WERMELING ET ALANDAND

BIOAVAILABILITY
PHARMACOKINETICS
PK OF
PHARMACODYNAMICS
LORAZEPAM

Bioavailability and Pharmacokinetics

of Lorazepam after Intranasal, Intravenous,
and Intramuscular Administration
Daniel Paul H. Wermeling, PharmD, Jodi Lynn Miller, PharmD,
Sanford Mitchell Archer, MD, Jose M. Manaligod, MD, and Anita C. Rudy, PhD

The purpose of this study was to evaluate the pharmacokinetic

profile of intranasal lorazepam in comparison to currently established administration routes. Eleven healthy volunteers
completed this randomized crossover study. On three occasions, each separated by a 1-week washout, subjects received
a 2 mg dose of lorazepam via the intranasal, intravenous, or
intramuscular route. Blood samples were collected serially
from 0 to 36 hours. Noncompartmental methods were used to
determine pharmacokinetic parameters. Lorazepam was
well absorbed following intranasal administration with a
mean (%CV) bioavailability of 77.7 (11.1). Intranasal administration resulted in a faster absorption rate than intramuscu-

orazepam, a benzodiazepine, is available both

orally and parenterally.1 It is used clinically as an
anxiolytic, as a treatment for status epilepticus, preoperatively, and as an adjunct for nausea management,
and it has recently been studied for its potential use in
acute psychotic situations.1-5 In many of these cases, it
is necessary to administer lorazepam via the intravenous (IV) or intramuscular (IM) route for rapid onset of
action and assured dose bioavailability.
An alternative route of administration, one that
would avoid the use of needles while continuing to
provide rapid effect, should prove extremely useful in
a variety of clinical settings. In particular, it would be
highly beneficial in the pediatric setting. Alternative
From the Drug Product Evaluation Unit of the University of Kentucky College
of Pharmacy (Dr. Wermeling, Dr. Miller, Dr. Rudy) and the Division of OtolaryngologyHead and Neck Surgery, University of Kentucky Chandler
Medical Center (Dr. Archer, Dr. Manaligod). This study was financially supported by Intranasal Technology, Inc., Pomona, New York. Submitted for
publication December 6, 2000; revised version accepted July 2, 2001.
Address for reprints: Daniel Paul H. Wermeling, PharmD, University of Kentucky, College of Pharmacy, 800 Rose Street, C-117, Lexington, KY
40536-0093.

J Clin Pharmacol 2001;41:1225-1231

lar administration. Elimination profiles were comparable between all three routes. The concentration-time profile for
intranasal delivery demonstrated evidence of a double peak
in several subjects, suggesting partial oral absorption. Females were found to have significantly higher AUC values
than males for all three delivery routes. Overall, this study
demonstrated favorable pharmacokinetics of intranasal
lorazepam in relation to standard administration methods.
Intranasal delivery could provide an alternative, noninvasive
delivery route for lorazepam.
Journal of Clinical Pharmacology, 2001;41:1225-1231
2001 the American College of Clinical Pharmacology

routes of delivery include rectal or intranasal (IN) administration. The rectal route has been evaluated for
lorazepam but was found to have a slow absorption rate
in humans6 and was found to undergo extensive
first-pass metabolism in dogs.7 The IN route has been
studied previously in humans as well.8 It was found to
have a moderate concentration profile, as evidenced by
its 51% absolute bioavailability. Other benzodiazepines,
such as midazolam9,10 and diazepam,8,11 have also been
examined intranasally in humans with promising
results.
The purpose of this study was to determine whether
IN administration would provide comparable
bioavailability and pharmacokinetic profiles with respect to intravascular and intramuscular delivery.
MATERIALS AND METHODS
Subjects
Twelve (6 male, 6 female) healthy volunteers (Table I)
within the age range of 18 to 35 years were eligible for
enrollment in this study. The screening evaluation con-

1225

WERMELING ET AL

Table I Subject Demographics and Administration Sequence

Dosing Sequence
Subject

Age (years)

