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

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.

Keywords

Acylglucuronides Alkaline hydrolysis DFT Kinetics Migration Thermodynamics 

Supplementary material

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

References

  1. 1.
    Kaspersen FM, Van Boeckel CAA (1987) A review of the methods of chemical synthesis of sulphate and glucuronide conjugates. Xenobiotica 17:1451–1471CrossRefGoogle Scholar
  2. 2.
    Stachulski AV, Jenkins GN (1998) The synthesis of O-glucuronides. Nat Prod Rep 15:173–186CrossRefGoogle Scholar
  3. 3.
    Picard N et al (2005) Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos 33:139–146CrossRefGoogle Scholar
  4. 4.
    Schutz E et al (1999) Identification of a pharmacologically active metabolite of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil. Clin Chem (Washington, D C) 45:419–422Google Scholar
  5. 5.
    Shipkova M et al (1999) Identification of glucoside and carboxyl-linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil. Br J Pharmacol 126:1075–1082CrossRefGoogle Scholar
  6. 6.
    Shipkova M et al (2000) Determination of the acyl glucuronide metabolite of mycophenolic acid in human plasma by HPLC and Emit. Clin Chem (Washington, D C) 46:365–372Google Scholar
  7. 7.
    Grillo MP et al (2003) Studies on the chemical reactivity of diclofenac acyl glucuronide with glutathione: Identification of diclofenac-S-acyl-glutathione in rat bile. Drug Metab Dispos 31:1327–1336CrossRefGoogle Scholar
  8. 8.
    Johnson CH et al (2007) NMR spectroscopic studies on the in vitro acyl glucuronide migration kinetics of ibuprofen ((±)-(R,S)-2-(4-Isobutylphenyl) propanoic acid), its metabolites, and analogues. Anal Chem (Washington, DC, United States) 79:8720–8727CrossRefGoogle Scholar
  9. 9.
    Vanderhoeven SJ et al (2004) NMR and QSAR studies on the transacylation reactivity of model 1Î2-O-acyl glucuronides. I: Design, synthesis and degradation rate measurement. Xenobiotica 34:73–85CrossRefGoogle Scholar
  10. 10.
    Corcoran O et al (2001) HPLC/1H NMR spectroscopic studies of the reactive α−1-O-acyl isomer formed during acyl migration of S-naproxen Î2-1-O-acyl glucuronide. Chem Res Toxicol 14:1363–1370CrossRefGoogle Scholar
  11. 11.
    Hansen-Moeller J et al (1988) Isolation and identification of the rearrangement products of diflunisal 1-O-acyl glucuronide. J Pharm Biomed Anal 6:229–240CrossRefGoogle Scholar
  12. 12.
    Spahn-Langguth H, Benet LZ (1992) Acyl glucuronides revisited: is the glucuronidation process a toxification as well as a detoxification mechanism? Drug Metab Rev 24:5–47CrossRefGoogle Scholar
  13. 13.
    Wang J et al (2004) A novel approach for predicting acyl glucuronide reactivity via Schiff base formation: development of rapidly formed peptide adducts for LC/MS/MS measurements. Chem Res Toxicol 17:1206–1216CrossRefGoogle Scholar
  14. 14.
    Park BK, Coleman JW, Kitteringham NR (1987) Drug disposition and drug hypersensitivity. Biochem Pharmacol 36:581–590CrossRefGoogle Scholar
  15. 15.
    Boelsterli UA, Zimmerman HJ, Kretz-Rommel A (1995) Idiosyncratic liver toxicity of nonsteroidal antiinflammatory drugs: molecular mechanisms and pathology. Crit Rev Toxicol 25:207–235CrossRefGoogle Scholar
  16. 16.
    Berry NG et al (2009) Synthesis, transacylation kinetics and computational chemistry of a set of arylacetic acid 1[small beta]-O-acyl glucuronides. Org Biorgan Chem 7:2525–2533CrossRefGoogle Scholar
  17. 17.
    Bender ML (1960) Mechanisms of catalysis of nucleophilic reactions of carboxylic acid derivatives. Chem Rev (Washington, DC, United States) 60:53–113CrossRefGoogle Scholar
  18. 18.
