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Journal article
Transacylation and hydrolysis of the acyl glucuronides of ibuprofen and its α-methyl-substituted analogues investigated by 1H NMR spectroscopy and computational chemistry: Implications for drug design
Journal of pharmaceutical and biomedical analysis, Vol.246, 116238
2024
Abstract
Drugs and drug metabolites containing a carboxylic-acid moiety can undergo in vivo conjugation to form 1-β-O-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 monitor the hydrolysis, transacylation, and anomerisation behaviours 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 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 for each of the 4 AGs, together with the overall degradation 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.
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Details
- Title
- Transacylation and hydrolysis of the acyl glucuronides of ibuprofen and its α-methyl-substituted analogues investigated by 1H NMR spectroscopy and computational chemistry: Implications for drug design
- Authors/Creators
- Selena E. Richards - Khalifa University of Science and TechnologyPeter R. Bradshaw - Imperial College LondonCaroline H. Johnson - Yale UniversityAndrew V. Stachulski - University of LiverpoolToby J. Athersuch - Imperial College LondonJeremy K. Nicholson - Murdoch University, Health Futures InstituteJohn C. Lindon - Imperial College LondonIan Wilson - Imperial College London
- Publication Details
- Journal of pharmaceutical and biomedical analysis, Vol.246, 116238
- Publisher
- Elsevier B.V
- Identifiers
- 991005670270107891
- Copyright
- © 2024 The Authors.
- Murdoch Affiliation
- Australian National Phenome Centre
- Language
- English
- Resource Type
- Journal article
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- 1 Clinical & Life Sciences
- 1.181 Molecular Toxicology
- 1.181.399 NSAIDs and COX Inhibitors
- Web Of Science research areas
- Chemistry, Analytical
- Pharmacology & Pharmacy
- ESI research areas
- Pharmacology & Toxicology