Weight (kg)

25
20
NAa
22
20
20
20
21
26
21
26
21

58.6
56.8
NAa
75.2
65.9
67.7
62.7
72.3
79.8
80.4
77.5
79.5

1
2
3
4
5
6
7
8
9
10
11
12

Gender

F
F
F
F
F
F
M
M
M
M
M
M

Ethnicity

Period 1

Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Asian
Caucasian
Caucasian
Caucasian

IV
IN
IM
IM
IV
IN
IM
IN
IV
IM
IN
IV

Period 2

IM
IV
NAa
IV
IN
IM
IV
IM
IN
IN
IV
IM

Period 3

IN
IM
NAa
IN
IM
IV
IN
IV
IM
IV
IM
IN

IV, intravenous; IM, intramuscular; IN, intranasal.

a. NA, not applicable. Subject 3 dropped from the study following the first dosing period.

sisted of a medical history, physical and nasal examinations, and clinical laboratory tests. Subjects were excluded from participation based on the presence of any
clinically significant laboratory values or disease
states, including acute or chronic nasal symptoms and
physical abnormalities of the nasal passage. Subjects
were also excluded for tobacco use within the past 2
years, presence of alcohol or substance abuse within
the past 5 years, and pregnancy or if not willing to abstain or use barrier methods of birth control during the
study period. Written informed consent was obtained.
The institutional review board of the University of
Kentucky approved this study.
Study Procedures
This was a randomized, three-way crossover, singledose study with each treatment separated by a washout
period of 1 week. All 12 subjects reported to the study
center at 18:00 the night prior to the study day and remained in the center until the last blood draw was obtained, approximately 36 hours after dosing. During
each experiment period, subjects were administered
the study drug via either the IV, IM, or IN route as determined by a previously constructed randomization
schedule (Table I).
Drug administration occurred at approximately
08:00 on each study day. Except for water ad libitum or
a caffeine-free drink or juice, subjects underwent an
overnight fast of at least 8 hours. No fluids were allowed 1 hour prior to or after dosing. Standardized
meals were provided at 12:00 and 18:00 each day and
breakfast at 08:00 on day 2 of each study period. No
1226

J Clin Pharmacol 2001;41:1225-1231

xanthine-containing foods or beverages were allowed

for 48 hours prior to dosing and until the last blood
sample was collected for each study period. No medications known to affect lorazepam pharmacokinetics
were allowed within 7 days prior to each study period
or during any study period.
Vital signs consisting of blood pressure, respiratory
rate, and pulse rate were measured at selected preset
times throughout the study. Pulse oximetry monitoring
was available for any volunteer who remained overly
sedated for longer than 8 hours. Adverse events were
recorded as they occurred. Subjects were specifically
questioned about adverse events while vital signs were
recorded. Nasal examinations to detect any local adverse reactions were performed by an otolaryngologist
prior to study drug administration, 2 to 4 hours after administration, and at the poststudy evaluation.
Venous blood samples (10 ml) were collected from
an indwelling catheter placed solely for study purposes. Samples were obtained at 0 (predose), 5, 15, 30,
and 45 minutes and 1, 2, 3, 4, 8, 12, 18, 24, and 36 hours
after lorazepam administration was completed. The
samples, directly collected in Vacutainer tubes containing sodium heparin, were separated into their respective plasma and cell components by a refrigerated
centrifuge (4C). The plasma was transferred to polypropylene tubes and stored at approximately 70C.
Dose Administration
A standard 2.0 mg dose of lorazepam was used for all
routes of administration. Subjects remained seated in
bed at a 30- to 45-degree angle for 2 hours following