    Garcias RC et al (2003) Theoretical study of the alkaline hydrolysis of an aza-Î2-lactam derivative of clavulanic acid. Chem Phys Lett 372:275–281CrossRefGoogle Scholar
  19. 19.
    Xiong Y, Zhan C-G (2004) Reaction pathways and free energy barriers for alkaline hydrolysis of insecticide 2-trimethylammonioethyl methylphosphonofluoridate and related organophosphorus compounds: electrostatic and steric effects. J Org Chem 69:8451–8458CrossRefGoogle Scholar
  20. 20.
    Frisch MJ et al (2004) Gaussian 03, Revision C.02, edn. I. Gaussian 2004, Wallingford, CTGoogle Scholar
  21. 21.
    Zhao Y, Truhlar DG (2004) Hybrid meta density functional theory methods for thermochemistry, thermochemical kinetics, and noncovalent interactions: the MPW1B95 and MPWB1K models and comparative assessments for hydrogen bonding and van der Waals interactions. J Phys Chem A 108:6908–6918CrossRefGoogle Scholar
  22. 22.
    Zhan C-G, Landry DW, Ornstein RL (2000) Energy barriers for alkaline hydrolysis of carboxylic acid esters in aqueous solution by reaction field calculations. J Phys Chem A 104:7672–7678CrossRefGoogle Scholar
  23. 23.
    Trouillas P et al (2004) A theoretical study of the conformational behavior and electronic structure of taxifolin correlated with the free radical-scavenging activity. Food Chem 88:571–582CrossRefGoogle Scholar
  24. 24.
    Trouillas P et al (2006) A DFT study of the reactivity of OH groups in quercetin and taxifolin antioxidants: the specificity of the 3-OH site. Food Chem 97:679–688CrossRefGoogle Scholar
  25. 25.
    Anouar E et al (2009) New aspects of the antioxidant properties of phenolic acids: a combined theoretical and experimental approach. Phys Chem Chem Phys 11:7659–7668CrossRefGoogle Scholar
  26. 26.
    Moller C, Plesset MS (1934) Note on the approximation treatment for many-electron systems. Phys Rev 46:618–622CrossRefGoogle Scholar
  27. 27.
    Grimme S (2003) Improved second-order M[o-slash]ller–Plesset perturbation theory by separate scaling of parallel- and antiparallel-spin pair correlation energies. J Chem Phys 118:9095–9102CrossRefGoogle Scholar
  28. 28.
    Pliego JR Jr, Riveros JM (2002) A theoretical analysis of the free-energy profile of the different pathways in the alkaline hydrolysis of methyl formate in aqueous solution. Chem Eur J 8:1945–1953CrossRefGoogle Scholar
  29. 29.
    Vilkas MJ, Zhan C-G (2008) An efficient implementation for determining volume polarization in self-consistent reaction field theory. J Chem Phys 129:194109/194101–194109/194107CrossRefGoogle Scholar
  30. 30.
    Cossi M et al (2002) New developments in the polarizable continuum model for quantum mechanical and classical calculations on molecules in solution. J Chem Phys 117:43–54CrossRefGoogle Scholar
  31. 31.
    Tomasi J, Mennucci B, Cammi R (2005) Quantum mechanical continuum solvation models. Chem Rev (Washington, DC, United States) 105:2999–3093CrossRefGoogle Scholar
  32. 32.
    Abraham MH (1984) Thermodynamics of solution of homologous series of solutes in water. J Chem Soc Faraday Trans 1 Phys Chem Condens Phase 80:153–181Google Scholar
  33. 33.
    Jang YH et al (2002) pKa values of guanine in water: density functional theory calculations combined with Poisson−Boltzmann Continuum−Solvation Model. J Phys Chem B 107:344–357CrossRefGoogle Scholar
  34. 34.
    Premaud A et al (2006) Determination of mycophenolic acid plasma levels in renal transplant recipients co-administered sirolimus: comparison of an enzyme multiplied immunoassay technique (EMIT) and liquid chromatography-tandem mass spectrometry. Ther Drug Monit 28:274–277CrossRefGoogle Scholar

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

Personalised recommendations