sdfghj

ORIGINAL ARTICLE
Different effects of light food on pharmacokinetics and
pharmacodynamics of three benzodiazepines, quazepam,
nitrazepam and diazepam
A. Yamazaki* MS, Y. Kumagai MD, T. Fujita MD, T. Hasunuma MD, S.Yokota ,
M. Maeda , Y. Otani MD and M. Majima* MD
*Department of Molecular Pharmacology, Kitasato University Graduate School of Medicinal graduate
course, Kanagawa, Clinical Trial Center, Kitasato University East Hospital, Kanagawa and Center for
Clinical Pharmacology, Kitasato Institute, Kanagawa, Japan
SUMMARY
Objective: Quazepam, nitrazepam and diazepam
are administered under fed or fasted conditions
for insomnia or anxiety disorder. Light bedtime
food may have clinically relevant effects on the
plasma levels of those drugs and hence on psychomotor
performance. This study assessed the
effect of light food on the pharmacokinetics and
pharmacodynamics of these drugs.
Method: Twenty-one eligible subjects were
randomized to one of three groups of seven subjects:
quazepam 20 mg, diazepam 5 mg or nitrazepam
5 mg. Each healthy subject took a single
oral dose of the assigned drug after overnight
fasting and after light food, on a separate occasion.
Blood samples were collected until 72 h
after dosing. The plasma samples were assayed
using high-pressure liquid chromatography with
spectrophotometric detection. Reaction time,
critical flicker fusion test and visual analogue
scales were conducted.
Results: The peak plasma concentration (Cmax)
and area under the concentration–time curve
(AUC) of quazepam with light food were 1Æ2-fold
[90% confidence interval (CI): 1Æ1–1Æ5; P < 0Æ05]
and 1Æ5-fold (90% CI: 1Æ3–1Æ9; P < 0Æ05) higher
than that without light food, respectively. For
nitrazepam and diazepam, the time to peak was
delayed about 1 h in fed condition (P > 0Æ05).
However it had no effect on their Cmax and AUC.
Reaction time of quazepam with light food was
prolonged at 4 and 6 h after dosing and its area
under the effect–time curve from 0 to 10 h was
increased (P < 0Æ05).
Conclusion: Light food increased the bioavailability
of quazepam and affected psychomotor
performance. Light food delayed Tmax of nitrazepam
and diazepam but had no effect on Cmax and
AUC.
Keywords: benzodiazepine, food–drug interactions,
pharmacodynamics, pharmacokinetics
INTRODUCTION
Quazepam, nitrazepam and diazepam are benzodiazepine
drugs used in insomnia or anxiety disorder.
Food may have significant effects on the
bioavailability of various drugs (1, 2). Quazepam,
nitrazepam and diazepam are highly lipophillic (3,
4) and their absorption is often enhanced by food
(1). Increased bioavailability of drugs have been
reported not only with fatty meals but also with
protein or carbohydrate meals (5). Therefore, a very
low fat meal or a light food such as a bed-time
snack may interact with these benzodiazepines.
The effect of food on the pharmacokinetics of
quazepam have been reported by Yasui-Furukori
et al. (4, 6) and Kim et al. (7). However, the effect of
light food such as a bed time snack on the drug’s
pharmacokinetics and pharmacodynamics is not
known. There is also little information on the effects
of food on oral diazepam and published studies
have used a variety of foods (8). Furthermore, oral
Received 2 June 2006, Accepted 26 November 2006
Correspondence: Akira Yamazaki, Department of Molecular
Pharmacology, Kitasato University Graduate School of Medicinal
graduate course, 1-15-1 Kitasato, Sagamihara, Kanagawa
2288555, Japan. Tel.: +81 42 778 8111; fax: +81 42 778 8111;
e-mail: yamazaa@jcom.home.ne.jp
Journal of Clinical Pharmacy and Therapeutics (2007) 32, 31–39
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd 31
nitrazepam has not been assessed for the possibility
of drug–food interaction. Therefore, we evaluated
the effect of light food on the pharmacokinetics and
pharmacodynamics of quazepam, nitrazepam and
diazepam in healthy subjects.
