Abstract
There is increasing in vitro and in vivo evidence indicating that acyl glucuronides of various drugs are chemically reactive and potentially cause organ toxicity. Such conjugates are chemically unstable, undergoing hydrolysis and pH-dependent intramolecular migration to generate isomers and covalent binding with various tissue proteins to result in drug-protein adducts. This review highlights the reactivity of drug acyl glucuronides and commonly used analytical techniques for these metabolites and resultant drug-protein adducts used in preclinical and clinical studies. The stability of acyl glucuronides is dependent on many factors including pH, temperature, nature of the aglycon, and the presence of plasma or albumin. Drug acyl glucuronides may cause toxicity either through changes in the functional properties of the modified proteins, through initiation of antigen-mediated immune responses, or unknown mechanisms. The conjugates and sometimes the drug-protein adducts can achieve appreciable blood concentrations following drug administration. With careful sample handling procedures (e.g. quick cooling and acidification) during preclinical and clinical studies, drug acyl glucuronides in biological matrixes can be reliably identified and quantitated using appropriate analytical methods such as HPLC, LC-MS and NMR techniques. The drug-protein adducts can also be identified and determined using these highly sensitive chromatographic techniques after proper sample processing. In addition, their protein adducts with plasma or cellular 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 in vivo. Further studies are needed to explore the clinical and toxicological implications of acyl glucuronides of various drugs and to establish the relationships between the toxicity of drugs and their acyl glucuronide levels by close monitoring using above analytical techniques.
Keywords: Acyl glucuronides, Reactivity, Drug-protein adducts, Analysis
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