Van Vleet Terry R, Liu Hong, Lee Anthony, Blomme Eric A G
Abbvie, Development Sciences, Department of Preclinical Safety, United States.
Abbvie, Development Sciences, Biomeasure and Metabolism, United States.
Toxicol Lett. 2017 Apr 15;272:1-7. doi: 10.1016/j.toxlet.2017.03.003. Epub 2017 Mar 7.
Acyl glucuronides are important metabolites of compounds with carboxylic acid moieties and have unique properties that distinguish them from other phase 2 metabolites. In particular, in addition to being often unstable, acyl glucuronide metabolites can be chemically reactive leading to covalent binding with macromolecules and toxicity. While there is circumstantial evidence that drugs forming acyl glucuronide metabolites can be associated with rare, but severe idiosyncratic toxic reactions, many widely prescribed drugs with good safety records are also metabolized through acyl glucuronidation. Therefore, there is a need to understand the various factors that can affect the safety of acyl glucuronide-producing drugs including the rate of acyl glucuronide formation, the relative reactivity of the acyl glucuronide metabolite formed, the rate of elimination, potential proteins being targeted, and the rate of aglucuronidation. In this review, these factors are discussed and various approaches to de-risk the safety liabilities of acyl glucuronide metabolites are evaluated.
酰基葡萄糖醛酸是含有羧酸部分的化合物的重要代谢产物，具有使其有别于其他Ⅱ相代谢产物的独特性质。特别是，酰基葡萄糖醛酸代谢产物除了常常不稳定外，还可能具有化学反应性，导致与大分子共价结合并产生毒性。虽然有间接证据表明，形成酰基葡萄糖醛酸代谢产物的药物可能与罕见但严重的特异质性毒性反应有关，但许多安全性记录良好且广泛处方的药物也通过酰基葡萄糖醛酸化进行代谢。因此，有必要了解各种可能影响产生酰基葡萄糖醛酸的药物安全性的因素，包括酰基葡萄糖醛酸的形成速率、形成的酰基葡萄糖醛酸代谢产物的相对反应活性、消除速率、潜在的靶向蛋白以及去葡萄糖醛酸化速率。在本综述中，将对这些因素进行讨论，并评估降低酰基葡萄糖醛酸代谢产物安全风险的各种方法。
