Single-Dose Kinetics of Prazepam, a Precursor of Desmethyldiazepam MARCIA S. HARMATZ.
JEROLD
P
is a benzodiazepine
RAZEPAM
izer
possessing
propylmethyl is
a
(DMDZ)
prior
circulation, during
the
of intact or
first
reaching
only
the by
pass
trace
This study parameters
tabolite DMDZ of prazepam.
after
a
and
liver.24
not
in
assessed of the
single
the me-
oral
dose
at 0.25, dosage.
In
til
time
assay.
of
desmethyldiazepam by
Methods
healthy
giving
(Table I). five females
volunteers written
There ranging
years. All were cal or psychiatric a history Each dose with
termined
of identifiable medidisease, and none had
of regular drug subject received
overnight
fast.
or liquid given.
for
(two ml of
10-mg water
They
abstained
3 hours
after
20-mg tablets) after an
from the
drug
food was
sion
August-September,
Co., 1979
Morris
Plains,
N.J.
were
described
were
iterative to
de-
elsewhere.5
DMDZ
de-
nonlinear
analysis.6’7
Data
following
func-
the
(e-”-’&
A..
=
C is the
where at
time
of
DMDZ
tercept
exponents appearance
tion
dosage; to the
prior
fo
start
A is a hybrid
fi
ka and
and
were
half-life
used
values and
(tia)
are
to
calculate
for
DMDZ
elimination
data points were the above equation, from of
The
elapsing
exponents
mined
concentra-
inhybrid
representing phases of DMDZ and elimination, respectively.
pearance
When with
DMDZ prazepam
appearance; term;
e_.(t-to))
-
plasma
t after
is the lag time
The
of Warner-Lambert
additional
gas-liquid
regression
C
parent From the Clinical Pharmacology Unit, Massachusetts General Hospital, and the Psychopharmacology Research Laboratory, Massachusetts Mental Health Center, Boston, Mass. Supported by Grant MH-12279 from the United States Public Health Service and Grant 77-611 from the Foundations’ Fund for Research in Psychiatry. * Verstran, Warner-Chilcott Laboratories, Divi-
an
concentrations
for
fitted
3, 4, hours
hours. Plasma at -20#{176}C un-
(DMDZ)
weighted
were
2.5, 168
tion:
tion
use. a single
cases
Plasma
as by
points
2.0,
and
electron-capture
least-squares
consent
were seven males and in age from 22 to 42
free
of prazepam* 100 to 200
participated
informed
1.5,
120,
at 144 stored
variables
hepa-
administration
1.0, 96,
some
chromatography
and
Twelve after
0.75,
drawn and
of
cannula into
drug
72,
sample was was separated
Kinetic Materiflis
before 0.5,
drawn
Butterfly
venipuncture
24, 48,
termined
were
indwelling
tubes
after
detect-
samples
separate
6, 8, 12,
concentrations
systemic blood. pharmacokinetic
an
by
rinized
systemic
the are
blood
through or
1
dealkylation
through
prazepam
reach
1)
desmethyldiazepam
probably
Levels able
to
N-1-cyclo(Fig.
to
Venous
tranquil-
large
substituent
transformed
DIVOLL ALLEN. R.N.. DAVID J. GREENBLATT, M.D.. BA.. and RICHARD I. SHADER. M.D. Boston, Mass.
the relation
and smoking DMDZ level,
the
not tifl
terminal
plasma of
consistent was deter-
log-linear sex,
ap(tfl).
concentration age,
ap-
body
porcurve. weight,
habits to the peak plasma the time of the peak level, 445
ALLEN,
GREENBLATT,
HARMATZ,
AND
SHADER
GLUCURONIDE
L
CI-
cr 3-IIYDROXY
PRAZEPAM
PRAZEPAM
+
+ GLUCURONIDE
-
DES METHYLDIAZEPAM
Fig.
tfl
and
1. Metabolic
determined
was
OX AZE PAM
by
pathway
multiple
of prazepam overlap
gression
analysis.5.9
and
Results
was
minimal.
70.5
kg
weight.
(Table
with
DMDZ 12
First-order
observed
subjects
(Fig.
those
subjects
mean
lag
other six not first
2). was
time
only The
59.3
was
24.1
six
of
mean
minutes, minutes.
and In
tion” pattern was of was
observed
first-order far
(Fig.
8).
more
common
of among
Two-variable cated that sex
was
body
(r
446
weight
to
192.5
hours,
with
hours.
regression
highly =
0.84).
could
highest (r
as of
in
DMDZ
concentration
determinant
parison
of
coefficients
analysis
indi-
els
correlated
with
insignificant
Furthermore,
cent)
highest
Sex
were
the (Table
Journal
the was
was
the as
plasma
most
(F
by =
4.74;
important
indicated
II);
A vari-
explained
standardized
by
com-
regression
higher
peak
lev-
female sex. Only (7 and 31 per
in of
ex-
analysis smoking
overall
factors
variability The
was
was
measured
associated with proportions of
DMDZ
variables. of
independent
0.05).
