title: Molecular mechanism of renal tubular secretion of the antimalarial drug chloroquine.
abstract: 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.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Müller
authors.forename: Jörg
authors.initials: J
authors.lastname: König
authors.forename: Hartmut
authors.initials: H
authors.lastname: Glaeser
authors.forename: Ingrid
authors.initials: I
authors.lastname: Schmidt
authors.forename: Oliver
authors.initials: O
authors.lastname: Zolk
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
authors.forename: Renke
authors.initials: R
authors.lastname: Maas
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000378:metabolism*; D002460:Cell Line; D002738:Chloroquine / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2
chemical_list: D000962:Antimalarials; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; D002738:Chloroquine