Pharmacokinetics, Pharmacodynamics and Drug Transport and Metabolism
Pharmacokinetic Profile of 1-Methylnicotinamide Nitrate in Rats
Malgorzata Szafarz
1
, Kamil Kus
2
, Maria Walczak
2, 3
, Agnieszka Zakrzewska
2
,
Michal Niemczak
4
, Juliusz Pernak
4
, Stefan Chlopicki
2, 5, *
1
Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688,
Poland
2
Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, Poland
3
Chair and Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland
4
Department of Chemical Technology, Poznan University of Technology, Berdychowo 4, Poznan 60-965, Poland
5
Chair of Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, Krakow 31-531, Poland
article info
Article history:
Received 15 November 2016
Revised 4 January 2017
Accepted 5 January 2017
Keywords:
1-methylnicotinamide nitrate
pharmacokinetics
bioavailability
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 (MNANO
3
) in
comparison to nitrite (MNANO
2
) or chloride (MNACl) in rats. The bioavailability of MNA administered as
MNANO
3
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 56.65mM) for intragastrically administered MNANO
2
comparing to MNANO
3
(1.92 h,
21.74mM) or MNACl (0.63 h,16.13mM). 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.
© 2017 American Pharmacists Association
®
. Published by Elsevier Inc. All rights reserved.
Introduction
1-Methylnicotinamide (MNA), the major metabolite of nicotin-
amide, is formed by nicotinamide N-methyltransferase.
1
For a long
time it has been considered to be biologically inactive; however,
lately the pharmacological activity of MNA has been discovered
putting a novel perspective on its therapeutic potential. Anti-
inflammatory effect of MNA was first demonstrated after its
topical application to patients with a number of skin diseases such
as acne vulgaris, contact dermatitis, as well as rosacea.
2,3
In
experimental studies, it was discovered that MNA possesses a
unique profile of antithrombotic activity related to the activation
of COX-2/PGI
2
(cyclooxygenase-2/prostacyclin) pathway.
4
Sub-
sequently, it was reported that PGI
2
-releasing properties contrib-
uted to anti-inflammatory,
5
antiatherosclerotic,
6
gastroprotective,
7
hepatoprotective,
8,9
and antimetastatic
10
effects of MNA. It has
been also proven that treatment with MNA improved nitric
oxide (NO)-dependent endothelial function in diabetic or hyper-
triglyceridemic rats
11
as well as in humans.
12
Furthermore, long-
term supplementation with MNA resulted in an improvement of
exercise capacity in diabetic mice.
13
Despite a number of reports demonstrating in various experi-
mental models significant pharmacological activity of MNA (given
as chloride salt in most cases of experimental studies at a dose of
100 mg/kgd0.73 mmol/kg), only limited information regarding its
pharmacokinetic (PK) behavior is available and there are no reports
characterizing the PK profile of this compound in experimental
animals. MNA is an endogenous organic cation and is eliminated
almost exclusively by renal excretion. It is a substrate for a number
of different membrane transporters,
14
it is not bound to plasma
proteins,
15
and it is metabolized to N-methyl-2-pyridone-5-
carboxamide (2-PY) and N-methyl-4-pyridone-3-carboxamide
(4-PY) by aldehyde oxidase.
16
Besides being a substrate for active
transporters, MNA is also a quaternary base with a permanent
positive charge; therefore, its biological availability was suspected
to be rather low. The low bioavailability (BA) is a disadvantage for
* Correspondence to: Stefan Chlopicki (Telephone: þ48 12 664 54 64; Fax: þ48 12
297 46 15).
E-mail address: stefan.chlopicki@jcet.eu (S. Chlopicki).
Contents lists available at ScienceDirect
Journal of Pharmaceutical Sciences
journal homepage: www.jpharmsci.org
http://dx.doi.org/10.1016/j.xphs.2017.01.022
0022-3549/© 2017 American Pharmacists Association
®
. Published by Elsevier Inc. All rights reserved.
Journal of Pharmaceutical Sciences xxx (2017) 1-7