Potent and specific inhibition of mMate1-mediated efflux of type I organic cations in the liver and kidney by pyrimethamine.
This report describes a potent and selective inhibitor of multidrug and toxin extrusion (MATE) protein, pyrimethamine (PYR), and examines its effect on the urinary and biliary excretion of typical Mate1 substrates in mice. In vitro inhibition studies demonstrated that PYR is a potent inhibitor of mouse (m)Mate1 (K(i) = 145 nM) among renal organic cation transporters mOctn1 and mOctn2 (K(i) > 30 microM), mOct1 (K(i) = 3.6 microM), and mOct2 (K(i) = 6.0 microM). PYR inhibited the uptake of metformin by kidney brush-border membrane vesicles (BBMVs) (K(i) = 41 nM) and canalicular membrane vesicles in the presence of outward gradient of H+. PYR treatment significantly increased the kidney-to-plasma ratio of tetraethylammonium, and both the liver- and kidney-to-plasma ratios of metformin in mice, whereas it did not affect their plasma concentrations and urinary excretion rates. Furthermore, the plasma lactate concentration, a biomarker for inhibition of gluconeogenesis by metformin, was significantly higher in the PYR-treated group than in the control group. These results not only suggest the importance of mMate1 in the efflux of organic cations into the urine and bile in mice but also the importance of canalicular efflux mediated by MATE proteins for the therapeutic efficacy of metformin. PYR is a potent inhibitor of human (h)MATE1 and hMATE2-K (K(i) = 77 and 46 nM, respectively) and H+ and organic cation exchanger in human kidney BBMVs (K(i) = 31 nM) in the presence of outward gradient of H+. Taken together, PYR can be used as a potent probe inhibitor of human MATE transporters.
Ito
Sumito
S
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Kusuhara
Hiroyuki
H
Kuroiwa
Yushun
Y
Wu
Chunyong
C
Moriyama
Yoshinori
Y
Inoue
Katsuhisa
K
Kondo
Tsunenori
T
Yuasa
Hiroaki
H
Nakayama
Hideki
H
Horita
Shigeru
S
Sugiyama
Yuichi
Y
D000818:Animals; D001648:Bile Canaliculi / Q000378:metabolism; D001692:Biological Transport; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D019344:Lactic Acid / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D008871:Microvilli / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D011739:Pyrimethamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D019789:Tetraethylammonium / Q000493:pharmacokinetics*
C514424:MATE1 protein, mouse; D027701:Organic Cation Transport Proteins; D019344:Lactic Acid; D019789:Tetraethylammonium; D008687:Metformin; D011739:Pyrimethamine