| Disposition of gemfibrozil and gemfibrozil acyl glucuronide in the rat isolated perfused liver. | |
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MedLine Citation:
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PMID: 8886608 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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B C Sallustio; B A Fairchild; K Shanahan; A M Evans; R L Nation |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 24 ISSN: 0090-9556 ISO Abbreviation: Drug Metab. Dispos. Publication Date: 1996 Sep |
Date Detail:
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Created Date: 1997-02-12 Completed Date: 1997-02-12 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 984-9 Citation Subset: IM |
Affiliation:
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Department of Clinical Pharmacology, Queen Elizabeth Hospital, Woodville, South Australia. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antilipemic Agents / metabolism* Bile / metabolism Gemfibrozil / analogs & derivatives*, chemistry, metabolism*, pharmacokinetics Glucuronates / chemistry, metabolism*, pharmacokinetics Kinetics Liver / metabolism* Male Perfusion Rats Rats, Sprague-Dawley |
| Chemical | |
Reg. No./Substance:
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0/Antilipemic Agents; 0/Glucuronates; 25812-30-0/Gemfibrozil; 91683-38-4/gemfibrozil 1-O-acylglucuronide |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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