MATERIALS AND METHODS
Materials
Doral tablets (20 mg quazepam), Benzalin tablets
(5 mg nitrazepam) and Cercine tablets (5 mg diazepam)
were purchased from Mitsubishi Pharma
Corporation (Osaka, Japan), Shionogi & Co., Ltd
(Osaka, Japan) and Takeda Pharmaceutical Company
Ltd (Osaka, Japan), respectively. The light
food was used a Japanese traditional healthy bedtime
snack, ‘otyaduke’ which is cooked as follows:
boiled rice 100 g sprinkled with ‘otyadukenori’ 6 g
(Nagatanien Co., Ltd, Tokyo, Japan) was poured
150 mL of hot water. Otyadukenori consisted of
sodium, cubic rice crackers and dried seaweed
flakes. It contained approximately 166 kcal (0Æ44 g
lipid, 37Æ8 g carbohydrates, 2Æ7 g protein and
sodium 1Æ9 mg).
Study design and clinical protocol
This study was approved by the institutional
review board at Kitasato East hospital and all
subjects provided written informed consent prior
to any study procedures. Twenty-one healthy male
volunteers between the ages of 20 and 33 years
(22Æ5 ± 2Æ9) and body mass index within 18Æ9–
26Æ6 kg/m2 (21Æ6 ± 2Æ3) were enrolled for the study.
Study subjects were determined to be healthy by a
complete medical history, physical examination,
alcohol and drug abuse history, vital signs, 12-lead
electrocardiogram, and laboratory tests, serologic
test for syphilis and virology tests (HIV, hepatitis B
and hepatitis C). Subjects were excluded if they
had any of the following: subjects with evidence of
donation of blood more than 200 mL within
1 month or more than 400 mL within 3 months
before this study; subjects who were enrolled in
any other clinical study within 4 months prior to
this study; subjects predisposed to drug hypersensitivity
reactions; subjects who were considered
unsuitable for participation in this study by the
investigator.
This was a randomized, parallel dosing, twoway
crossover, single-dose study in 21 healthy men
with a 2-week washout between the drug administrations.
Twenty-one eligible subjects were randomized
to one of three cohort groups (seven
subjects each): (i) a single 20 mg tablet of quazepam,
(ii) a single 5 mg tablet of diazepam, and (iii)
a single 5 mg tablet of nitrazepam.
Eligible subjects were admitted to the study site
on the day before dose administration on each of
the two treatment periods. The subjects slept at
least 8 h before the start of each study session. The
subjects received a study drug with 200 mL of
water 30 min after the light food and under fasting
condition. The subjects and persons in charge of
psychomotor function tests were not aware of
which study drug was administered to the subjects.
The pharmacist who administered the study drug
to the subjects was unblinded to it. Blood was
collected at pre-dose and at 0Æ5, 1, 2, 3, 4, 5, 6, 8, 12,
24, 48 and 72 h after dosing. All subjects fasted for
at least 10 h before and until 4 h after dosing. All
subjects received a standardized lunch and supper
4 and 10 h after dosing, respectively. The volunteers
were not allowed to use any medication
within 24 h preceding the treatment as well as
during the entire study. Alcohol, caffeine, cola,
beverage including grapefruit and smoking was
prohibited for 12 h prior to and following drug
administration. The volunteers had to avoid
excessive physical exercise throughout the study.
Analytical procedures
The plasma samples were assayed using high-pressure
liquid chromatography with spectrophotometric
detection (HPLC/UV) and column switching.
Quazepam and its metabolite 2-oxoquazepam,
N-desmethyl-2-oxoquazepam and cisapride as an
internal standard were supplied by Mitsubishi
Pharma Corporation. Diazepam and its metabolite
N-desmethyl-diazepam and nitrazepam were purchased
from Sigma–Aldrich Japan K.K. (Tokyo,
Japan).
The plasma samples were assayed for quazepam,
2-oxoquazepam, N-desmethyl-2-oxoquazepam.
After sample alkalization with 0Æ5 mL of
NaOH (0Æ05 mol/L), the test compound and internal
standard, cisapride, were extracted from
plasma using toluene-n-heptane (15 : 85, v/v). The
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
32 A. Yamazaki et al.
organic phase was evaporated to dryness and the
residue was dissolved with 800 lL of mobile phase.