BIOAVAILABILITY AND PK OF LORAZEPAM

each drug administration. For IV administration, 2.0

mg in 2.0 ml sterile solution was given at a rate of 0.5
ml/min over 4 minutes followed by 2.0 ml normal saline at a rate of 0.5 ml/15 seconds to flush the port. This
resulted in a total infusion time of 5 minutes. The IV
dose was administered in the arm contralateral to
where the catheter was placed for blood withdrawal.
IM lorazepam, 2.0 mg in 1.0 ml sterile solution, was administered as a single deep muscle injection into the
frontal thigh area using standard techniques. Before IN
administration, subjects gently blew their nose. Using
the Pfeiffer unit dose spray pump (Pfeiffer of America,
Princeton, NJ), a single spray of lorazepam (1.0 mg/100
l) was administered to the lateral nasal wall of each
nostril. Subjects were not allowed to blow their nose
for 60 minutes following administration.

viding the dose by AUC0-. Volume of distribution at

steady state and for elimination (Vss and Vz) were determined by moment curves.13
Statistical
Considerations
Sample size was determined by clinical feasibility
rather than standard calculations using alpha and
power estimates. Posteriori statistical analysis was performed using an ANOVA model to evaluate sequence,
subject (sequence), treatment, and period for carryover
effects. Gender effects were also evaluated in the
model. Log-transformed AUC and Cmax values were
used to calculate ratios and 90% confidence intervals
(CI) for the three delivery routes. A p-value of < 0.05
was considered significant.

Assay of Samples
Sample analysis was conducted using a liquid chromatography/mass spectrometry/mass spectroscopy assay.
The internal standard was deuterated lorazepam.
Using 1.0 ml of human plasma, the lower limit of sensitivity was 0.10 ng/ml. The upper limit of detection was
25.0 ng/ml. Samples with concentrations greater than
25.0 ng/ml were diluted to a concentration between
0.10 and 25.0 ng/ml and reanalyzed. Coefficients of
variation for within- and between-batch analysis were
0.0% to 11.1% and 4% to 10%, respectively. Accuracy
was 90.0% to 110.0%.
Pharmacokinetic
Analysis
Pharmacokinetic parameters were determined using
standard noncompartmental methods with log-linear
least squares regression analysis to determine the elimination rate constants (WinNonlin, Pharsight Corp.,
Palo Alto, CA). The areas under the concentration versus time curves from time zero to infinity (AUC0-) were
calculated by a combination of the linear and logarithmic trapezoidal rules, with extrapolation to infinity by
dividing the last measurable serum concentration by
the elimination rate constant (z).12 Values for the maximum concentration (Cmax) and time to Cmax (tmax) were
determined by visual inspection of concentration versus time data for each subject. The elimination half-life
was determined from 0.693/ z . The absolute
bioavailability (F) for the IN and IM dosage forms, assuming equal 2 mg doses, was determined by F =
AUC I N , 0 - /AUC I V, 0 - for the IN dose and F =
AUCIM,0-/AUCIV,0- for the IM dose. Clearance (CL for IV
and CL/F for IN and IM doses) was determined by diPHARMACOKINETICS AND PHARMACODYNAMICS

RESULTS
A total of 11 volunteers completed all study periods.
Subject demographics are listed in Table I. Subject
number 3 dropped out after the first dosing period due
to personal reasons not related to the experimental procedures and subsequently was not included in any
mean or pharmacokinetic calculations. The mean (SD)
weight of the 11 completing subjects was 70.4 (8.7) kg.
The age of subjects ranged from 20 to 26 years, with a
mean of 22.0 years. All, except 1 subject, were
Caucasian.
No significant adverse events occurred throughout
the three study periods. A complete listing of side effects for each respective delivery route is provided in
Table II. Overall, drowsiness/sleepiness was the most
commonly reported effect. Pain at site of injection,
heavy feeling, and blurred vision were also frequently noted during the study. Adverse events associated specifically with IN delivery included bad taste,
cool feeling in the nose and throat, and a burning sensation. No local adverse reactions were detected in the
nasal passage by the otolaryngologist. No clinically significant vital sign changes were observed during the
entire study course.
The mean pharmacokinetic parameters for the IV,
IM, and IN administrations are listed in Table III. The
median tmax achieved for IM delivery was six times the
tmax for IN delivery. The resulting Cmax attained via IV
administration was more than twofold greater than the
Cmax following IM or IN administration. The AUC0-t and
AUC0- were both found to be larger for IV and IM delivery in comparison with the IN route. A mean
bioavailability of 77.7% was observed for IN administration compared with the other routes (~100%).
1227

