations in vivo. Further investigation is required to ascertain whether acyl glucuronide clearance is sufficient to prevent covalent modification of endogenous proteins and consequentially a potential immunological response.
酰基葡萄糖醛酸苷化是哺乳动物中大多数羧酸类药物的主要代谢结合反应。这种生物转化的生理后果尚未完全研究清楚，但包括对药物代谢、蛋白质结合、分布和清除的影响，这些影响会影响药理学和毒理学结果。相比之下，酰基葡萄糖醛酸苷异常但广泛的化学反应性引起了更多的关注。具体来说，酰基葡萄糖醛酸苷与蛋白质的复杂转酰基和糖化反应引发了关于代谢为酰基葡萄糖醛酸苷的药物安全性的大量无定论的争论。有人假设这些共价修饰可能引发特发性药物不良反应。然而，尽管有大量关于酰基葡萄糖醛酸苷与蛋白质反应的体外数据，但体内酰基葡萄糖醛酸苷形成加合物的证据有限且可能存在歧义。蛋白质加合物与药物不良反应之间的因果关系仍然不确定。本综述从生理、药理和毒理角度评估了酰基葡萄糖醛酸苷的内在反应性、代谢稳定性和药代动力学特性。尽管有许多实验已经描述了酰基葡萄糖醛酸苷与蛋白质的反应，但这些反应在体内可能会因缀合物的快速清除而大大减弱。因此，为了阐明酰基葡萄糖醛酸苷形成与毒理学现象之间的关系，应该在体内确定蛋白质加合物浓度的同时，对系统暴露于酰基葡萄糖醛酸苷的详细药代动力学分析。需要进一步研究以确定酰基葡萄糖醛酸苷的清除是否足以防止内源性蛋白质的共价修饰，从而避免潜在的免疫反应。