The clean-up and preconcentration of sample
(500 lL) was performed on C8 TSK-BSA (5 lm,
10 · 4Æ6 mm ID) pretreatment column from Tosoh
Corporation, Tokyo, Japan. The mobile phase consisted
of acetnitrile and phosphate buffer
(0Æ02 mol/L, pH 4Æ6) (13 : 87, v/v) and was delivered
at a flow rate of 1Æ2 mL/min. Subsequent
separations were carried out on C18 STR ODS-II
analytical column (5 lL, 150 · 4Æ6 mm ID, Shimadzu
Techno-Research Inc., Tokyo, Japan) analytical
column. The mobile phase consisted of
acetnitrile and phosphate buffer (0Æ02 mol/L, pH
4Æ6) (13 : 87, v/v) for quazepam and 2-oxoquazepam,
and acetnitrile, perchloric acid (6 mol/L) and
phosphate buffer (0Æ02 mol/L, pH 4Æ6)
(41Æ5 : 0Æ05 : 58Æ45, v/v/v) for N-desmethyl-2-oxoquazepam
and was delivered at a flow rate of
0Æ6 mL/min. The peak was detected using a UV
detector set at 286 nm for diazepam and 254 nm for
metabolite. Relative errors at 30 ng/mL of quazepam,
2-oxoquazepam, N-desmethyl-2-oxoquazepam
were 2Æ5%, 3Æ9% and 2Æ6%, respectively. The
limit of quantification was 0Æ7 ng/mL for each
compound.
The plasma samples for nitrazepam, diazepam
and N-desmethyl-diazepam were assayed by same
method except the following. The samples were
alkalized with 0Æ5 mL of NaOH (0Æ5 mol/L) for
nitrazepam assay, and with 0Æ5 mL NaOH
(0Æ01 mol/L) for diazepam and N-desmethyl-diazepam.
Relative errors at 15 ng/mL of nitrazepam,
diazepam and N-desmethyl-diazepam were 3Æ2%,
2Æ9% and 2Æ9%, respectively. The limit of quantification
was 0Æ8 ng/mL for each compound.
Pharmacodynamic measures
Psychomotor function tests were conducted before
and 2, 4, 6, 10 and 24 h after drug administration.
The subject’s agility and ability to react from
cognition to movement was assessed using reaction
time (RT). Subjects were required to press an
electrical switch, when a yellow light flashed. The
special equipment consisted of a light stimulus
generator (T.T.K.331), a digital timer (T.T.K.315), a
push-button switch set and a selective reaction
control (T.T.K.333) (Takei Scientific Instruments
Co., Niigata, Japan). This produced random
sequences of three-colour stimuli (yellow, red and
blue light). The RTs and the computed average RT
of 10 stimuli were calculated at each point. Critical
Flicker Fusion Test (CFFT) assessed the subject’s
wakefulness and degree of fatigue. The score was
determined by measuring the frequency for distinguishing
the flicker from 12 runs of ascending
and 12 runs of descending frequencies. Lightemitting
diodes (Leeds Flicker Fusion Tester Type
II, T.T.K.501.b; Takei Scientific Instruments Co.)
produced the stimuli. The seated subjects peered
through a cylindrical tube to see the flickers with
both eyes in a quiet room. Subjects were required
to depress an electrical switch, when flicker fusion
(continuous lighting) was observed for ascending
CFFT or continuous lighting flickering for descending
CFFT. The number of flicks per second
(Hz) was recorded. Visual analogue scales (VAS)
were used to subjectively rate sedation using 0–
100 mm VAS, as described by Norris (9), and
Bond and Lader (10). In this study the six indicators
were selected to assess three domains of
sedation with two indicators each: mental sedation
(alert–drowsy and clear headed–muzzy),
tranquilization (calm–excited and relaxed–tense),
and physical sedation (well coordinated–clumsy
and energetic–lethargic).
Pharmacokinetic and pharmacodynamic analysis
Individual plasma concentration–time profiles was
analysed by using a non-compartmental method,
using WINNONLIN (Pharsight Corporation, Mountain
View, CA, USA). The following parameters were
obtained: Cmax and Tmax were determined from
observed data. Area under the plasma concentration–
time curve from time zero to the last quantifiable
concentration (AUClast) was determined by the
linear trapezoidal rule. The terminal rate constant
(kel) was determined by linear regression of the
terminal linear portion of the ln concentration–time
curve. The terminal half-life (t1/2) was calculated as
ln/kel. The mean transit time (MTT) was calculated
as the area under the first moment curve (AUMC)/
AUC. AUMC was determined by the linear trapezoidal
rule, and the following pharmacodynamic
parameters were obtained: the area under the
effect–time curve (AUC) was determined by the
trapezoidal rule from 0 to 10 h and from 0 to 24 h
for RT and CFFT. For RT and VAS, a raw score was
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
Food and benzodiazepines interactions 33
used. The CFFT variables were assessed by changed
scores from baseline.
Statistical analysis
Differences in pharmacokinetic parameters (excluding
Tmax) and pharmacodynamic parameters (RT
and CFFT) were evaluated using a paired t-test.
