N-Methylnicotinamide Is an Endogenous Probe for Evaluation of Drug-Drug Interactions Involving Multidrug and Toxin Extrusions (MATE1 and MATE2-K)

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 mu mol/l) and MATE2-K (K-m 422 +/- 63 mu mol/l) as well as a basolateral influx transporter, organic cation transporter 2 (K-m 318 +/- 29 mu mol/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 mu mol/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.