Potent and specific inhibition of mMate1-mediated efflux of type I organic cations in the liver and kidney by pyrimethamine

Sumito Ito, Hiroyuki Kusuhara, Yushun Kuroiwa, Chunyong Wu, Yoshinori Moriyama, Katsuhisa Inoue, Tsunenori Kondo, Hiroaki Yuasa, Hideki Nakayama, Shigeru Horita, Yuichi Sugiyama

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Abstract

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 (Ki = 145 nM) among renal organic cation transporters mOctn1 and mOctn2 (Ki > 30 μM), mOct1 (Ki = 3.6 μM), and mOct2 (Ki = 6.0 μM). PYR inhibited the uptake of metformin by kidney brush-border membrane vesicles (BBMVs) (Ki = 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 (Ki = 77 and 46 nM, respectively) and H+ and organic cation exchanger in human kidney BBMVs (Ki = 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.

Original languageEnglish
Pages (from-to)341-350
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume333
Issue number1
DOIs
Publication statusPublished - Apr 2010

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Pyrimethamine
Cations
Kidney
Metformin
Liver
Microvilli
Membranes
Tetraethylammonium
Gluconeogenesis
Bile
Lactic Acid
Proteins
Biomarkers
Urine
Control Groups

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

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Potent and specific inhibition of mMate1-mediated efflux of type I organic cations in the liver and kidney by pyrimethamine. / Ito, Sumito; Kusuhara, Hiroyuki; Kuroiwa, Yushun; Wu, Chunyong; Moriyama, Yoshinori; Inoue, Katsuhisa; Kondo, Tsunenori; Yuasa, Hiroaki; Nakayama, Hideki; Horita, Shigeru; Sugiyama, Yuichi.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 333, No. 1, 04.2010, p. 341-350.

Research output: Contribution to journalArticle

Ito, S, Kusuhara, H, Kuroiwa, Y, Wu, C, Moriyama, Y, Inoue, K, Kondo, T, Yuasa, H, Nakayama, H, Horita, S & Sugiyama, Y 2010, 'Potent and specific inhibition of mMate1-mediated efflux of type I organic cations in the liver and kidney by pyrimethamine', Journal of Pharmacology and Experimental Therapeutics, vol. 333, no. 1, pp. 341-350. https://doi.org/10.1124/jpet.109.163642
Ito, Sumito ; Kusuhara, Hiroyuki ; Kuroiwa, Yushun ; Wu, Chunyong ; Moriyama, Yoshinori ; Inoue, Katsuhisa ; Kondo, Tsunenori ; Yuasa, Hiroaki ; Nakayama, Hideki ; Horita, Shigeru ; Sugiyama, Yuichi. / Potent and specific inhibition of mMate1-mediated efflux of type I organic cations in the liver and kidney by pyrimethamine. In: Journal of Pharmacology and Experimental Therapeutics. 2010 ; Vol. 333, No. 1. pp. 341-350.
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