DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on March 24, 2008; DOI: 10.1124/dmd.108.021089

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.108.021089v1
36/7/1438    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Author home page(s):
Toshiaki Makino
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Makino, T.
Right arrow Articles by Mizukami, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Makino, T.
Right arrow Articles by Mizukami, H.


Received for publication February 19, 2008.
Revised March 20, 2008.
Accepted for publication March 21, 2008.

Down-regulation of a hepatic transporter Mrp2 is involved in alteration of pharmacokinetics of glycyrrhizin and its metabolites in a rat model of chronic liver injury

Toshiaki Makino 1*, Nobuhiro Ohtake 2, Akito Watanabe 1, Naoko Tsuchiya 2, Sachiko Imamura 2, Seiichi Iizuka 2, Makoto Inoue 3, Hajime Mizukami 1

1 Department of Pharmacognosy, Graduate School of Pharmaceutical Science, Nagoya City University 2 Tsumura Research Laboratories, Tsumura Co. Ltd. 3 Laboratory of Medicinal Resources, School of Pharmacy, Aich Gakuin University

* Address correspondence to: E-mail: makino{at}phar.nagoya-cu.ac.jp

Abstract

Glycyrrhizin (GL) has been used to treat chronic hepatitis in Japan and Europe. It is thought to induce pseudoaldosteronism via inhibition of type 2 11{beta}-hydroxysteroid dehydrogenase (11{beta}-HSD2) by glycyrrhetinic acid (GA), a major metabolite of GL. A previous clinical study suggested that 3-monoglucuronyl-glycyrrhetinic acid (3MGA), another metabolite of GL, might play a more important role in the pathogenesis of pseudoaldosteronism. The present study evaluates the pharmacokinetics of GL and its metabolites in rats with chronic liver injury induced by a choline-deficient L-amino acid-defined (CDAA) diet to clarify the relationship between 3MGA and pseudoaldosteronism. In rats fed a CDAA-diet, plasma concentrations and urinary eliminations of GL and 3MGA were markedly higher than in the rats fed control diet; the plasma concentration of GA was unaffected, when GL was orally administered. Immunohistochemical analysis revealed the suppression of levels of multi-drug resistance-associated protein 2 (Mrp2) and its localization in the hepatic tissue of rats fed a CDAA-diet. When 3MGA was intravenously injected in rats fed a CDAA-diet or injected in Mrp2-dysfunctional Eisai hyperbilirubinemic rats (EHBRs), plasma concentrations of 3MGA were higher and biliary excretion of 3MGA was lower than in each control group. The results suggested that 3MGA would be excreted to bile via hepatic Mrp2, and that its dysfunction would reduce 3MGA clearance. 3MGA accumulated by liver fibrosis resulted in the increased excretion through renal tubule and might be strongly related to the pathogenesis of pseudoaldosteronism because 11{beta}-HSD2 is expressed in renal tubular epithelial cells.


Key words: ABC transporters, adverse drug reactions, hepatic elimination, hepatobiliary transport, liver injury, MRP, pharmacokinetics, renal elimination




Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2008 by the American Society for Pharmacology and Experimental Therapeutics.