Evaluation of Systemic and Brain Pharmacokinetic Parameters for Repurposing Metformin Using Intravenous Bolus Administration
Journal of Pharmacology and Experimental Therapeutics,
Год журнала:
2024,
Номер
392(1), С. 100013 - 100013
Опубликована: Май 22, 2024
Metformin's
potential
in
treating
ischemic
stroke
and
neurodegenerative
conditions
is
of
growing
interest.
Yet,
the
absence
established
systemic
brain
pharmacokinetic
(PK)
parameters
at
relevant
preclinical
doses
presents
a
significant
knowledge
gap.
This
study
highlights
these
PK
importance
using
pharmacologically
to
pharmacodynamics
related
diseases.
A
liquid
chromatography
with
tandem
mass
spectrometry
method
measure
metformin
levels
plasma,
brain,
cerebrospinal
fluid
was
developed
validated.
In
vitro
assays
examined
tissue
binding
metabolic
stability.
Intravenous
bolus
administration
C57BL6
mice
covered
low-
high-dose
range
maintaining
pharmacological
relevance.
Quantification
used
assess
parameters,
such
as
unidirectional
blood-to-brain
constant
(Kin)
unbound
brain-to-plasma
ratio
(Kp,
uu,
brain).
Metformin
exhibited
no
mouse
plasma
remained
metabolically
stable.
It
rapidly
entered
reaching
detectable
little
5
minutes.
Kin
value
1.87
±
0.27
μL/g/min
obtained.
As
dose
increased,
Kp,
showed
decreased
value,
implying
saturation,
but
this
did
not
affect
an
increase
absolute
concentrations.
quantifiable
30
minutes
over
time,
concentrations
lower
than
those
across
all
doses.
Our
findings
emphasize
selection
based
on
for
studies.
We
anticipate
further
investigations
focusing
PKs
disease
conditions,
stroke.
SIGNIFICANCE
STATEMENT:
The
establishes
crucial
diseases,
addressing
emphasizes
selecting
highlight
metformin's
rapid
entry,
minimal
binding,
necessity
considering
studies
provides
foundation
future
into
efficacy
disease(s).
Язык: Английский
Imidazole Bioisostere Activators of Endopeptidase Neurolysin with Enhanced Potency and Metabolic Stability
ACS Medicinal Chemistry Letters,
Год журнала:
2024,
Номер
15(4), С. 510 - 517
Опубликована: Март 29, 2024
The
peptidase
neurolysin
(Nln)
has
been
validated
as
a
potential
target
for
developing
therapeutics
ischemic
stroke
(IS).
Overexpression
of
Nln
in
mouse
model
IS
provides
significant
cerebroprotection,
leading
to
reduced
infarction
size
and
edema
volume.
Pharmacological
inhibition
the
post-stroke
brain
worsens
neurological
outcomes.
A
virtual
screen
identified
dipeptide
small-molecule
activators
Nln.
Optimization
studies
resulted
class
peptidomimetic
compounds
with
promising
activity.
However,
these
still
possessed
an
amide
bond
that
compromised
their
stability
plasma
brain.
Herein,
we
report
synthesis
characterization
series
bioisosteres
based
on
our
leads.
Imidazole-based
afford
scaffolds
increased
potency
activate
combined
enhanced
significantly
better
permeability
over
original
hits.
Язык: Английский
Systemic and Brain Pharmacokinetics of Milnacipran in Mice: Comparison of Intraperitoneal and Intravenous Administration
Pharmaceutics,
Год журнала:
2023,
Номер
16(1), С. 53 - 53
Опубликована: Дек. 29, 2023
Milnacipran
is
a
dual
serotonin
and
norepinephrine
reuptake
inhibitor,
clinically
used
for
the
treatment
of
major
depression
or
fibromyalgia.
Currently,
there
are
no
studies
reporting
pharmacokinetics
(PK)
milnacipran
after
intraperitoneal
(IP)
injection,
despite
this
being
primary
administration
route
in
numerous
experimental
using
drug.
Therefore,
present
study
was
designed
to
investigate
PK
profile
IP-administered
mice
compare
it
intravenous
(IV)
route.
First
liquid
chromatography–mass
spectrometry
(LC-MS/MS)
method
developed
validated
accurately
quantify
biological
samples.
The
blood
brain
samples
collected
at
various
time-points
post-administration.
Non-compartmental
analyses
were
employed
determine
key
parameters.
maximum
concentration
(Cmax)
drug
plasma
5
min
IP
administration,
whereas
brain,
60
both
routes
administration.
Curiously,
majority
parameters
similar
irrespective
route,
bioavailability
92.5%
injection.
These
findings
provide
insight
into
milnacipran’s
absorption,
distribution,
elimination
characteristics
first
time
should
be
valuable
future
pharmacological
studies.
Язык: Английский