Acyl glucuronides are electrophilic metabolites that are readily hydrolyzed, undergo intramolecular rearrangement, and mediate the covalent binding of many acidic drugs to endogenous proteins. Gemfibrozil is extensively metabolized to gemfibrozil acyl glucuronlde In humans and rats. The aims of this study were to demonstrate the reactivity of gemfibrozil glucuronide, determine whether gemfibrozil formed covalently bound protein adducts in vlvo, describe the pharmacokinetics of adduct formation, and examine the role of gemfibrozil glucuronide In adduct formation. Rats were admInIstered 150 mg/kg gemfibrozil daily for up to 37 days and killed 1, 2, 5, 10, 19, and 37 days after commencement of dosing, and 1, 2, 3, 8, 17, and 30 days after cessation of dosing. Plasma, liver, kidney, and heart were examined for adduct forma-tion. Plasma was quantitatively the most important site for formation of gemfibrozil-protein adducts with mean (SE) steady-state concentrations of 31.40 (2.40) ng/mg protein attained by approxi-mately the 10th day of dosing. Adduct half-life in plasma was 3.1 days, consistent with the elimination half-life of albumin. Mean (SE) kidney, liver, and heart steady-state adduct concentrations were 2.13 (0.11), 0.89 (0.35), and 0.95 (0.07) ng/mg protein, respectively. The rate of gemfibrozil-protein adduct accumulation seemed greatest in liver, but was similar in kidney and plasma, with-2x, 16x, and 30x accumulation, respectively, over the dosing interval. In all tissues, adduct half-lives were significantly greater than those of the noncovalently bound gemfibrozil or gemfibrozil glucuronide. In vitro incubations with rat serum albumin at 37#{176} Cconfirmed the role of gemfibrozil acyl glucuronide In the formation of covalently bound gemfibrozil-albumin adducts, and demonstrated the time-dependent Intramolecular rearrangement and hydrolysis of gemfibrozil glucuronide that had a half-life of-14 hr.

Gemfibrozil is a fibrate hypolipidemic agent structurally related to clofibrate. In clinical use, it is recommended as the drug of choice for the management of hyperlipidaemias involving raised triglyceride concentrations(1, 2), and has been shown to be clinically effective in lowering the incidence of coronary heart disease(1, 2). In both humans and rats, gemfibrozil is metabolized by phase I and phase II pathways forming a number of oxidative metabolites and glucuronide conjugates(fig. 1)(1, 3-5). One of the major metabolic products formed is gemfibrozil 1-O-f3-acyl glucuronide, which seems to be excreted both in urine and bile in humans(3, 4), and primarily bile in rats (5). The urinary recovery of gemfibrozil and its metabolites in humans is shown in fig. 1, and up to 50% of a dose of gemfibrozil may be excreted in urine as gemfibrozil 1-O--acyl glucuronide(3). It is now well established(6) that acyl glucuronides are chemically reactive, electrophilic species that readily undergo nonenzymic nu-cleophilic substitution reactions with: 1) free hydroxyl anions resulting in hydrolysis of the conjugate and regeneration of the parent acid; 2) the hydroxyl groups on the glucuronic acid moiety resulting in intramolecular migration of the xenobiotic moiety from the 1-O-3-