WERMELING ET AL

Table II Incidence of Adverse Events

Number of Subjects
with Complaint
Adverse Event

Back pain
Bad taste
Blurred vision
Burning/coolness in nose
Burning/coolness in throat
Ceiling moving
Chemical smell
Dazed/confused
Diarrhea
Disconnected/incoherent
Dizziness/lightheaded
Drowsiness/sleepiness
Euphoria/giddiness
Eyes heavy
Eyes watery
Floating sensation
Flu/cold-like symptoms
Groggy/heavy feeling
Headache
Hiccups
Muscle tension/soreness
Nausea
Pain at injection site
Pallor
Phlegm in throat
Postnasal drainage
Pulse elevated
Relaxed
Slow response time
Thirsty
Warm

IV

IM

IN

1
6
1
8
7

1
1
1
1
4
10
1
1

1
1
1
3
10

1
2
10
2
11

1
2
3
1
2

6
1
2
2
5
1

1
3
2
1
1

1
1
2
1

2
1

1
1

IV, intravenous; IM, intramuscular; IN, intranasal.

The average lorazepam concentration-time plots

from 0 to 4 hours and 0 to 36 hours are shown in Figure
1. The plots for all three routes appear similar from 3 to
36 hours, suggesting the major differences occur during
the first hours of administration. The rise in lorazepam
plasma concentrations during the first hour is especially distinctive, with IV as the most rapid followed by
IN and IM, respectively. The latter portion of the graph
shows that IV and IM are fairly comparable in concentration magnitude while IN remains at a slightly lower
level.
Following IN administration, a second absorption
phase was detected in 5 subjects. Lorazepam appeared
1228

J Clin Pharmacol 2001;41:1225-1231

rapidly in the bloodstream initially after IN dosing.

Within a time range of approximately 1 to 3.5 hours of
the initial plasma concentration rise, another slight increase was observed. This is shown for 1 selected subject in whom the trend was well pronounced (Figure 2).
The latter increase is most likely attributed to oral absorption from drug that passed into the pharynx area
and was consequently ingested.
As determined by the ANOVA model, carryover effects for AUC0-t, AUC0-, and Cmax were found to be insignificant. No significant gender differences were observed in Cmax, but females were found to have
significantly higher AUC0-t (p = 0.0001) and AUC0- (p =
0.0001) values compared with males for all delivery
routes. The ratios and 90% CI for IM/IV and IN/IV Cmax
parameters were very similar (Table IV). This was also
reflected in the direct comparison of IN to IM, which resulted in CI of 0.72 to 1.24. AUC values for IN to both IV
and IM ranged from 74% to 77% with low data variability, as evidenced by the relatively tight CI.
DISCUSSION
Pharmacokinetic parameters attained in the present
study are comparable to values in the literature following administration of IV or IM lorazepam at an equivalent dose.14-17 To our knowledge, only one other study
has been conducted using IN lorazepam.8 Lau and
Slattery8 administered a total lorazepam dose of 4 mg
using a solution concentrated at 4 mg/100 l. The dose
was delivered via a pipette and was divided between
each nostril. Their resultant parameters (mean [SD])
were as follows: Cmax 18.7 (5.9), tmax range 0.5 to 4.0
hours, and bioavailability 51% (11.9). The parameters
in the present study (Table III) are more favorable than
previously reported. The Cmax values observed from
both studies are comparable even though the dose used
by Lau and Slattery was twice the dose presently administered. In addition, their solution was four times
more concentrated, and only half the volume was used
for administration. Their bioavailability was approximately 24% lower, and the tmax range was much larger,
suggesting slower, decreased uptake. In comparison,
the present formulation and delivery device appear to
provide faster, increased drug absorption.
Observation of the plasma concentration plots and
calculated parameters indicate that IN delivery seems
to primarily parallel IM delivery with exception to tmax
and bioavailability. IN lorazepam reaches its maximum
concentration at least two times faster than IM. However, IN has a bioavailability of approximately 78%,
while IM bioavailability is practically 100%. The relatively small variation present in the pharmacokinetic

