Acyl glucuronide reactivity in perspective



Bradshaw, Peter R, Athersuch, Toby J, Stachulski, Andrew V and Wilson, Ian D ORCID: 0000-0002-8558-7394
(2020) Acyl glucuronide reactivity in perspective. DRUG DISCOVERY TODAY, 25 (9). pp. 1639-1650.

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Abstract

Acyl glucuronidation is a common metabolic fate for acidic drugs and their metabolites and, because these metabolites are reactive, they have been linked to adverse drug reactions (ADRs) and drug withdrawals. However, alternative routes of metabolism leading to reactive metabolites (e.g., oxidations and acyl-CoA thioesters) mean that unambiguous proof that acyl glucuronides are toxic is lacking. Here, we review the synthesis and reactivity of these metabolites, and describe the use of molecular modelling and in vitro and in vivo reactivity assessment of acyl glucuronide reactivity. Based on the emerging structure-dependent differences in reactivity and protein adduction methods for risk assessment for acyl glucuronide-forming acid drugs or drug candidates in drug discovery/development are suggested.

Item Type: Article
Uncontrolled Keywords: Animals, Humans, Glucuronides, Acylation
Depositing User: Symplectic Admin
Date Deposited: 03 Aug 2020 07:43
Last Modified: 18 Jan 2023 23:38
DOI: 10.1016/j.drudis.2020.07.009
Open Access URL: https://doi.org/10.1016/J.DRUDIS.2020.07.009
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3095895