Document Detail


Molecular mechanism of renal tubular secretion of the antimalarial drug chloroquine.
MedLine Citation:
PMID:  21518836     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The antimalarial drug chloroquine is eliminated to a significant extent by renal tubular secretion. The molecular mechanism of renal chloroquine secretion remains unknown. We hypothesized that organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1), localized in the basolateral and luminal membranes of proximal tubule cells, respectively, are involved in chloroquine transport. The interaction of chloroquine with both transporters was investigated using single-transfected human embryonic kidney 293 (HEK293)-MATE1 cells in uptake experiments and single-transfected Madin-Darby canine kidney II (MDCK)-OCT2 and MDCK-MATE1 cells as well as double-transfected MDCK-OCT2-MATE1 cells grown as polarized monolayers on transwell filters. In HEK293-MATE1 cells, chloroquine competitively inhibited MATE1-mediated metformin uptake (K(i) = 2.8 μM). Cellular accumulation of chloroquine was significantly lower (P < 0.001) and transcellular chloroquine transport was significantly increased (P < 0.001) in MDCK-MATE1 and MDCK-OCT2-MATE1 cells compared to vector control cells after basal addition of chloroquine (0.1 to 10 μM). In contrast, no difference in cellular accumulation or transcellular transport of chloroquine was observed between MDCK-OCT2 and vector control cells. In line with an oppositely directed proton gradient acting as a driving force for MATE1, basal-to-apical transport of chloroquine by MDCK-OCT2-MATE1 cells increased with decreasing apical pH from 7.8 to 6.0. Transcellular transport of chloroquine by MDCK-OCT2-MATE1 cells was inhibited by cimetidine, trimethoprim, and amitriptyline. Our data demonstrate that chloroquine is a substrate and potent competitive inhibitor of MATE1, whereas OCT2 seems to play no role in chloroquine uptake. Concomitantly administered MATE1 inhibitors are likely to modify the renal secretion of chloroquine.
Authors:
Fabian Müller; Jörg König; Hartmut Glaeser; Ingrid Schmidt; Oliver Zolk; Martin F Fromm; Renke Maas
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Publication Detail:
Type:  Journal Article     Date:  2011-04-25
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  55     ISSN:  1098-6596     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-17     Completed Date:  2011-10-14     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3091-8     Citation Subset:  IM    
Affiliation:
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antimalarials / metabolism*
Cell Line
Chloroquine / metabolism*
Dogs
Humans
Kidney Tubules / cytology,  metabolism*
Organic Cation Transport Proteins / genetics,  metabolism
Chemical
Reg. No./Substance:
0/Antimalarials; 0/MATE1 protein, human; 0/Organic Cation Transport Proteins; 0/SLC22A2 protein, human; 54-05-7/Chloroquine
Comments/Corrections

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