Acylglucuronide in alkaline conditions: Migration vs. hydrolysis

Abstract : 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.
Type de document :
Article dans une revue
Liste complète des métadonnées

https://hal-unilim.archives-ouvertes.fr/hal-00937889
Contributeur : Vincent Sol <>
Soumis le : mardi 28 janvier 2014 - 21:52:25
Dernière modification le : mercredi 31 juillet 2019 - 12:18:03

Lien texte intégral

Identifiants

Collections

Citation

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, Springer Verlag (Germany), 2013, 19 (6), pp.2423-2432. ⟨10.1007/s00894-013-1790-3⟩. ⟨hal-00937889⟩

Partager

Métriques

Consultations de la notice

100