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

Selena E. Richards; Peter R. Bradshaw; Caroline H. Johnson; Andrew V. Stachulski; Toby J. Athersuch; Jeremy K. Nicholson; John C. Lindon; Ian Wilson

doi:10.1016/j.jpba.2024.116238

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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

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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

Selena E. Richards, Peter R. Bradshaw, Caroline H. Johnson, Andrew V. Stachulski, Toby J. Athersuch, Jeremy K. Nicholson, John C. Lindon and Ian Wilson

Journal of pharmaceutical and biomedical analysis, Vol.246, 116238

2024

DOI: https://doi.org/10.1016/j.jpba.2024.116238

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Abstract

1H Nuclear Magnetic Resonance Spectroscopy

Acyl glucuronide migration

Density Functional Theory

Drug toxicity

Kinetics

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. [Display omitted]

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 Technology
Peter R. Bradshaw - Imperial College London
Caroline H. Johnson - Yale University
Andrew V. Stachulski - University of Liverpool
Toby J. Athersuch - Imperial College London
Jeremy K. Nicholson - Murdoch University, Health Futures Institute
John C. Lindon - Imperial College London
Ian Wilson - Imperial College London
Publication Details: Journal of pharmaceutical and biomedical analysis, Vol.246, 116238
Publisher: Elsevier B.V
Identifiers: 991005670270107891
Murdoch Affiliation: Australian National Phenome Centre
Language: English
Resource Type: Journal article

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 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