Differences in Tmax were evaluated using Wilcoxon’s
matched-pairs signed ranks. VAS was not
evaluated statistically due to the large inter-individual
variance. Each pharmacodynamic parameter
at each time point was used for statistical
analysis for comparing fed and fasting states. Differences
were considered significant when
P < 0Æ05. The 90% confidence intervals (CIs) of the
fed/fasting ratios for Cmax and AUClast (log transformed)
were determined.
RESULTS
Pharmacokinetics
Mean plasma concentration–time profiles of quazepam
following single-dose oral administration
are illustrated in Fig. 1. Relevant pharmacokinetic
parameters corresponding to the plasma concentration
profiles are listed in Table 1. It is seen that
the plasma concentration–time profiles of quazepam
between fasting and fed conditions are different.
The 90% CIs of ratios for Cmax and AUClast
were 1Æ1–1Æ5 and 1Æ3–1Æ9, respectively, for the fed
relative to the fasted state indicating that the rate
and the extent of quazepam absorption were
increased when administered with food. Similar
results were found using the paired t-test (P < 0Æ05).
Other pharmacokinetic parameters, Tmax, t1/2 and
MTTlast, did not change significantly. Contrary to
the parent compound, its metabolites, 2-oxoquazepam
and N-desmethy-2-oxoquazepam were not
significantly different between fasted and fed conditions,
except t1/2 of 2-oxoquazepam (Table 1).
For nitrazepam and diazepam, mean plasma
concentration–time profiles following single-dose
oral administration are illustrated in Figs 2 and 3.
There were no significant differences between
the fed and fasting states with regard to Cmax and
AUClast (P > 0Æ05). The 90% CIs of ratios for Cmax
Table 1. Pharmacokinetic parameters (mean ± SD) for quazepam and its metabolites under fasted and fed conditions
(n = 7)
Quazepam 2-Oxoquazepam N-desmethyl-2-oxoquazepam
Fasted Fed Fasted Fed Fasted Fed
Cmax (ng/mL) 44Æ7 ± 38Æ0 52Æ8 ± 36Æ9* 21Æ2 ± 5Æ3 21Æ9 ± 5Æ8 35Æ7 ± 9Æ7 32Æ6 ± 9Æ4
Ratio; 90% CI 1Æ2; 1Æ1–1Æ5 1Æ0; 0Æ9–1Æ2 0Æ9; 0Æ9–1Æ4
Tmax (h) 2 (2–3) 2 (2–4) 3 (2–4) 3 (2–4) 24 (8–24) 12 (12–48)
AUClast (ngÆh/mL) 291 ± 181 445 ± 227* 168 ± 48 174 ± 57 2237 ± 639 2019 ± 604
Ratio; 90% CI 1Æ5; 1Æ3–1Æ9 1Æ0; 0Æ8–1Æ3 0Æ9; 0Æ9–1Æ3
t1/2 (h) 14Æ3 ± 4Æ8 16Æ8 ± 4Æ4 17Æ6 ± 4Æ3 14Æ2 ± 4Æ4* NA NA
MTTlast (h) 10Æ0 ± 2Æ3 12Æ1 ± 1Æ6 11Æ2 ± 2Æ8 10Æ7 ± 3Æ0 10Æ0 ± 2Æ3 12Æ1 ± 1Æ6
For Cmax and AUClast, 90% confidence intervals (CIs) are determined for the ratios between fed and fasting states. Tmax is reported as
median and range. NA = not applicable.
*Difference from fasted condition at P < 0Æ05: significance was tested by paired t-test, except Tmax was tested by Wilcoxon’s matchedpairs
signed ranks.
0
10
20
30
40
50
60
70
0 5 10 15 20 25
Hours
Plasma quazepam (ng/mL)
Fasted
Fed
Fig. 1. Plasma concentration of quazepam after oral
administration of 20 mg quazepam under fasted and fed
conditions. Data are shown as mean and SEM (n = 7).
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
34 A. Yamazaki et al.
and AUClast of nitrazepam were 1Æ0–1Æ1 and 0Æ9–1Æ1,
and those of diazepam were 0Æ9–1Æ1 and 1Æ0–1Æ2
(Table 2). Comparison of Tmax, however, indicated
that there was a statistically significant increase in
Tmax in the fed vs. fasted state (P > 0Æ05). Both Tmax of
nitrazepam and diazepam were delayed about 1 h in
fed condition (Table 2). Elimination half-life and
MTTlast did not change upon food ingestion either
for nitrazepam or diazepam. N-desmethyl-diazepam
was not significantly difference between fasted
and fed conditions. The plasma concentration of
N-desmethyl-diazepam continuously increased up
to the last sampling point.
