Disposition of gemfibrozil and gemfibrozil acyl glucuronide in the rat isolated perfused liver

Benedetta C. Sallustio, Barbara A. Fairchild, Kathryn Shanahan, Allan M. Evans, Roger L. Nation

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Abstract

Acyl glucuronides are reactive electrophilic metabolites and in viva are 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 glucuronide metabolite, l-O- gemfibrozil-̄-D-glucuronide. Using a recirculating design, erythrocyte-free perfusion medium containing 1% (w/v) albumin 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-β-D-glucuronide (N = 4) at initial concentrations of 120 μM end 21 μM, respectively. In the gemfibrozil parfusions, the mean (SD) total perfusate clearance, half-life, hepatic extraction ratio of gemfibrozil, and the fraction of eliminated gemfibrozil excreted in bile as the glucuronide conjugate were 2.73 (0.30) ml/min, 78.9 (5.6) min, 0.091 (0.012), and 0.347 (0.154), respectively. In the 1-O-gemfibrozil-β-D-glucuronide perfusions, the mean (so) total parfusete clearance, half-life, hepatic extraction ratio, and fraction excreted in bile as the glucuronide conjugate were 19.5 (2.1) ml/min, 8.7 (0.9) min, 0.649 (0.068), and 0.534 (0.077), respectively. The higher hepatic extraction ratio for 1-O-gemfibrozil-β-D-glucuronide could mostly be attributed to its higher unbound fraction in perfusate (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 absence of a liver, showed negligible degradation of 1-O-gemfibrozil-β-D-glucuronide over 90 min. However, in the presence of a liver, approximately 25% of l-O-gemifbrozil-β-D-glucuronide added to perfusate was hydrolyzed to gemfibrozil over 90 min. The study demonstrates the importance of the liver in the formation, uptake, hydrolysis, and excretion of 1-O-gemfibrozil-β-D-glucuronide.

Original languageEnglish
Pages (from-to)984-989
Number of pages6
JournalDrug Metabolism and Disposition
Volume24
Issue number9
Publication statusPublished - 1 Sep 1996

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