Szafarz Malgorzata, Kus Kamil, Walczak Maria, Zakrzewska Agnieszka, Niemczak Michal, Pernak Juliusz, Chlopicki Stefan
Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland.
Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, Poland.
J Pharm Sci. 2017 May;106(5):1412-1418. doi: 10.1016/j.xphs.2017.01.022. Epub 2017 Jan 30.
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) in comparison to nitrite (MNANO) or chloride (MNACl) in rats. The bioavailability of MNA administered as MNANO equaled 22.4% as compared to MNANO or MNACl (9.2% and 9.1%, respectively). Moreover, in single-pass intestinal perfusion experiments, effective permeability of MNA given as MNANO was higher as compared to MNA administered as MNANO or MNACl. In turn, t was the shortest and C the highest (0.22 h and 56.65μM) for intragastrically administered MNANO comparing to MNANO (1.92 h, 21.74μM) or MNACl (0.63 h, 16.13μM). Transfer constant between central and peripheral compartments (k) and volume of distribution (V) for MNANO (0.33 h and 1.96 L/kg) were higher as compared to MNANO or MNACl (0.11 h, 0.08 h for k and 1.05 L/kg, 0.76 L/kg for V, 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 represents a bifunctional compound.
