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31 99
31 99
31 99
Articles
Jpn.
J. Pharm.
31
Pharmacokinetics
Continuous
of Midazolam
Kiyotaka
Care
Sci.
(2005)
Hemodiafiltration
and/or
Health
(2) 99-104
using a Polymethyl
Methacrylate
Polysulfone Membrane
Hirata*1.2, Yoshiaki
Masaaki
Matsumoto2,
Kanae
Ohno2,
Yamamoto3
June
Accepted
The
objectives
of
critically
ill
lymethyl
methacrylate
of
midazolam
were
in
measured
tabolites
was
glucuronide
%,
=0
.8223),
but
the
need
was
for
with
noted.
there
show
affected
The
extraction
5.0%,
(ICU)
no
chromatography
rates
4.8
for
correlation
the
sedation
PS
membrane
be
the
treated
by
The
be
influence
risk
taken
into
CHDF
CHDF
using
of
midazolam
PMMA
high
for
CHDF
the
PS
levels
of
drug
and
the
its
the
metabolites
its
PS
active
me-
membrane.
membrane
were
between
PMMA
was
1.3
the
used
(r2=
(r2
0.0361).
glucuron-
glucuronide
adjustment
for
1-
membrane
1-hydroxymidazolam
1-hydroxymidazolam
dose
po-
1-hydroxymidazolam
observed
using
pharmacokinetics
active
of
in
using
and
a PS
was
of
metabolites
and/or
membrane
elimination
in
on
and
a PMMA
accumulation
account
active
(CHDF)
CHDF
correlation
when
the
its
midazolam
using
positive
affect
of
of
of
pharmacokinetics
concentrations
not
and
hemodiafiltration
concentration
did
midazolam
though
creatinine
used.
the
by
substances
these
was
and
1-hydroxymidazolam,
membrane
therefore
of
continuous
concentrations
respectively.
serum
between
a PMMA
should
74.4%,
and
by
study
being
or
these
and
accumulation
liquid
were
200l
membrane
to
midazolam
8,
the
ultrafiltration
who
2004
treated
(PS)
liquid
of
of
being
and
failure
using
risk
polysulfone
concentration
CHDF
when
prolonged
the
unit
a
renal
and
was
that
evaluate
serum
accumulation
13.4%,
while
it
The
glucuronide
results
ide
and/or
patients.
high-performance
hydroxymidazolam
These
to
care
(PMMA)
progressive
and
were
intensive
patients
were
3.0%
an
these
seven
no
study
in
by
in
There
this
patients
1,
November
patients
and
undergoing
CHDF.
Key
words\pharmacokinetics,
midazolam,
continuous
hemodiafiltration,
polymethyl
methacrylate,
polysulfone
mem-
brane
hemodynamic
support,
and a shorter duration of the episode of renal failure and intensive care unit (ICU) admission1,2).
Introduction
Since
su-
worldwide
mechanical
ventilation,
served in severe renal failure patients after receiving a longterm infusion of midazolam, the pharmacokinetic studies of
midazolam
For intensive-care
patients
vantages
from multiple
organ
over intermittent
suffering
hemodialysis
better metabolic
1,3
1-1-5;1-1-5
3-3165;3-3165
to provide ad-
control,
, Sendagi,
increased
Bunkyo-ku,
, Higashi-tamagawagakuen,
Tokyo,
been
particularly
frequently
of patients
used
receiving
in ICUs, because
of its
short elimination half-life, water solubility, and a lack of serious adverse effects3'4). However, data concerning the influnot been evaluated.
because of a better
has
sedation
Recently,
developed.
113-8603
sedation
have
ob-
sidered important.
Machidashi,
Japan
Tokyo,
194-8543Japan
many
types of membrane
However,
few
for
data on the
100
Vol.31,
between
10
livered
h
and
by
and
rate
of
time
3.
The
samples
the
lites.
Blood
study
period.
flow
pump
Tosoh),
Table
MDZ: midazolam,
PMMA: polymethyl
1.
flow
water.
method
described
cation.
Test
regression,
ratios
internal
to
was
drolysis
tween
the
with
total
was
midazolam
the
slope
in
and
the
unconjugated
added
AP:acute
with
following
with
a slight
the
by
the
modifi-
HPLC
column.
plotting
the
Total
samples
for
drug
pancreatitis
5 h.
peak
to
concentrations,
intercept.
same
standard,
diluting
1-hydroxymida-zolam
Data.
