Document Detail


Itraconazole-Induced Cholestasis: Involvement of the Inhibition of Bile Canalicular Phospholipid Translocator MDR3/ABCB4.
MedLine Citation:
PMID:  21056966     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Biliary secretion of bile acids and phospholipids, both of which are essential components of biliary micelles, are mediated by the bile salt export pump (BSEP/ABCB11) and multidrug resistance 3 P-glycoprotein (MDR3/ABCB4), respectively, and their genetic dysfunction leads to the acquisition of severe cholestatic diseases. In the present study, we found two patients with itraconazole (ITZ)-induced cholestatic liver injury with markedly high serum ITZ concentrations. To characterize the effect of ITZ on bile formation in vivo, biliary bile acids and phospholipids were analyzed in ITZ-treated rats, and it was revealed that biliary phospholipids, rather than bile acids, were drastically reduced in the presence of clinically relevant concentrations of ITZ. Moreover, by using MDR3-expressing LLC-PK1 cells, we found that MDR3-mediated efflux of [(14)C]phosphatidylcholine was significantly reduced by ITZ. In contrast, BSEP-mediated transport of [(3)H]taurocholate was not significantly affected by ITZ, which is consistent with our in vivo observations. In conclusion, this study suggests the involvement of the inhibition of MDR3-mediated biliary phospholipids secretion in ITZ-induced cholestasis. Our approach may be useful for analyzing mechanisms of drug-induced cholestasis and evaluating the cholestatic potential of clinically used drugs and drug candidates.
Authors:
Takashi Yoshikado; Tappei Takada; Takehito Yamamoto; Hiroko Yamaji; Kousei Ito; Tomofumi Santa; Hiromitsu Yokota; Yutaka Yatomi; Haruhiko Yoshida; Jun Goto; Shoji Tsuji; Hiroshi Suzuki
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Publication Detail:
Type:  Journal Article     Date:  2010-11-05
Journal Detail:
Title:  Molecular pharmacology     Volume:  79     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-19     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  241-50     Citation Subset:  IM    
Affiliation:
Department of Pharmacy, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. tappei-tky@umin.ac.jp.
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