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 MNANO3equaled 22.4% as compared to MNANO2or MNACl (9.2% and 9.1%, respectively). Moreover, in single-pass intestinal perfusion experiments, effective permeability of MNA given as MNANO3was higher as compared to MNA administered as MNANO2or MNACl. In turn, tmaxwas the shortest and Cmaxthe highest (0.22 h and 56.65μM) for intragastrically administered MNANO2comparing 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-1and 1.96 L/kg) were higher as compared to MNANO2or MNACl (0.11 h-1, 0.08 h-1for kcpand 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, MNANO3represents a bifunctional compound.
Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland.
Malgorzata
M
Szafarz
Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, Poland.
Kamil
K
Kus
Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, Poland; Chair and Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland.
Maria
M
Walczak
Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, Poland.
Agnieszka
A
Zakrzewska
Department of Chemical Technology, Poznan University of Technology, Berdychowo 4, Poznan 60-965, Poland.
Michal
M
Niemczak
Department of Chemical Technology, Poznan University of Technology, Berdychowo 4, Poznan 60-965, Poland.
Juliusz
J
Pernak
Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, Poland; Chair of Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, Krakow 31-531, Poland. Electronic address: stefan.chlopicki@jcet.eu.
Stefan
S
Chlopicki
D000818:Animals; D001682:Biological Availability; D008297:Male; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D009566:Nitrates / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D009566:Nitrates; D009536:Niacinamide; C024058:N(1)-methylnicotinamide
1-methylnicotinamide nitrate; bioavailability; pharmacokinetics; rats