BIOAVAILABILITY AND PK OF LORAZEPAM

Table III Pharmacokinetic Parameters of Lorazepam

Parameter

2 mg IV

tmax (h)a
Cmax (ng/ml)
t1/2 (h)
AUC0-t (ngh/ml)
AUC0- (ngh/ml)
CL or CL/F (L/h)
Vss (L)
Vz or Vz/F (L)
F (%)

2 mg IM

0.1
(0.083-1.017)
47.6
(57.8)
16.6
(27.3)
386.8
(19.4)
500.8
(30.8)
4.3
(27.0)
93.2
(11.9)
97.8
(15.2)
Assume 100%

3
22.6
17.4
372.8
506.2
4.3

2 mg IN

(0.5-8.017)
(28.9)
(38.1)
(16.4)
(33.7)
(28.5)

0.5
21.4
18.5
288.0
393.5
5.7

(10.8)
(10.2)

140.1
77.7

99.2
100.9

(0.25-2)
(24.3)
(28.3)
(25.4)
(38.0)
(31.8)

(16.8)
(11.1)

Values are presented as mean (%CV); n = 11. IV, intravenous; IM, intramuscular; IN, intranasal.
a. Median and range given for tmax.

40

80

Concentration (ng/mL)

Concentration (ng/mL)

100

60
40
20

30

20

10

0
0

Time (h)

Figure 2. Plasma concentration-time profile of lorazepam after a 2

mg intranasal dose in subject 2.

Concentration (ng/mL)

60
50
40
30
20
10
0
0

12

18

24

30

36

Time (h)

Figure 1. Mean plasma concentration-time profiles from 0 to 4

hours (top) and 0 to 36 hours (bottom) for lorazepam after a single 2
mg dose administered via the intravenous ( ), intramuscular ( ), or
intranasal ( ) route. Error bars represent standard deviation.

parameters (Tables III and IV) did not differ between

the three administration routes, suggesting no greater
subject variability results from IN delivery.
Clinical significance of pharmacokinetic differences
between these administration routes was not determined. Even though pharmacodynamic assessments
PHARMACOKINETICS AND PHARMACODYNAMICS

were not included in the study design, based on the

concentration versus time profiles (Figure 1), IN would
be expected to have a pharmacological profile resembling IM delivery. In addition, a faster onset of action
would be anticipated with IN delivery. Rapid onset, yet
avoidance of invasive administration using needles,
would be advantageous in a variety of clinical settings.
The diminished IN bioavailability leads to several
possible explanations. Some of the drug may simply
not have been absorbed through the nasal mucosa and
was subsequently cleared from the nose via normal
physiologic mechanisms. These processes occur at an
average rate of approximately 5 to 6 mm/min, resulting
in clearance of the nasal passage every 20 to 30 minutes.18 Another explanation for lower bioavailability is
metabolism by phase II enzymes present in the nasal
mucosa.19 The major metabolite of lorazepam is
lorazepam glucuronide. Once conjugated, the metabolite is renally excreted. 20,21 Active glucuronyl
1229

WERMELING ET AL

Table IV Ratios and 90% Confidence Intervals (CI) for Pharmacokinetic Parameters
a

Mean
Parameter

Log (AUC0-)
Log (AUC0-t)
Log (Cmax)

IV

484.1
380.54
42.14

IM

IN

487.46
369.63
22.29

373.72
279.75
21.09

IM/IV (90% CI)

1.01
0.97
0.53

(0.95-1.07)
(0.91-1.04)
(0.40-0.69)

