Abstract：
Drugs and drug metabolites containing a carboxylic-acid moiety can undergo in vivo conjugation to form 1-β-O-acyl-glucuronides (1-β-O-AGs). In addition to hydrolysis, these conjugates can undergo spontaneous acyl migration, and anomerisation reactions, resulting in a range of positional isomers. Facile transacylation has been suggested as a mechanism contributing to the toxicity of acyl glucuronides, with the kinetics of these processes thought to be a factor. Previous 1H NMR spectroscopic and HPLC-MS studies have been conducted to measure the degradation rates of the 1-β-O-AGs of three nonsteroidal anti-inflammatory drugs (ibufenac, R-ibuprofen, S-ibuprofen) and a dimethyl-analogue (termed here as \"bibuprofen\"). These studies have also determined the relative contributions of hydrolysis and acyl migration in both buffered aqueous solution, and human plasma. Here, a detailed kinetic analysis is reported, providing the individual rate constants for the acyl migration and hydrolysis reactions observed in buffer for each of the 4 AGs, together with the overall degradation rate constants of the parent 1-β-O-AGs. Computational modelling of the reactants and transition states of the transacylation reaction using density functional theory indicated differences in the activation energies that reflected the influence of both substitution and stereochemistry on the rate of transacylation/hydrolysis.
摘要：
含有羧酸部分的药物和药物代谢物可以在体内进行缀合以形成1-β-O-酰基-葡糖苷酸(1-β-O-AG)。除了水解，这些缀合物可以经历自发的酰基迁移，和阴离子化反应，导致一系列位置异构体。容易的转酰化已被认为是导致酰基葡糖醛酸的毒性的机制。这些过程的动力学被认为是一个因素。先前的1HNMR光谱和HPLC-MS研究已经进行了测量三种非甾体抗炎药的1-β-O-AG的降解速率（伊布芬酸，R-布洛芬,S-布洛芬）和二甲基类似物（此处称为“布洛芬”）。这些研究还确定了两种缓冲水溶液中水解和酰基迁移的相对贡献，和人类血浆。这里,报告了详细的动力学分析，为4个AG中的每一个提供在缓冲液中观察到的酰基迁移和水解反应的单独速率常数，以及母体1-β-O-AG的总降解速率常数。使用密度泛函理论对反应物和转酰反应的过渡态进行计算建模，表明活化能的差异反映了取代和立体化学对转酰/水解速率的影响。
