title: Acyl glucuronide metabolites: Implications for drug safety assessment.
abstract: Acyl glucuronides are important metabolites of compounds with carboxylic acid moieties and have unique properties that distinguish them from other phase 2 metabolites. In particular, in addition to being often unstable, acyl glucuronide metabolites can be chemically reactive leading to covalent binding with macromolecules and toxicity. While there is circumstantial evidence that drugs forming acyl glucuronide metabolites can be associated with rare, but severe idiosyncratic toxic reactions, many widely prescribed drugs with good safety records are also metabolized through acyl glucuronidation. Therefore, there is a need to understand the various factors that can affect the safety of acyl glucuronide-producing drugs including the rate of acyl glucuronide formation, the relative reactivity of the acyl glucuronide metabolite formed, the rate of elimination, potential proteins being targeted, and the rate of aglucuronidation. In this review, these factors are discussed and various approaches to de-risk the safety liabilities of acyl glucuronide metabolites are evaluated.
authors.affiliation: Abbvie, Development Sciences, Department of Preclinical Safety, United States. Electronic address: terry.vanvleet@abbvie.com.
authors.forename: Terry R
authors.initials: TR
authors.lastname: Van Vleet
authors.affiliation: Abbvie, Development Sciences, Biomeasure and Metabolism, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Abbvie, Development Sciences, Biomeasure and Metabolism, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: Lee
authors.affiliation: Abbvie, Development Sciences, Department of Preclinical Safety, United States.
authors.forename: Eric A G
authors.initials: EAG
authors.lastname: Blomme
mesh_terms: D000215:Acylation; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D012449:Safety
chemical_list: D020719:Glucuronides; D004364:Pharmaceutical Preparations
keywords: Acyl glucuronides; Clinical; Elimination; Idiosyncratic; Metabolite; Pharmacokinetics; Preclinical; Protein binding; Reactive; Safety testing; Toxicology