IN/IV (90% CI)

0.77
0.74
0.5

(0.73-0.82)
(0.69-0.79)
(0.38-0.65)

IN/IM (90% CI)

0.77
0.76
0.95

(0.72-0.82)
(0.71-0.81)
(0.72-1.24)

IV, intravenous; IM, intramuscular; IN, intranasal.

a. Values reflect the least squares geometric means.

transferase (GT) enzymes have been detected in the nasal mucosa.19,22,23 One study did not find any evidence
of GT activity in the human nasal mucosa. However,
this enzyme exists in multiple forms, only one of which
was analyzed in that particular study.24 Last, as evidenced by the second peak (Figure 2), partial oral absorption of the dose could have played a role in the
bioavailability, especially if nasal clearance took place.
Considering oral bioavailability is about 90% and any
first-pass effect is considered minimal for
lorazepam,20,25 it is not probable that this would account for approximately 20% of the dose. Therefore,
the decreased bioavailability is assumed to result from
a combination of events.
Midazolam and diazepam, two other benzodiazepines, have also been studied intranasally.9-11
Bjrkman et al 10 and Burstein et al 9 found IN
midazolam to have a mean (SD) bioavailability of 83
(15) and 50 (13), respectively. Gizurarson et al11 found
IN diazepam bioavailability to be 50.4% 23.3%.
These reported values, in addition to the present study,
suggest that the maximum bioavailability expected
from IN benzodiazepine delivery can be estimated at
80%.
The second peak phenomenon is most likely attributed to oral absorption. Maximum concentration following oral lorazepam occurs approximately 0.5 to 3
hours after dose administration.21,25 The second peak in
the present study occurred within this time frame, suggesting that the rise in concentration was in fact due to
ingestion. This phenomenon has been observed with
other IN drug formulations,9,26 as well as several oral
medications.27 One study28 of particular interest addresses the occurrence of double peaks in plasma concentrations following oral administration of a benzodiazepine, alprazolam, to rats. The suggested
mechanism is a reduction in gastric motility resulting
from the muscle-relaxant properties of alprazolam.
This mechanism may explain why further absorption
in subjects 1 and 12 (data not shown) did not occur until approximately 3 to 4 hours after dose administra1230

J Clin Pharmacol 2001;41:1225-1231

tion. Lorazepam absorbed intranasally may have decreased gastric motility, therefore delaying subsequent
oral absorption from the gastrointestinal tract.
Gender differences in benzodiazepine pharmacokinetic profiles have been studied previously. Several of these studies found no significant
pharmacokinetic differences between genders.29-31 Alternatively, Yonkers et al32 conducted a literature review and concluded that young women may require
lower doses of benzodiazepines. In this review, they
also suggested that benzodiazepines that undergo
conjugative metabolism have a slower elimination in
women than men. Kristjnsson and Torsteinsson33
found that females had a significantly higher elimination rate constant for oral alprazolam. In the same
study, significant gender differences were also noted in
the clearance, which was found to be significantly
faster in females. The present study found statistically
significant gender differences in AUC values, with females having higher AUC0-t and AUC0- than males.
This study was not designed to determine clinical significance of this difference. It should be noted, however, that these present data were not body weight normalized for analysis. This could potentially affect the
observed gender difference. The conflicting reports in
the medical literature on this topic suggest that it may
be an area of interest for future studies.
In conclusion, lorazepam appears to be well absorbed via the IN administration route. It has a faster
absorption rate than IM and comparable elimination
profiles with IV and IM delivery. No significant adverse
effects were noted with any of the administration
routes in this study. The concentration versus time
profile for IN lorazepam suggests it may provide an
alternate, noninvasive delivery route. Further
pharmacodynamic and efficacy studies need to be conducted to determine its relevance in clinical situations.
Despite the relatively small number of subjects, this
study has demonstrated favorable pharmacokinetics of
IN lorazepam in relation to existing standard administration methods.

BIOAVAILABILITY AND PK OF LORAZEPAM

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