title: N-methylnicotinamide is an endogenous probe for evaluation of drug-drug interactions involving multidrug and toxin extrusions (MATE1 and MATE2-K).
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.
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ito
authors.forename: H
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Y
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Y
authors.initials: Y
authors.lastname: Moriyama
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.forename: T
authors.initials: T
authors.lastname: Kondo
authors.forename: H
authors.initials: H
authors.lastname: Nakayama
authors.forename: S
authors.initials: S
authors.lastname: Horita
authors.forename: K
authors.initials: K
authors.lastname: Tanabe
authors.forename: H
authors.initials: H
authors.lastname: Yuasa
authors.forename: Y
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000328:Adult; D004347:Drug Interactions; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008871:Microvilli; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D011739:Pyrimethamine / Q000494:pharmacology; D055815:Young Adult
chemical_list: D027701:Organic Cation Transport Proteins; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; D009536:Niacinamide; C008472:N-methylnicotinamide; D011739:Pyrimethamine