DISPOSITION OF ACYL GLUCURONIDES & THEIR PROTEIN ADDUCTS

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Drugs, other xenobiotics and endogenous compounds that contain the ubiquitous carboxylic acid functional group are often metabolized by conjugation with glucuronic acid to form acyl (ester linked) glucuronides. It is now well documented that such metabolites can reach appreciable concentrations in blood, are labile, undergoing pH-dependent intramolecular acyl migration to isomeric conjugates of glucuronic acid or hydrolysis and may react irreversibly with plasma or tissue proteins, both in vitro and in vivo. Currently scientists are well aware of the instability of acyl glucuronides, their potential to react covalently with proteins and their postulated link with toxicity, through either apparent untoward immunological responses or by modification of critical proteins. A better understanding of the phenomenon may lead to newly developed drugs with less adverse reactions. Drugs metabolized to acyl glucuronides are still being identified to have unacceptable toxicity as shown by the withdrawal of suprofen in the U.S. in 1988 and that of ketorolac from German and French market in 1994. The reaction of acyl glucuronides with proteins appears to be by either of two mechanisms, nucleophilic displacement and imine formation after acyl migration, though which is more dominant or toxicologically significant in vivo has not been resolved. Until recently, there was no cause-effect relationship established between covalent adducts formed by acyl glucuronides and toxicity; nor was there an animal model for any adverse reactions due to acyl glucuronides. However, recently a relationship between acyl glucuronide formation rates, instability and observed hepatobiliary toxicity in mice and rats for a sense of phenyl glycines under development as drugs was reported. This series of phenyl carboxylic acid offers an opportunity to systematically study potential mechanisms for acyl glucuronide mediated toxicity. These considerations indicate that continued research on the disposition and reactivity of acyl glucuronides is warranted and lead to the following research questions: 1. Is there a correlation between covalent binding of acidic compounds to proteins in vivo or in vitro and observed toxicity for acids metabolized to acyl glucuronides?; and 2. Can the reactivity of acyl glucuronides be predicted by understanding of the chemistry of these acidic compounds and the mechanisms involved in their binding to proteins? These questions will be addressed through a coordinated series of in vitro experiments and small animal studies using reactive and stable acyl glucuronides as well as by computational modeling of the chemical processes involved.