Pharmacokinetic interactions between donafenib and empagliflozin or henagliflozin , lenvatinib and empagliflozin or henagliflozin in rats
Abstract
Donafenib(DONA)
and
lenvatinib(LEN)
are
small-molecule
tyrosine
kinase
inhibitors(TKI)
that
used
to
treat
advanced
hepatocellular
carcinoma(HCC).Empagliflozin
henagliflozin
sodium-glucose
cotransporter
2(T2DM)
inhibitors
type
2
diabetes(T2DM).Empagliflozin
henaglifiozin
uridine
diphosphate
glucuronosyltransferase(UGT)1A9,
Substrate
of
P-glycoprotein
(P-gp)
breast
cancer
resistance
protein
(BCRP)Donafenib
is
metabolized
by
UGT1A9
an
inhibitor
lenvatinib
a
substrate
for
P-gp
BCRP.T2DM
one
the
risk
factors
HCC
progression,
so
two
drugs
may
be
in
combination
clinical
practice,
but
there
lack
clear
information
about
drug
interactions.
Therefore,
present
study
aimed
reveal
extent
interactions
between
donafenib,
empagliflozin
rats
explore
possible
mechanisms.Rats
were
divided
into
fourteen
groups
(n
=
6)
received
empaglifiozin(1,2),henagliflozin(3,4,)donafenib(5),
lenvatinib(6),
empaglifiozin
donafenib
(7),
hennagliflozin
(8),
lenvatinib(9)
,henagliflozin
(10),donafenib
(11),
(12),lenvatinib
empaglifiozin(13),lenvatinib
henagliflozin(14).
The
concentrations
determined
ultra-performance
liquid
chromatography-tandem
mass
spectrometry
(UPLC-MS/MS)
method.
messenger
RNA
(mRNA)
expressions
measured
quantitative
RT-PCR.
Multiple
administration
reduced
area
under
concentration-time
curve
(AUC0
−
t
AUC0−∞)
33.46%
32.7%
respectively.
apparent
clearance
rate
(CLz/F)
volume
distribution
(Vd/F)
66.7%
95.2%,
half-life
(T1/2)
was
prolonged
17.6%.Henagliflozin
modest
decreased
AUC0
AUC0−∞
27.8%
26.9%.
CLz/F
2.6-fold
compared
control
group.Multiple
doses
caused
increased
57.5%and58.5%.
significantly
39.9%
.The
multiple
maximum
plasma
concentration
(Cmax)
65.5%,
177.0%
and178.0%,
Vz/F
hanagliflozin
64.1%
45.1%.Multiple
18.7%
and21.4%,
accelerated
30.0%.
After
constant
gliflozin,
20.3%
20.9%,
respectively,
1.30-flod.Multiple
had
no
significant
effect
on
pharmacokinetics
henagliflozin.The
pharmacokinetic
results
suggest
it
important
take
special
care
these
applications.
Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown
Published: June 14, 2024
Language: Английский