JEROLD
P
is a benzodiazepine
RAZEPAM
izer
possessing
propylmethyl is
a
(DMDZ)
prior
circulation, during
the
of intact or
first
reaching
only
the by
pass
trace
This study parameters
tabolite DMDZ of prazepam.
after
a
and
liver.24
not
in
assessed of the
single
the me-
oral
dose
at 0.25, dosage.
In
til
time
assay.
of
desmethyldiazepam by
Methods
healthy
giving
(Table I). five females
volunteers written
There ranging
years. All were cal or psychiatric a history Each dose with
termined
of identifiable medidisease, and none had
of regular drug subject received
overnight
fast.
or liquid given.
for
(two ml of
10-mg water
They
abstained
3 hours
after
20-mg tablets) after an
from the
drug
food was
sion
August-September,
Co., 1979
Morris
Plains,
N.J.
were
described
were
iterative to
de-
elsewhere.5
DMDZ
de-
nonlinear
analysis.6’7
Data
following
func-
the
(e-”-’&
A..
=
C is the
where at
time
of
DMDZ
tercept
exponents appearance
tion
dosage; to the
prior
fo
start
A is a hybrid
fi
ka and
and
were
half-life
used
values and
(tia)
are
to
calculate
for
DMDZ
elimination
data points were the above equation, from of
The
elapsing
exponents
mined
concentra-
inhybrid
representing phases of DMDZ and elimination, respectively.
pearance
When with
DMDZ prazepam
appearance; term;
e_.(t-to))
-
plasma
t after
is the lag time
The
of Warner-Lambert
additional
gas-liquid
regression
C
parent From the Clinical Pharmacology Unit, Massachusetts General Hospital, and the Psychopharmacology Research Laboratory, Massachusetts Mental Health Center, Boston, Mass. Supported by Grant MH-12279 from the United States Public Health Service and Grant 77-611 from the Foundations’ Fund for Research in Psychiatry. * Verstran, Warner-Chilcott Laboratories, Divi-
an
concentrations
for
fitted
3, 4, hours
hours. Plasma at -20#{176}C un-
(DMDZ)
weighted
were
2.5, 168
tion:
tion
use. a single
cases
Plasma
as by
points
2.0,
and
electron-capture
least-squares
consent
were seven males and in age from 22 to 42
free
of prazepam* 100 to 200
participated
informed
1.5,
120,
at 144 stored
variables
hepa-
administration
1.0, 96,
some
chromatography
and
Twelve after
0.75,
drawn and
of
cannula into
drug
72,
sample was was separated
Kinetic Materiflis
before 0.5,
drawn
Butterfly
venipuncture
24, 48,
termined
were
indwelling
tubes
after
detect-
samples
separate
6, 8, 12,
concentrations
systemic blood. pharmacokinetic
an
by
rinized
systemic
the are
blood
through or
1
dealkylation
through
prazepam
reach
1)
desmethyldiazepam
probably
Levels able
to
N-1-cyclo(Fig.
to
Venous
tranquil-
large
substituent
transformed
DIVOLL ALLEN. R.N.. DAVID J. GREENBLATT, M.D.. BA.. and RICHARD I. SHADER. M.D. Boston, Mass.
the relation
and smoking DMDZ level,
the
not tifl
terminal
plasma of
consistent was deter-
log-linear sex,
ap(tfl).
concentration age,
ap-
body
porcurve. weight,
habits to the peak plasma the time of the peak level, 445
ALLEN,
GREENBLATT,
HARMATZ,
AND
SHADER
GLUCURONIDE
L
CI-
cr 3-IIYDROXY
PRAZEPAM
PRAZEPAM
+
+ GLUCURONIDE
-
DES METHYLDIAZEPAM
Fig.
tfl
and
1. Metabolic
determined
was
OX AZE PAM
by
pathway
multiple
of prazepam overlap
gression
analysis.5.9
and
Results
was
minimal.
70.5
kg
weight.
(Table
with
DMDZ 12
First-order
observed
subjects
(Fig.
those
subjects
mean
lag
other six not first
2). was
time
only The
59.3
was
24.1
six
of
mean
minutes, minutes.
and In
tion” pattern was of was
observed
first-order far
(Fig.
8).
more
common
of among
Two-variable cated that sex
was
body
(r
446
weight
to
192.5
hours,
with
hours.
regression
highly =
0.84).
could
highest (r
as of
in
DMDZ
concentration
determinant
parison
of
coefficients
analysis
indi-
els
correlated
with
insignificant
Furthermore,
cent)
highest
Sex
were
the (Table
Journal
the was
was
the as
plasma
most
(F
by =
4.74;
important
indicated
II);
A vari-
explained
standardized
by
com-
regression
higher
peak
lev-
female sex. Only (7 and 31 per
in of
ex-
analysis smoking
overall
factors
variability The
was
was
measured
associated with proportions of
DMDZ
variables. of
independent
0.05).
