Journal of Molecular Modeling

, Volume 19, Issue 6, pp 2423–2432 | Cite as

Acylglucuronide in alkaline conditions: migration vs. hydrolysis

  • Florent Di Meo
  • Michele Steel
  • Picard Nicolas
  • Pierre Marquet
  • Jean-Luc Duroux
  • Patrick Trouillas
Original Paper


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.


Acylglucuronides Alkaline hydrolysis DFT Kinetics Migration Thermodynamics 



The authors thank the “Conseil Régional du Limousin” for financial support and CALI (CAlcul en LImousin) for computing facilities. The authors also gratefully acknowledge the support by COST (COST Action CM0804 “Chemical Biology with Natural Compounds”) and the Operational Program Research and Development for Innovations–European Regional Development Fund (project CZ.1.05/2.1.00/03.0058 of the Ministry of Education, Youth and Sports of the Czech Republic).

Supplementary material

894_2013_1790_MOESM1_ESM.pdf (270 kb)
ESM 1 (PDF 269 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Florent Di Meo
    • 1
  • Michele Steel
    • 1
  • Picard Nicolas
    • 2
    • 3
    • 4
  • Pierre Marquet
    • 2
    • 3
    • 4
  • Jean-Luc Duroux
    • 1
  • Patrick Trouillas
    • 1
    • 5
    • 6
  1. 1.School of PharmacyUniversité de LimogesLimoges CedexFrance
  2. 2.Inserm, UMR-S850LimogesFrance
  3. 3.Laboratory of Medical PharmacologyUniversité de LimogesLimogesFrance
  4. 4.Department of Pharmacology-ToxicologyCHU LimogesLimogesFrance
  5. 5.Service de Chimie des Matériaux NouveauxUniversité de Mons-HainautMonsBelgium
  6. 6.Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of SciencePalacký University OlomoucOlomoucCzech Republic

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