Pharmacokinetic Profile of 1-Methylnicotinamide Nitrate in Rats

Treatment with 1-methylnicotinamide (MNA), a major metabolite of nicotinamide, exerts antithrombotic, anti-inflammatory, and vasoprotective effects. Yet, pharmacokinetic (PK) profile of MNA has not been fully characterized. In the present work, we analyze the PK profile of the MNA given as a nitrate (MNANO3) in comparison to nitrite (MNANO2) or chloride (MNACl) in rats. The bioavailability of MNA administered as MNANO3 equaled 22.4% as compared to MNANO2 or MNACl (9.2% and 9.1%, respectively). Moreover, in single-pass intestinal perfusion experiments, effective permeability of MNA given as MNANO3 was higher as compared to MNA administered as MNANO2 or MNACl. In turn, tmax was the shortest and Cmax the highest (0.22 h and 56.65μM) for intragastrically administered MNANO2 comparing to MNANO3 (1.92 h, 21.74μM) or MNACl (0.63 h, 16.13μM). Transfer constant between central and peripheral compartments (kcp) and volume of distribution (Vss) for MNANO3 (0.33 h−1 and 1.96 L/kg) were higher as compared to MNANO2 or MNACl (0.11 h−1, 0.08 h−1 for kcp and 1.05 L/kg, 0.76 L/kg for Vss, respectively). In conclusion, we characterized PK profile of MNA and demonstrated that nitrate ion augmented bioavailability and favorably modified PK profile of MNA. Furthermore, given vasoprotective properties of MNA as well as nitrate, MNANO3 represents a bifunctional compound.