Pharmacokinetic Profile of 1-Methylnicotinamide Nitrate in Rats

Abstract

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, t_max was the shortest and C_max 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 (k_cp) and volume of distribution (V_ss) 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 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, MNANO₃ represents a bifunctional compound.

Keywords: 1-methylnicotinamide nitrate; bioavailability; pharmacokinetics; rats.