Pharmacodynamics
Quazepam, nitrazepam and diazepam had CNSdepressant
effect assessed by several psychomotor
function tests up to 24 h after drug administration.
For quazepam, food produced significant changes
on RT (Fig. 4). RT was prolonged at 4 and 6 h after
dosing in fed condition (P < 0Æ05). The AUC0–10 of
RT was significant different between the fasted and
fed conditions (P < 0Æ05) (Table 3). Subjects seemed
drowsier at 2 h in the fed condition (alert–drowsy
and clear headed–muzzy) of VAS (Fig. 5). There
were no differences in the other pharmacodynamic
measures of quazepam between the two conditions.
For nitrazepam and diazepam, RT and CFFT
showed no significant differences between the
fasted and fed conditions (Figs 4 and 6). On mental
sedation VAS and CFFT, subjects who were
Table 2. Pharmacokinetic parameters (mean ± SD) for nitrazepam, and diazepam and its metabolites under fasted and
fed conditions (n = 7)
Nitrazepam Diazepam N-desmethyl-diazepam
Fasted Fed Fasted Fed Fasted Fed
Cmax (ng/mL) 51Æ8 ± 4Æ6 52Æ0 ± 4Æ9 109Æ9 ± 28Æ4 107Æ0 ± 25Æ4 33Æ0 ± 7Æ8 29Æ9 ± 10Æ 2
Ratio; 90% CI 1Æ0; 1Æ0–1Æ1 1Æ0; 0Æ9–1Æ1 0Æ9; 1Æ0–1Æ4
Tmax (h) 1 (1–2) 2 (0Æ5–2)* 1 (0Æ5–2) 2 (1–3)* 72 (48–72) 72 (72–72)
AUClast (ngÆh/mL) 1401 ± 370 1383 ± 284 2411 ± 842 2272 ± 819 1911 ± 488 1732 ± 580
Ratio; 90% CI 1Æ0; 0Æ9–1Æ1 0Æ9; 1Æ0–1Æ2 0Æ9; 0Æ9–1Æ4
t1/2 (h) 37Æ2 ± 5Æ3 35Æ1 ± 5Æ4 38Æ3 ± 12Æ5 38Æ2 ± 12Æ7 NA NA
MTTlast (h) 26Æ1 ± 1Æ0 25Æ8 ± 1Æ0 25Æ6 ± 1Æ7 25Æ0 ± 2Æ2 41Æ1 ± 1Æ9 40Æ7 ± 1Æ4
For Cmax and AUClast, 90% confidence intervals (CIs) are determined for the ratios between fed and fasting states. Tmax is reported as
median and range. NA, not applicable.
*Difference from fasted condition at P < 0Æ05: significance was tested by paired t-test, except Tmax was tested by Wilcoxon’s matchedpairs
signed ranks.
Plasma diazepam (ng/mL)
0 5 10 15 20 25
Hours
0
20
40
60
80
120
100 Fasted
Fed
Fig. 3. Plasma concentration of diazepam after oral
administration of 5 mg diazepam under fasted and fed
conditions. Data are shown as mean and SEM (n = 7).
Plasma nitrazepam (ng/mL)
0 5 10 15 20 25
Hours
0
10
20
30
40
50
60
Fasted
Fed
Fig. 2. Plasma concentration of nitrazepam after oral
administration of 5 mg nitrazepam under fasted and fed
conditions. Data are shown as mean and SEM (n = 7).
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
Food and benzodiazepines interactions 35
administered nitrazepam seemed drowsier at 2 h
in both fasted and fed condition. Subjects who were
administered diazepam did not show this effect.
The tranquillization score VAS was not significantly
altered for any of the three drugs. Among
these drugs, the mental sedation VAS increased at
2 h in subjects who were administered quazepam
in fed condition and nitrazepam in both fed and
fasted conditions when compared with subjects
who were administered diazepam. Quazepam with
light food increased RT while nitrazepam
decreased the CFFT in both condition.
