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 (MNANO(3)) in comparison to nitrite (MNANO(2)) or chloride (MNACl) in rats. The bioavailability of MNA administered as MNANO3 equaled 22.4% as compared to MNANO(2) or MNACl (9.2% and 9.1%, respectively). Moreover, in single-pass intestinal perfusion experiments, effective permeability of MNA given as MNANO(3) was higher as compared to MNA administered as MNANO(2) or MNACl. In turn, t(max) was the shortest and C-max the highest (0.22 h and 56.65 mu M) for intragastrically administered MNANO(2) comparing to MNANO(3) (1.92 h, 21.74 mu M) or MNACl (0.63 h, 16.13 mu M). Transfer constant between central and peripheral compartments (k(cp)) and volume of distribution (V-ss) for MNANO(3) (0.33 h(-1) and 1.96 L/kg) were higher as compared to MNANO(2) or MNACl (0.11 h(-1), 0.08 h(-1) for k(cp) and 1.05 L/kg, 0.76 L/kg for V-ss, 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, MNANO(3) represents a bifunctional compound. (C) 2017 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.