INTERACTION OF HUMAN SERUM ALBUMIN WITH THE ELECTROPHILIC METABOLITE

Acyl glucuronides are electrophilic metabolites that are readily hydrolyzed, undergo intramolecular rearrangement, and bind co-valently to endogenous proteins. Gemfibrozil is a fibrate lipid-lowering agent that is extensively metabolized to an acyl glucuro-nide conjugate in humans. The aims of this study were to examine the interactions of 1-O-gemfibrozil-b-D-glucuronide with human serum albumin. The degradation of 1-O-gemfibrozil-b-D-glucuro-nide (;200 mM) was examined in vitro during incubations at 37°C with phosphate buffer (pH 7.4 or 9.0), solutions of human serum albumin (pH 7.4), or fresh human plasma (pH 7.4). The effects of diazepam, oxyphenbutazone, and gemfibrozil on the degradation of 1-O-gemfibrozil-b-D-glucuronide, and its reversible binding to albumin were also studied. A pilot in vivo study was performed on two patient volunteers administered 1 g/day po gemfibrozil. 1-O-Gemfibrozil-b-D-glucuronide was unstable, with degradation half