DISCUSSION
This study is a randomized, parallel dosing, twoway
crossover study to evaluate the effect of light
100
150
200
250
300
350
Reaction time (ms) Reaction time (ms) Reaction time (ms)
Fasted
Fed
100
150
200
250
300
350 Fasted
Fed
100
150
200
250
300
350 Fasted
Fed
Quazepam
Nitrazepam
Diazepam
*
*
0 5 10 15 20 25
Hours
0 5 10 15 20 25
Hours
0 5 10 15 20 25
Hours
Fig. 4. Reaction time of quazepam, nitrazepam and
diazepam under fasted and fed conditions. Data are
shown as mean and SD (n = 7). *Difference from fasted
condition at P < 0Æ05.
Table 3. Pharmacodynamic parameters (mean and range) for quazepam, nitrazepam and diazepam under fasted and fed conditions (n = 7)
Quazepam Nitrazepam Diazepam
Fasted Fed Fasted Fed Fasted Fed
RT
AUC0–10 (msÆh) 2275 (1912–2516) 2514* (2365–2686) 2510 (1869–3551) 2426 (2089–2890) 2343 (1979–2763) 2419 (1958–3157)
AUC0–24 (msÆh) 5496 (4766–6287) 5685 (5319–6285) 5714 (4300–7762) 5747 (4934–7202) 5482 (4927–6268) 5725 (4983–7355)
CFFT
AUC0–10 (HzÆh) 3Æ5 ()2Æ6 to 19Æ5) 3Æ4 ()8Æ8 to 18Æ2) )9Æ7 ()26Æ8 to 5Æ3) )6Æ8 ()18Æ2 to 4Æ1) )4Æ4 ()17Æ1 to 5Æ8) )3Æ1 ()24Æ7 to 10Æ0)
AUC0–24 (HzÆh) 13Æ8 ()4Æ3 to 46Æ3) 10Æ1 ()16Æ6 to 34Æ0) )13Æ1 ()54Æ2 to 14Æ6) )4Æ3 ()26Æ6 to 23Æ7) )10Æ8 ()49Æ2 to 30Æ9) )5Æ1 ()41Æ0 to 30Æ2)
RT, reaction time; CFFT, critical flicker fusion test.
*Difference from fasted condition at P < 0Æ05: significance was tested by paired t-test.
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
36 A. Yamazaki et al.
food on the pharmacokinetics and pharmacodynamics
of quazepam, nitrazepam and diazepam.
As quazepam is characterized by low solubility
and high fat-solubility, with increased absorption
with fatty meals, the absorption of quazepam was
influenced by food intake. Yasui-Furukori et al.
(4, 6) reported that Cmax and AUC of quazepam
increased 2Æ3-fold with a standard breakfast (fat
30Æ2 g; 660 kcal) or low-fat meal (fat 5Æ9 g; 440 kcal).
Kim et al. (7) also reported Cmax of quazepam 1Æ6-
fold higher with food. Dietary fat increases bile
secretion and gastrointestinal fluid volume, providing
a better dissolution medium for poorly dissolving
drugs (1, 2). This effect may explain the
increased Cmax and AUC. However, increased
bioavailability of drugs in the presence of food may
be due not only to fat content but also to protein
and carbohydrate contents (5). The present study
shows that a very low fat meal such a light food
may alter quazepam pharmacokinetics. The 90%
CI of the mean ratio for Cmax and AUClast in fed vs.
fasted subjects overlapped but extended beyond
the 0Æ8–1Æ25 region for bioequivalence (the 90% CIs
of Cmax and AUClast were 1Æ1–1Æ5 and 1Æ3–1Æ9,
respectively) (11). Other pharmacokinetic parameters,
Tmax, t1/2 and MTTlast were not different. This
study used a Japanese traditional healthy bedtime
snack, ‘otyaduke’, as a light food. It is reasonable to
assume that the light food which contained mainly
carbohydrates might increase release of bile salts
and lipolysis products. The presence of food may
also prolong gastric emptying period and increase
splanchnic blood flow.
For oral administration of diazepam, this study
results are similar to those previously observed.
Robert and Leff (12) reported the time to peak
20
30
40
50
60
70
80
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
VAS: mental (mm)
VAS: physical (mm) VAS: physical (mm) VAS: physical (mm)
VAS: mental (mm) VAS: mental (mm)
20
30
40
50
60
70
80
20
30
40
50
60
70
80
M1-Fasted M1-Fed
M2-Fasted M2-Fed
20
30
40
50
60
70
80
P1-Fasted P1-Fed
P2-Fasted P2-Fed
20
30
40
50
60
70
80
20
30
40
50
60
70
80
.
