REACTIVITY OF GEMFIBROZIL 1-O-BETA-ACYL GLUCURONIDE - PHARMACOKINETICS OF COVALENTLY BOUND GEMFIBROZIL-PROTEIN ADDUCTS IN RATS

Acyl glucuronides are electrophilic metabolites that are readily hydro lyzed, undergo intramolecular rearrangement, and mediate the covalent binding of many acidic drugs to endogenous proteins. Gemfibrozil is ex tensively metabolized to gemfibrozil acyl glucuronide in humans and ra ts. The aims of this study were to demonstrate the reactivity of gemfi brozil glucuronide, determine whether gemfibrozil formed covalently bo und protein adducts in vivo, describe the pharmacokinetics of adduct f ormation, and examine the role of gemfibrozil glucuronide in adduct fo rmation. 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. Pla sma, liver, kidney, and heart were examined for adduct formation. Plas ma was quantitatively the most important site for formation of gemfibr ozil-protein adducts with mean (SE) steady-state concentrations of 31. 40 (2.40) ng/mg protein attained by approximately the 10th day of dosi ng. Adduct half-life in plasma was 3.1 days, consistent with the elimi nation 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 add uct accumulation seemed greatest in liver, but was similar in kidney a nd plasma, with similar to 2x, 16x, and 30x accumulation, respectively , over the dosing interval. In all tissues, adduct half-lives were sig nificantly greater than those of the noncovalently bound gemfibrozil o r gemfibrozil glucuronide. In vitro incubations with rat serum albumin at 37 degrees C confirmed the role of gemfibrozil acyl glucuronide in the formation of covalently bound gemfibrozil-albumin adducts, and de monstrated the time-dependent intramolecular rearrangement and hydroly sis of gemfibrozil glucuronide that had a half-life of similar to 14 h r.