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

BC Sallustio, BA Fairchild, K Shanahan, AM Evans and RL Nation

Department of Clinical Pharmacology, Queen Elizabeth Hospital, Woodville, South Australia.

Acyl glucuronides are reactive electrophilic metabolites and in vivo 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, 1-O-gemfibrozil-beta-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-beta-D-glucuronide (N = 4) at initial concentrations of 120 microM and 21 microM, respectively. In the gemfibrozil perfusions, 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, 76.9 (5.6) min, 0.091 (0.012), and 0.347 (0.154), respectively. In the 1-O-gemfibrozil-beta-D-glucuronide perfusions, the mean (SD) total perfusate 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-beta-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-beta-D-glucuronide over 90 min. However, in the presence of a liver, approximately 25% of 1-O-gemfibrozil-beta-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-beta-D- glucuronide.

Volume 24, Issue 9, pp. 984-989, 09/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				I. S. Westley, L. R. Brogan, R. G. Morris, A. M. Evans, and B. C. Sallustio ROLE OF MRP2 IN THE HEPATIC DISPOSITION OF MYCOPHENOLIC ACID AND ITS GLUCURONIDE METABOLITES: EFFECT OF CYCLOSPORINE Drug Metab. Dispos., February 1, 2006; 34(2): 261 - 266. [Abstract] [Full Text] [PDF]

				Y. Shitara, M. Hirano, H. Sato, and Y. Sugiyama Gemfibrozil and Its Glucuronide Inhibit the Organic Anion Transporting Polypeptide 2 (OATP2/OATP1B1:SLC21A6)-Mediated Hepatic Uptake and CYP2C8-Mediated Metabolism of Cerivastatin: Analysis of the Mechanism of the Clinically Relevant Drug-Drug Interaction between Cerivastatin and Gemfibrozil J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 228 - 236. [Abstract] [Full Text] [PDF]

				L. Sabordo, B. C. Sallustio, A. M. Evans, and R. L. Nation Hepatic Disposition of the Acyl Glucuronide 1-O-Gemfibrozil-beta -D-glucuronide: Effects of Clofibric Acid, Acetaminophen, and Acetaminophen Glucuronide J. Pharmacol. Exp. Ther., October 1, 2000; 295(1): 44 - 50. [Abstract] [Full Text]

				L. Sabordo, B. C. Sallustio, A. M. Evans, and R. L. Nation Hepatic Disposition of the Acyl Glucuronide1-O-Gemfibrozil-beta -D-Glucuronide: Effects of Dibromosulfophthalein on Membrane Transport and Aglycone Formation J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 414 - 420. [Abstract] [Full Text]

				K. J. Dix, D. P. Coleman, and A. R. Jeffcoat Comparative Metabolism and Disposition of Gemfibrozil in Male and Female Sprague-Dawley Rats and Syrian golden Hamsters Drug Metab. Dispos., January 1, 1999; 27(1): 138 - 146. [Abstract] [Full Text]

				B. F. Thomas, J. P. Burgess, D. P. Coleman, N. M. Scheffler, A. R. Jeffcoat, and K. J. Dix Isolation and identification of novel metabolites of gemfibrozil in rat urine Drug Metab. Dispos., January 1, 1999; 27(1): 147 - 157. [Abstract] [Full Text]