The influence of physicochemical properties on the reactivity and stability of acyl glucuronides^†

Abstract

1. Formation of 1-O-acyl-β-d-glucuronide conjugates is a significant pathway in the metabolism of drugs containing a carboxylic acid group. The formation of acyl glucuronides results in an increase in both the aqueous solubility and molecular mass of the conjugate in comparison to the parent drug and thus facilitates excretion in both urine and bile.

2. Acyl glucuronides are effectively esters, which undergo first order decomposition by both hydrolysis and the intra-migration of the acyl group around the glucuronide ring to yield 2-, 3- and 4-O-glucuronic acid esters which, unlike the metabolically formed 1-O-acyl-β-d-glucuronides, are not substrates for β-glucuronidase. The first order degradation half-life is therefore a composite value of these two reactions and a useful indicator of chemical reactivity and potential toxicity.

3. Intra-molecular migration is expected to be the predominant pathway due to entropic considerations.

4. Such conjugates, together with their isomeric ester derivatives, react with nucleophilic sites on proteins and small endogenous molecules, such as glutathione, which potentially contributes to the observed toxicity and adverse drug reactions associated with some drugs.

5. Examination of the stability of the 1-O-acyl-β-d-glucuronides of aryl acetic acid, α-carbon substituted aryl acetic acid, aliphatic and aromatic acids, as determined by their first order degradation half-lives, indicates the significance of electronic and steric features that contribute to conjugate stability under physiological conditions.

6. Examination of the of the electronic properties of the carbonyl carbon atom in acyl glucuronides, as measured by the pKa of the parent acid, together with the steric substituents about the acyl carbonyl provides insight into the reactivity of these conjugates.

7. The investigations reported herein on a large number of 1-O-acyl-β-d-glucuronides has allowed rationalisation of their physicochemical properties in relation to the structure of the parent drug and has the potential to contribute to the design of carboxylic acid containing drug molecules with increased stability of a major metabolite with potential reduction in toxicity and adverse drug reactions.

Keywords:

• 1-O-acyl-β-d-glucuronides
• carboxylic acids
• glucuronide conjugation
• acyl migration
• physicochemical properties
• electronic and steric properties

Acknowledgements

The authors wish to acknowledge the use of the Chemicalize database part of the EPSRC funded National Chemical Database Service hosted by the Royal Society of Chemistry.