Document Detail

Hepatic disposition of the acyl glucuronide 1-O-gemfibrozil-beta-D-glucuronide: effects of clofibric acid, acetaminophen, and acetaminophen glucuronide.
MedLine Citation:
PMID:  10991959     Owner:  NLM     Status:  MEDLINE    
Glucuronidation of carboxylic acid compounds results in the formation of electrophilic acyl glucuronides. Because of their polarity, carrier-mediated hepatic transport systems play an important role in determining both intra- and extrahepatic exposure to these reactive conjugates. We have previously shown that the hepatic membrane transport of 1-O-gemfibrozil-beta-D-glucuronide (GG) is carrier-mediated and inhibited by the organic anion dibromosulfophthalein. In this study, we examined the influence of 200 microM acetaminophen, acetaminophen glucuronide, and clofibric acid on the disposition of GG (3 microM) in the recirculating isolated perfused rat liver preparation. GG was taken up by the liver, excreted into bile, and hydrolyzed within the liver to gemfibrozil, which appeared in perfusate but not in bile. Mean +/- S. D. hepatic clearance, apparent intrinsic clearance, hepatic extraction ratio, and biliary excretion half-life of GG were 10.4 +/- 1.4 ml/min, 94.1 +/- 17.9 ml/min, 0.346 +/- 0.046, and 30.9 +/- 4.9 min, respectively, and approximately 73% of GG was excreted into bile. At the termination of the experiment (t = 90 min), the ratio of GG concentrations in perfusate, liver, and bile was 1:35:3136. Acetaminophen and acetaminophen glucuronide had no effect on the hepatic disposition of GG, suggesting relatively low affinities of acetaminophen conjugates for hepatic transport systems or the involvement of multiple transport systems for glucuronide conjugates. In contrast, clofibric acid increased the hepatic clearance, extraction ratio, and apparent intrinsic clearance of GG (P <.05) while decreasing its biliary excretion half-life (P <.05), suggesting an interaction between GG and hepatically generated clofibric acid glucuronide at the level of hepatic transport. However, the transporter protein(s) involved remains to be identified.
L Sabordo; B C Sallustio; A M Evans; R L Nation
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  295     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2000 Oct 
Date Detail:
Created Date:  2000-11-03     Completed Date:  2000-11-03     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  44-50     Citation Subset:  IM    
Department of Clinical Pharmacology, The Queen Elizabeth Hospital, Woodville, South Australia.
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MeSH Terms
Acetaminophen / analogs & derivatives*,  pharmacology*
Biological Transport / drug effects
Clofibric Acid / pharmacology*
Gemfibrozil / analogs & derivatives*,  pharmacokinetics
Glucuronates / pharmacokinetics*
Liver / metabolism*
Rats, Sprague-Dawley
Reg. No./Substance:
0/Glucuronates; 103-90-2/Acetaminophen; 16110-10-4/acetaminophen glucuronide; 25812-30-0/Gemfibrozil; 882-09-7/Clofibric Acid; 91683-38-4/gemfibrozil 1-O-acylglucuronide

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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