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

Clin Pharmacol Ther. 2012 Nov;92(5):635-41. doi: 10.1038/clpt.2012.138. Epub 2012 Oct 10.

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 ± 18 µmol/l) and MATE2-K (K(m) 422 ± 63 µmol/l) as well as a basolateral influx transporter, organic cation transporter 2 (K(m) 318 ± 29 µmol/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 ± 55 µmol/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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Drug Interactions
  • Humans
  • Kidney / metabolism*
  • Male
  • Microvilli
  • Niacinamide / analogs & derivatives*
  • Niacinamide / metabolism
  • Organic Cation Transport Proteins / metabolism*
  • Pyrimethamine / pharmacology
  • Young Adult

Substances

  • MATE1 protein, human
  • MATE2-K protein, human
  • Organic Cation Transport Proteins
  • Niacinamide
  • N-methylnicotinamide
  • Pyrimethamine