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Article Dans Une Revue Journal of Molecular Modeling Année : 2013

Acylglucuronide in alkaline conditions: Migration vs. hydrolysis


This work rationalizes the glucuronidation process (one of the reactions of the phase II metabolism) for drugs having a carboxylic acid moiety. At this stage, acylglucuronides (AG) metabolites are produced, that have largely been reported in the literature for various drugs (e.g., mycophenolic acid (MPA), diclofenac, ibuprofen, phenylacetic acids). The competition between migration and hydrolysis is rationalized by adequate quantum calculations, combing MP2 and density functional theory (DFT) methods. At the molecular scale, the former process is a real rotation of the drug around the glucuconic acid. This chemical-engine provides four different metabolites with various toxicities. Migration definitely appears feasible under alkaline conditions, making proton release from the OH groups. The latter reaction (hydrolysis) releases the free drug, so the competition is of crucial importance to tackle drug action and elimination. From the theoretical data, both migration and hydrolysis appear kinetically and thermodynamically favored, respectively.

Dates et versions

hal-00937889 , version 1 (28-01-2014)



Florent Di Meo, M. Steel, P. Nicolas, Pierre Marquet, Jean-Luc Duroux, et al.. Acylglucuronide in alkaline conditions: Migration vs. hydrolysis. Journal of Molecular Modeling, 2013, 19 (6), pp.2423-2432. ⟨10.1007/s00894-013-1790-3⟩. ⟨hal-00937889⟩
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