N-methylnicotinamide is an endogenous probe for evaluation of drugdrug interactions involving multidrug and toxin extrusions (MATE1 and MATE2-K)

S. Ito, H. Kusuhara, Y. Kumagai, Y. Moriyama, K. Inoue, T. Kondo, H. Nakayama, S. Horita, K. Tanabe, H. Yuasa, Y. Sugiyama

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Abstract

Multidrug and toxin extrusion 1 (MATE1) and MATE2-K are H /organic cation exchangers mediating the efflux of cationic drugs into the urine. N-methylnicotinamide (NMN) was found to be an endogenous substrate of MATE1 (Michaelis constant (K m) 301 ± 18mol/l) and MATE2-K (K m 422 ± 63mol/l) as well as a basolateral influx transporter, organic cation transporter 2 (K m 318 ± 29mol/l). A potent MATE inhibitor, pyrimethamine, competitively inhibited the uptake by MATE1 and MATE2-K with inhibition constant (K i) values of 83 ± 15 and 56 ± 11 nmol/l, respectively. The uptake of NMN by human kidney brush border membrane vesicles with a H gradient was saturable (K m 360 ± 55mol/l) and completely inhibited by pyrimethamine. The renal clearance of endogenous NMN was 403 ± 61 in healthy male subjects, and it was significantly decreased to 119 ± 16 ml/min/kg by an oral dose of pyrimethamine (50 mg). These results support the utility of NMN as an endogenous in vivo probe for investigating MATE1 and MATE2-K in humans.

Original languageEnglish
Pages (from-to)635-641
Number of pages7
JournalClinical Pharmacology and Therapeutics
Volume92
Issue number5
DOIs
Publication statusPublished - Nov 2012

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Pyrimethamine
Cations
Kidney
Microvilli
Healthy Volunteers
Urine
Membranes
N-methylnicotinamide
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

N-methylnicotinamide is an endogenous probe for evaluation of drugdrug interactions involving multidrug and toxin extrusions (MATE1 and MATE2-K). / Ito, S.; Kusuhara, H.; Kumagai, Y.; Moriyama, Y.; Inoue, K.; Kondo, T.; Nakayama, H.; Horita, S.; Tanabe, K.; Yuasa, H.; Sugiyama, Y.

In: Clinical Pharmacology and Therapeutics, Vol. 92, No. 5, 11.2012, p. 635-641.

Research output: Contribution to journalArticle

Ito, S, Kusuhara, H, Kumagai, Y, Moriyama, Y, Inoue, K, Kondo, T, Nakayama, H, Horita, S, Tanabe, K, Yuasa, H & Sugiyama, Y 2012, 'N-methylnicotinamide is an endogenous probe for evaluation of drugdrug interactions involving multidrug and toxin extrusions (MATE1 and MATE2-K)', Clinical Pharmacology and Therapeutics, vol. 92, no. 5, pp. 635-641. https://doi.org/10.1038/clpt.2012.138
Ito, S. ; Kusuhara, H. ; Kumagai, Y. ; Moriyama, Y. ; Inoue, K. ; Kondo, T. ; Nakayama, H. ; Horita, S. ; Tanabe, K. ; Yuasa, H. ; Sugiyama, Y. / N-methylnicotinamide is an endogenous probe for evaluation of drugdrug interactions involving multidrug and toxin extrusions (MATE1 and MATE2-K). In: Clinical Pharmacology and Therapeutics. 2012 ; Vol. 92, No. 5. pp. 635-641.
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