PS: polysulfone,
al.5)
with
internal
onto
-glucuronidase
and
v/v)
and
obtained
and
against
measured
acetonitrile-methanol
extracted
injected
which
of
standard
determine
tion
were
injector
(150mm~4.6
the
et
HPLC
constant-
(30:15:55
were
high-
detector(242nm;
an
methanol
Boukhabza
midaby
sample
column
Clotiazepam,
in
the
un-
The
auto
6.5)
samples
during
at -80
LC-10AD
ultraviolet
dissolving
by
day
for
metabo-
unconjugated
an
TS
urine
collected
determined
was
(pH
ports
active
stored
SIL-10Axl
phase
solutions
height
not
and
(HPLC).
SPD-10A
buffer
its
serum
Octyl-80
an
The
Linear
32.5 }
did
sampling
every
and
following:
an
mobile
by
the
was
also
and
of
the
1 mL/min.
distilled
Demographic
methacrylate,
of
prepared
L/
at
was
and
filter,
were
chromatography
phosphate
rate
was
the
were
of
and
The
set
coagulation
filters
the
collected
concentrations
a TSK-GEL
Shimadzu).
de-
0.5
throughout
CHDF
after
separated
(Shimadzu),
(Shimadzu),
mm;
were
consisted
was
the
the
midazolam
was
liquid
equipment
180
through
and
1-hydroxymidazolam
performance
activated
and
of
of
mesilate
and
samples
of
Serum
The
flow
into
collected
before
samples
and
was
rate
analysis
assay
analysis.
zolam
2h
ultradiafiltrate
steady-state
60mM
2. CHDF
Vascular access for CHDF was obtained by the insertion
of an 11-Fr double lumen catheter (Argyle, 6011 A 20-W) in
either the femoral or the right internal jugular vein. CHDF
was performed using a hollow-fiber membrane (HEMOFEELR CH-1.0 L, Toray Medical Inc.) composed of a PMMA membrane and/or a high-flux capillary membrane
drug
circuit
and
at
24h.
were
CHDF
rate
hour
over
and
at
Nafamostat
150
ultrafiltration
samples
the
L/h.
between
significantly
Blood
of
1.3
(2005)
dialysate
flow
anticoagulant,
per
Sampling
til
an
blood
Ultradiafiltrate
and
maintained
mL/mmHg
change
0.8
as
was
the
pump.
between
administered
13.7
Methods
Standard
to
volumetric
procedure.
Materials
15mL/kg/min.
countercurrently
No.2
was
drug
the
used
concentra-
after
enzymatic
hy-
The
difference
be-
concentrations
was
taken
Vol.31,
as
conjugated
by
Yamanouchi
tomi
drug
UFC
Ltd.
from
Boehringer
analytical
4.
Japan),
and
was
(Manchester,
grade.
The
and
Pharmacokinetic
chemicals
used
quantitation
limit
(ER)
the
was
calculated
from
flow
a drug
in
the
blood
in
the
blood
calculated
flowing
out,
is
is
the
and
concentrations
constant
in
model
life
(t
1/2)
=0
.693/ke.
of
is
the
serum
of
ultrafiltration
obtained
used
to
after
midazolam
based
first-order
kinetics.
calculated
from
on
is
Seven
tures,
in
patients
of
durations
Table
0.45
mg/
The
kg
in
flow
rate
using
and
port
for
infusion
and
1 female)
concentrations
rates
of
1 and
linear regression;
blood
zolam concentrations
glucu-
level was
r2=0.8223).
ob-
In con-
level (least-squares
linear regression;
midazolam
r2=
and 1-hydroxymida-
The
intraverate
1-hydroxy-
elimination
half-
equation
: t 1/2
1-hydroxymi-dazolam,
1-hydroxymidazolam
glucuronide
maintained
of
midazolam,
glucuronide
CHDF
fea-
are
midazolam
0.03-
are
each
shown
infusion,
the concentrations
and
of midazolam,
of
1-
and 1-hydroxymidazolam
glucuronide
the therapeutic range in patient 6, al-
long-term
of 1-hydroxymidazolam
glucuron-
ide remained extremely high in patient 7 who showed deteriorating renal functions.
