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 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. Clinical Pharmacology & Therapeutics (2012); 92 5, 635–641. doi: 10.1038/clpt.2012.138