DISPOSITION OF GEMFIBROZIL AND GEMFIBROZIL-ACYL-GLUCURONIDE IN THE RAT ISOLATED-PERFUSED LIVER

Acyl glucuronides are reactive electrophilic metabolites and in vivo a re readily hydrolyzed, undergo intramolecular rearrangement, and bind covalently to proteins. The isolated perfused liver preparation, using male Sprague-Dawley rats, was used to examine the hepatic disposition of the fibrate hypolipidemic agent gemfibrozil and its acyl glucuroni de metabolite, 1-O-gemfibrozil-beta-D-glucuronide. Using a recirculati ng design, erythrocyte-free perfusion medium containing 1% (w/v) album in was delivered to the liver via the portal vein at a flow rate of 30 ml/min, and for each experiment was spiked with either gemfibrozil (N = 4) or 1-O-gemfibrozil-beta-D-glucuronide (N = 4) at initial concent rations of 120 mu M and 21 mu M, respectively. In the gemfibrozil perf usions, the mean JSD) total perfusate clearance, half-life, hepatic ex traction ratio of gemfibrozil, and the fraction of eliminated gemfibro zil excreted in bile as the glucuronide conjugate were 2.73 (0.30) ml/ min, 76.9 (5.6) min, 0.091 (0.012), and 0.347 (0.154), respectively. I n the 1-O-gemfibrozil-beta-D-glucuronide perfusions, the mean (SD) tot al perfusate clearance, half-life, hepatic extraction ratio, and fract ion excreted in bile as the glucuronide conjugate were 19.5 (2.1) ml/m in, 8.7 (0.9) min, 0.649 (0.068), and 0.534 (0.077), respectively. The higher hepatic extraction ratio for 1-O-gemfibrozil-beta-D-glucuronid e could mostly be attributed to its higher unbound fraction in perfusa te (0.182), compared with that of the parent drug (0.004), because the conjugate had a lower intrinsic clearance (305 ml/min) compared with the aglycone (751 ml/min). Control perfusions, conducted in the absenc e of a liver, showed negligible degradation of 1-O-gemfibrozil-beta-D- glucuronide over 90 min. However, in the presence of a liver, approxim ately 25% of 1-O-gemfibrozil-beta-D-glucuronide added to perfusate was hydrolyzed to gemfibrozil over 90 min. The study demonstrates the imp ortance of the liver in the formation, uptake, hydrolysis, and excreti on of 1-O-gemfibrozil-beta-D-glucuronide.