N-methylnicotinamide is an endogenous probe for evaluation of drug-drug interactions involving multidrug and toxin extrusions (MATE1 and MATE2-K).
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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 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.
- PubMed ID
- 23047651 [ View in PubMed]
- 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 micromol/l) and MATE2-K (K(m) 422 +/- 63 micromol/l) as well as a basolateral influx transporter, organic cation transporter 2 (K(m) 318 +/- 29 micromol/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 micromol/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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions N-methylnicotinamide Multidrug and toxin extrusion protein 1 Protein Humans UnknownSubstrateDetails N-methylnicotinamide Multidrug and toxin extrusion protein 2 Protein Humans UnknownSubstrateDetails