Nitrazepam Nitrazepam
Diazepam Diazepam
Quazepam Quazepam
Fig. 5. Mean visual analogue scores
(VAS) of quazepam, nitrazepam
and diazepam under fasted and fed
conditions. Data are shown as
mental sedation (M1: alert-drowsy
and M2: clear headed-muzzy;
0–100 mm) and physical sedation
(P1: well coordinated-clumsy and
P2: energetic-lethargic; 0–100 mm).
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
Food and benzodiazepines interactions 37
(Tmax) was longer with triglyceride oil 18 g and
6 oz of fat-free milk than with water. Greenblatt
et al. (8) also reported that administration of diazepam
with food resulted in longer Tmax (1Æ2 h).
However the food in this study was not identical.
The Tmax of both nitrazepam and diazepam
increased with food. This effect might be the result
of prolonged gastric emptying time and small
intestinal transit time due to the presence of food.
The major plasma metabolites of quazepam are
2-oxoquazepam, N-desalkyl-2-oxoquazepam, and
3-hydroxy-2-oxoquazepam (13). Quazepam is
metabolized by CYP2C19 (14) as is diazepam to its
major, pharmacologically active plasma metabolite,
N-desmethyl-diazepam (15–18). Nitrazepam is
mainly metabolized to its 7-amino-derivative and
7-acetamino-derivative by acetylation (19), both of
which are pharmacologically inactive (20). These
pathways are known to be polymorphic to 2-oxoquazepam
and N-desalkyl-2-oxoquazepam and
are pharmacologically active (21, 22). Hilbert et al.
(22) reported that brain concentrations of quazepam
and its metabolites paralleled plasma concentrations
following single oral doses in mice. As the pharmacokinetics
of these metabolites were no different
between the fasted and fed conditions, increased
plasma quazepam was probably responsible for the
observed differences in the psychomotor function
tests. Norris (9) reported that nitrazepam (7Æ5 and
10 mg) altered mental sedation on the VAS by
approximately 20–25 mm, and physical sedation by
15–20 mm from the baseline, 80 min after single
administration. Luurila et al. (23) reported that nitrazepam
5 mg altered the drowsiness scale by
approximately 20 mm at 2 h. Nitrazepam and diazepam
both had CNS-depressant effect as assessed
by CFFT in both of the fasted and fed conditions. No
significant difference was seen between the fasted
and fed conditions. Therefore it is reasonable to
assume that the drug can be given with light food as
used in this study. Food with a high fat, protein or
fiber content may yield different results. Greenblatt
et al. (24) reported that with diazepam administered
intravenously, clinical activity, measured using
computerized analysis of the electroencephalogram,
was maximal at the end of the infusion. Because of its
high lipid solubility and extensive peripheral distribution,
diazepam appears to have a short duration
of clinical action after intravenous administration.
For oral administration, the rate-limiting step for the
onset of clinical action generally is attributable to the
rate of absorption. Nitrazepam is also high lipid
soluble. The Tmax of both nitrazepam and diazepam
increased in the fed condition. In conclusion, light
food increased the bioavailability of quazepam and
altered psychomotor performance. Light food also
delayed the Tmax of nitrazepam and diazepam but
had no effect on Cmax and AUClast.
ACKNOWLEDGEMENTS
The authors thank the staff at Kitasato East Hospital,
Clinical trial center for their excellent work
during the clinical conduct of the study, Mr
Yoshimasa Inoue for technical support of HPLC
measurement.
–5
–4
–3
–2
–1
0
1
2
–5
–4
–3
–2
–1
0
1
2
–5
–4
–3
–2
–1
0
1
2
Changed in CFFT (Hz) Changed in CFFT (Hz) Changed in CFFT (Hz)
Fasted
Fed
Fasted
Fed
Fasted
Fed
Quazepam
Nitrazepam
Diazepam
0 5 10 15 20 25
Hours
0 5 10 15 20 25
Hours
0 5 10 15 20 25
Hours
Fig. 6. Change in scores from baseline in critical flicker
fusion test (CFFT) of quazepam, nitrazepam and diazepam
under fasted and fed conditions. Data are shown as
mean and SD (n = 7).
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
38 A. Yamazaki et al.
REFERENCES
1. Fleisher D, Li C, Zhou Y et al. (1999) Drug, meal and
formulation interactions influencing drug absorption
after oral administration. Clinical implications.
Clinical Pharmacokinetics, 36, 233–254.
2. Singh BN (1999) Effects of food on clinical pharmacokinetics.
Clinical Pharmacokinetics, 37, 213–255.
