The elderly often take many drugs that contain the ubiquitous carboxylic acid functional group. A common metabolic pathway for such acids is linkage with the sugar, glucuronic acid, to yield acyl (ester) glucuronides. Recent evidence indicates that some acyl glucuronides are unstable, undergoing base catalyzed acyl migration to isomeric conjugates and hydrolysis at physiological pH. These acyl glucuronides can also react irreversibly with proteins in animals and humans. For zomepirac and tolmetin, the covalent binding to plasma proteins in humans correlates well with the cumulative plasma exposure to their acyl glucuronides. Because renal excretion is the major route of elimination for acyl glucuronides, the elderly may have increased exposure to acyl glucuronides leading to enhanced covalent binding to proteins. Other experiments with acidic antiinflammatory drugs strongly suggest that acyl glucuronides covalently bind to albumin via an imine intermediate formed with an amine function of the protein, and the free aldehyde of glucuronic acid which is exposed following acyl migration. This acyl glucuronide-mediated glycation of protein is analogous in many ways to the well-described post-translational glycation of proteins by reducing sugars which is elevated in uncontrolled diabetes. At present, the possible toxicological implications of the irreversible covalent binding of acyl glucuronides to proteins has not been determined, though there is substantial precedent that protein adducts can be correlated with tissue damage, immunological reactions and changes in the functional properties of proteins. Indeed, the glycation of proteins by glucose or fructose and subsequent formation of advanced glycation endproducts is hypothesized to be a likely cause of the sequelae observed in diabetes and the """"""""aging of proteins"""""""". Moreover, several drugs that form unstable and reactive acyl glucuronides, e.g. suprofen (Suprol), zomepirac (Zomax) and benoxaprofen (Oraflex), were withdrawn from the United States market due to an unacceptable incidence of severe adverse reactions. These considerations, and the fact that the elderly often have compromised ability to eliminate drugs and their metabolites because of progressive renal failure, have prompted the investigative team to ask the following questions regarding the binding of acyl glucuronides to proteins in the elderly, which this research proposal will address: 1) Does decreased renal function in the elderly lead to accumulation of acyl glucuronide metabolites?; 2) Does exposure of the elderly to acyl glucuronides result in significant covalent binding of acyl glucuronides to proteins in vivo?; 3) Does chronic administration of drugs which are metabolized to acyl glucuronides lead to advanced glycation endproducts formed from glycation of proteins by glucuronic acid?; and 4) Does glycation of proteins by glucuronic acid alter the function of proteins?
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