1-hydroxymiat
midazolam
hydroxymidazolam,
decreased to below
shown
at
for
7.6-527.6 h, respectively.
long-
clinical
midazolam
was
2 during
Their
of
1-hydroxymidazolam
patients
(least-squares
blood
receiving
studied.
infusion
weight/h
serum creatinine
trast, for the patients receiving CHDF using PS, 1-hydroxymidazolam glucuronide concentration did not correlate with
the
one-compartment
the
served
the
out.
between 1-hydroxymidazolam
and
serum creatinine
elimination
correlation
were
continuous
body
The
dazolam,
males
midazolam
and
1.
sedation.
pling
(6
infusion
concentration
0.0361
Results
term
glu-
ronide
blood
the
in
The
ke
CL
drug
the
and
equation6):
continuous
calculate
of
in
out.
drug
repre-
flowing
Qbo
concentration
with
was
where
Cbi
going
following
concentration
were
(ke)
open
the
QF
infusions
the
Cbi+QF
Cbi
Cbo
out,
nous
from
Cbo)/
in,
drug
A positive
following
where
of
rate
going
the
of
was
and 1-hydroxymidazolam
concentration
=Qbo~(Cbi-
1-hydroxymidazolam,
between 1-hydroxymidazolam
glucuronide concentration and
renal functions in the patients during CHDF using PMMA.
concentration
Clearance
rates (%) of
curonide were 1.3,3.0 and 13.4 and 5.0,4.8 and 74.4, respectively. The clearance (mL/min) during CHDF using PMMA
and PS for the three substances
8ng/
analysis
rate
the
of
1-hydroxymidazolam.
ER(%)=(Cbi-Cbo)~100/Cbi,
sents
zolam,
were
was
The extraction
Yoshiobtained
and -glucuronidase
Other
midazolam
Extraction
Cbo
by
was
England)
provided
clotiazepam
1-Hydroxymidazolam
reagent
both
equation:
Midazolam
Mannheim.
or
for
concentration.
Japan).
from
101
(2005)
(Tokyo,
(Osaka,
mL
No.2
samin
Fig. 1. Concentrations
of Midazolam and Active Metabolites at Each
Sampling Port in Patient 1 (Before=sampling
port before placement of the filter, After=sampling
port after placement of the
filter, Filtrate=ultradiafiltrate,
MDZ=midazolam,
1-OH MDZ=
1-hydroxymidazolam,
G=1-hydroxymidazolam
glucuronide).
102
Vol,31,
Fig. 2.
Fig. 3.
is
iolytic
water-soluble
anticonvulsant,
effects7). Midazolam
benzodiazepine
muscle relaxant
is rapidly
eliminated
with
(inactive)
hydroxymidazolam,
coma and respiratory
tabolism of midazolam
these
and 1-hydroxymidazolam
glu-
suppression.
Fig. 4.
Discussion
Midazolam
(2005)
sedative-hypnotic,
No.2
induce
prolonged
is hydroxylation
Vol.31,
No.2
103
(2005)
Fig. 5.
Fig. 6.
104
Vol.31,
References
1) R. Bellomo,
Boyce,
acute
M. Farmer,
Severe
acute
continuous
G. Parkin,
renal
C. Wright,
N.
failure : A comparison
of
hemodiafiltration
and
conventional
H.A.
Bruining,
versus continuous
J. Nephrol,
W. Weimar,
ill: Intermittent
arteriovenous
15, 192-200
(1995).
Acute
dialytic
hemodialysis
hemodiafiltration,
Am.
No.2
(2005)
3) P. Heizmann, M. Eckert, W.H. Ziegler, Pharmacokinetics and bioavailability of midazolam in man, Br. J.
Clin. Pharmacol., 16, 43S-49S (1983).
4) J.W. Dundee, N.J. Halliday, K.W. Harper, R.N. Brogden, Midazolam. A review of its pharmacological properties and therapeutic use, Drugs, 28, 519-543 (1984).
5) A. Boukhabza, A.A. Lugnier, P. Kintz, P. Mangin, Simultaneous HPLC analysis of the hypnotic benzodiazepines nitrazepam, estazolam, flunitrazepam, and triazolam in plasma, J. Anal. Toxicol., 15, 319-322 (1991).
6) H. Ueno, S. Oda, N. Kitamura, T. Sadahiro, H. Shiga,
T. Sugai, K. Naiki, S. Hikita, T. Hirano, N. Hirayama,
Y. Hirayama, T. Hoshino, K. Matsuda, T. Moriguchi,
K. Yokohari, E. Watanabe, "Theoretical consideration
and practice of CHDF", ed by H. Hirasawa, Sougouigaku, Inc., Tokyo, 2000, pp.41-44.
7) U. Ebert, R. Oertel, W. Kirch, Physostigmine reversal
of midazolam-induced electroencephalographic changes
in healthy subjects, Clin. Pharmacol. Ther., 67, 538548 (2000).
8) B.K. Wagner, D.A. O' Hara, Pharmacokinetics and
9)
10)
11)
12)