title: Acyl glucuronide drug metabolites: toxicological and analytical implications.
abstract: Although glucuronidation is generally considered a detoxification route of drug metabolism, the chemical reactivity of acyl glucuronides has been linked with the toxic properties of drugs that contain carboxylic acid moieties. It is now well documented that such metabolites can reach appreciable concentrations in blood. Furthermore, they are labile, undergo hydrolysis and pH-dependent intramolecular acyl migration to isomeric conjugates of glucuronic acid, and may react irreversibly with plasma proteins, tissue proteins, and with nucleic acids. This stable binding causes chemical alterations that are thought to contribute to drug toxicity either through changes in the functional properties of the modified molecules or through antigen formation with subsequent hypersensitivity and other immune reactions. Whereas in vitro data on the toxicity of acyl glucuronides have steadily accumulated, direct evidence for their toxicity in vivo is scarce. Acyl glucuronides display limited stability, which is dependent on pH, temperature, nature of the aglycon, and so on. Therefore, careful sample collection, handling, and storage procedures are critical to ensure generation of reliable pharmacologic and toxicologic data during clinical studies. Acyl glucuronides can be directly quantified in biologic specimens using chromatographic procedures. Their adducts with plasma or cell proteins can be determined after electrophoretic separation, followed by blotting. ELISA techniques have been used to assess the presence of antibodies against acyl glucuronide-protein adducts. This review summarizes the most recent evidence concerning biologic and toxicologic effects of acyl glucuronide metabolites of various drugs and discusses their relevance for drug monitoring. A critical evaluation of the available methodology is included.
authors.affiliation: Department of Clinical Chemistry, Georg-August-University, Göttingen, Germany. maria.shipkova@med.uni-goettingen.de
authors.forename: Maria
authors.initials: M
authors.lastname: Shipkova
authors.forename: Victor William
authors.initials: VW
authors.lastname: Armstrong
authors.forename: Michael
authors.initials: M
authors.lastname: Oellerich
authors.forename: Eberhard
authors.initials: E
authors.lastname: Wieland
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D020719:Glucuronides / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity*; D014453:Glucuronosyltransferase / Q000032:analysis / Q000378:metabolism; D006801:Humans; D004364:Pharmaceutical Preparations / Q000032:analysis / Q000378:metabolism*
chemical_list: D020719:Glucuronides; D004364:Pharmaceutical Preparations; D014453:Glucuronosyltransferase