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Acylglucuronide in alkaline conditions: migration vs. hydrolysis
Florent Di Meo1, Michele Steel, Picard Nicolas
1School of Pharmacy, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France. florent.di-meo@unilim.fr
Journal of Molecular Modeling
|February 20, 2013
Summary
This study explains how drugs with carboxylic acids become acylglucuronides (AG) during phase II metabolism. Quantum calculations reveal migration and hydrolysis competition, impacting drug action and elimination.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Computational Chemistry
- Medicinal Chemistry
Background:
- Glucuronidation is a key Phase II metabolic pathway for drug elimination.
- Acylglucuronide (AG) metabolites are formed from drugs containing a carboxylic acid moiety.
- Understanding AG formation is crucial due to their potential toxicity and impact on drug efficacy.
Purpose of the Study:
- To rationalize the glucuronidation process for carboxylic acid-containing drugs.
- To investigate the competition between AG migration and hydrolysis using computational methods.
- To elucidate the molecular mechanisms governing these metabolic pathways.
Main Methods:
- Utilized advanced quantum calculation methods, specifically MP2 and Density Functional Theory (DFT).
- Simulated the molecular dynamics of acylglucuronide formation and subsequent reactions.
- Analyzed the kinetic and thermodynamic favorability of migration and hydrolysis pathways.
Main Results:
- Identified acylglucuronide (AG) formation as a significant metabolic pathway for drugs like mycophenolic acid, diclofenac, and ibuprofen.
- Quantum calculations demonstrated that AG migration involves drug rotation around the glucuronic acid.
- Both migration (kinetically favored) and hydrolysis (thermodynamically favored) were found to be feasible under specific conditions, particularly alkaline pH.
Conclusions:
- The competition between AG migration and hydrolysis significantly influences drug action and elimination.
- Migration, favored under alkaline conditions, can lead to diverse metabolites with varying toxicities.
- Understanding these competing pathways is essential for predicting drug behavior and minimizing adverse effects.
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