3. Mendels J (1991) Criteria for selection of appropriate
benzodiazepine hypnotic therapy. Journal of Clinical
Psychiatry, 52(Suppl.), 42–46.
4. Yasui-Furukori N, Takahata T, Kondo T et al. (2003)
Time effects of food intake on the pharmacokinetics
and pharmacodynamics of quazepam. British Journal
of Clinical Pharmacology, 55, 382–388.
5. Doose DR, Minn FL, Stellar S et al. (1992) Effects of
meals and meal composition on the bioavailability of
fenretinide. Journal of Clinical Pharmacology, 32, 1089–
1095.
6. Yasui-Furukori N, Kondo T, Takahata T et al. (2002)
Effect of dietary fat content in meals on pharmacokinetics
of quazepam. Journal of Clinical Pharmacology,
42, 1335–1340.
7. Kim Y, Morikawa M, Ohsawa H et al. (2003) Effects
of foods on the pharmacokinetics and clinical efficacy
of quazepam. Nihon Shinkei Seishin Yakurigaku
Zasshi, 23, 205–210.
8. Greenblatt DJ, Allen MD, MacLaughlin DS et al.
(1978) Diazepam absorption: effect of antacids and
food. Clinical Pharmacology and Therapeutics, 24, 600–
609.
9. Norris H (1971) The action of sedatives on brain stem
oculomotor systems in man. Neuropharmacology, 10,
181–191.
10. Bond A, Lader M (1974) The use of analogue scales
in rating subjective feeling. British Journal of Medical
Psychology, 47, 211–218.
11. FDA (1992) FDA guidelines. Rockville, MD: Bioequivalence
Food and Drug Administration, Division of
Bioequivalence, Office of Generic Drugs. 1 July.
12. Roberts RJ, Leff RD (1989) Influence of absorbable
and nonabsorbable lipids and lipidlike substances on
drug bioavailability. Clinical Pharmacology and
Therapeutics, 45, 299–304.
13. Zampaglione N, Hilbert JM, Ning J et al. (1985)
Disposition and metabolic fate of 14C-quazepam in
man. Drug Metabolism and Disposition, 13, 25–29.
14. Fukasawa T, Yasui-Furukori N, Aoshima T et al.
(2004) Single oral dose pharmacokinetics of quazepam
is influenced by CYP2C19 activity. Therapeutic
Drug Monitoring, 26, 529–533.
15. Schwartz MA, Koechlin BA, Postma E et al. (1965)
Metabolism of diazepam in rat, dog, and man. Journal
of Pharmacology and Experimental Therapeutics, 149,
423–435.
16. De Morais SM, Wilkinson GR, Blaisdell J et al. (1994)
Identification of a new genetic defect responsible for
the olymorphism of (S)-mephenytoin metabolism in
Japanese. Molecular Pharmacology, 46, 594–598.
17. Bertilsson L, Henthorn TK, Sanz E et al. (1989)
Importance of genetic factors in the regulation of
diazepam metabolism: relationship to S-mephenytoin,
but not debrisoquin, hydroxylation phenotype.
Clinical Pharmacology and Therapeutics, 45, 348–355.
18. Dasberg HH (1975) Effects and plasma levels of Ndesmethyldiazepam
after oral administration in
normal volunteers. Psychopharmacologia, 43, 191–198.
19. Sawada H, Shinoara K (1971) On the urinary excretion
of nitrazepam and its metabolites. Archiv fu¨ r
Toxikologie, 28, 214–221.
20. Rieder J (1973) Plasma levels and derived pharmacokinetic
characteristics of unchanged nitrazepam in
man. Arzneimittel-Forschung, 23, 212–218.
21. Sieghart W (1983) Several new benzodiazepines
selectively interact with a benzodiazepine receptor
subtype. Neuroscience Letters, 38, 73–78.
22. Hilbert JM, Iorio L, Moritzen V et al. (1986) Relationships
of brain and plasma levels of quazepam,
flurazepam, and their metabolites with pharmacological
activity in mice. Life Sciences, 39, 161–168.
23. Luurila H, Olkkola KT, Neuvonen PJ (1995) Interaction
between erythromycin and nitrazepam in healthy
volunteers. Pharmacology and Toxicology, 76, 255–258.
24. Greenblatt DJ, Ehrenberg BL, Gunderman J et al.
(1989) Kinetic and dynamic study of intravenous
lorazepam: comparison with intravenous diazepam.
Journal of Pharmacology and Experimental Therapeutics,
250, 134–140.
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
Food and benzodiazepines interactions 39