Veterinary Anaesthesia and Analgesia, 2006, 33, 266–273 doi:10.1111/j.1467-2995.2005.00266.

RESEARCH PAPER

Pharmacokinetics of fentanyl after single intravenous

injection and constant rate infusion in dogs

Tadashi Sano* DVM, PhD, Ryohei Nishimura* DVM, PhD Hideko Kanazawa  PD, Eri Igarashi  PD, Yoshiko Nagata 
PD, Manabu Mochizuki* DVM, PhD & Nobuo Sasaki* DVM, PhD
*Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo,
Japan
 Laboratory of Physical Pharmaceutical Chemistry, Kyoritsu College of Pharmacy, Tokyo, Japan

Correspondence: Tadashi Sano, Laboratory of Veterinary Radiology and Radiation Biology, Department of Veterinary Medicine, Kitasato
University School of Veterinary Medicine, Higashi 23 Bancho 35-1, Towada, Aomori 034-8628, Japan. E-mail: tsano@vmas.kitasato-u.ac.jp

Sciences (Kyoto University) in Visual Basic (VBA)

Abstract
Objective To determine the plasma concentration
and define the pharmacokinetic characteristics of
fentanyl (10 lg kg)1) administered as a single
intravenous (IV) injection followed by: (a) no
further drug; or (b) a constant rate infusion (CRI)
of fentanyl 10 lg kg)1 hour)1 lasting 1, 3 or
4 hours in dogs.
Animals Fourteen healthy adult beagles (seven
males and seven females).
Experimental design Randomized cross-over design.
Materials and methods Dogs were randomly
assigned to four treatment groups. Drugs were
administered to each dog in a randomized cross-
over design with at least a 14-day washout
interval between experiments. All dogs received
an IV loading dose of fentanyl (10 lg kg)1). One
group received no further fentanyl. In others, the
loading dose was followed by a CRI of fentanyl
(10 lg kg)1 hour)1) for 1, 3 or 4 hours. Blood
samples were collected and plasma fentanyl con-
centrations determined using high-performance
liquid chromatography–mass spectrometry. Plasma
pharmacokinetic estimates were obtained by plot-
ting plasma concentrations versus time data and by
fitting the change in concentration to a pharma-
cokinetic model, using a purpose-built program
written by the Graduate School of Pharmaceutical
on Excel (Microsoft Corporation).
Results Plasma fentanyl concentration decreased
rapidly after single IV injection: the plasma concen-
tration–time curve best fitted a two-compartment
model. Pharmacokinetic variables for IV injection
were characterized by a short distribution half-time
(t1/2a was 4.5 minutes), a relatively long elimination
half time (t1/2b was 45.7 minutes), a large volume of
distribution (approximately 5 L kg)1) and high total
body clearance (77.9 mL minute)1 kg)1). Stable
plasma fentanyl levels were obtained in all CRI
groups although pharmacokinetic variables were
influenced by the duration of administration.
Conclusions and clinical relevance While this study
clarified the pharmacokinetic features of rapid IV
fentanyl injection and CRI in dogs, the plasma concen-
tration achieving analgesia was not and so further
research is needed. Further studies on the effects of
other sedatives and/or anaesthetics on fentanyl’s
disposition are also required as the drug is commonly
used with other agents.
Keywords constant rate infusion, dogs, fentanyl,
pharmacokinetics.
Introduction
Nociceptive stimulation by surgery may still induce
autonomic nervous system responses during

266
 Pharmacokinetics of fentanyl after single IV injection T Sano et al.
general anaesthesia with volatile or injectable
anaesthetics (Pascoe 2000) in which case additional
analgesia is required. Additional analgesia is also
required during total intravenous (IV) anaesthesia
because injectable anaesthetics like propofol have
weak or no analgesic effects (Smith et al. 1994).
Opioids are widely used to improve analgesia during
general anaesthesia.
Fentanyl citrate (N-phenylethyl-N-[1,2-phenyl-
ethyl 4-piperidyl] propanamide) has a high affinity
and intrinsic action at the opioid receptor (Villiger
et al. 1983; Boas & Villiger 1985). The drug’s
characteristics include a rapid onset and short
duration of action with a relative analgesic potency
of 75–100 times that of morphine (Yaksh et al.
1986). It has fewer adverse side effects, e.g. respir-
atory depression, overt sedation, and dysphoria
when compared with morphine in dogs (Freye et al.
1991). A single injection of fentanyl is commonly
used to produce short-duration analgesia during
anaesthesia. To prolong this effect, the drug must be
repeatedly injected at regular intervals – which may
cause respiratory depression (Yaksh et al. 1986;
Freye et al. 1991; Duke et al. 1994a,b) – or be
continuously infused. Pharmacokinetic information
is desirable because it allows the optimal dose for
obtaining adequate and stable plasma levels to be
determined. The pharmacokinetic characteristics of
fentanyl after single injections and/or infusions
have been studied in humans (McClain & Hug
1980; Shafer & Varvel 1991). Fentanyl accumula-
tion after constant rate infusion (CRI) exceeding
2 hours has also been reported in humans (Hughes
et al. 1992). Although pharmacokinetic studies of
fentanyl after a single injection indicate that the
pharmacokinetic characteristics are dose independ-
ent in dogs (Murphy et al. 1983), the pharmaco-
kinetics during and after CRI in dogs remain unclear.
This study was conducted to determine serial
blood fentanyl concentrations in dogs and to define
the drug’s pharmacokinetic characteristics after
single injection alone or after single injection
followed by CRIs applied for 1, 3 or 4 hours.
Materials and methods
Animals
This study was conducted in accordance with the
guidelines provided by the Animal Care Committee
of the Graduate School of Agricultural and Life
Sciences at the University of Tokyo. Fourteen heal-
 2006 Association of Veterinary Anaesthetists, 33, 266–273
thy (based on physical and haematological exam-
ination) 1- to 2-year-old beagles (seven males and
seven females; mean 1.3 year) with a body mass of
6.4–14.0 kg (mean 8.9 kg) were studied. They were
housed in individual cages maintained at constant
temperature and humidity. They were given food
once daily and were allowed free access to water.
Food was withheld for at least 12 hours before each
experiment.
The dogs were randomly assigned to four treat-
ment groups of six dogs each. Each dog was used in
one or two experiments in different treatment
groups. The interval between successive experi-
ments on the same dog was at least 14 days.
Administration of fentanyl
The four experimental groups were based on a
loading fentanyl dose, followed by: (a) no further
drug; or (b) one of three CRIs lasting 1, 3 or
4 hours. The CRI was determined as in previous
studies (Murphy et al. 1979, 1983, ). Group A dogs
received a single IV injection of 10 lg kg)1 fentanyl
(Fentanest; Sankyo Co. Ltd, Tokyo, Japan) via a
catheter placed in the cephalic vein. Blood samples
(2.5 mL) were collected from the catheter before
and 2.5, 5.0, 7.5, 10.0, 12.5, 15.0, 17.5, 20, 30,
45, 60, 90, 120, 180 and 240 minutes after fent-
anyl administration. In the other groups, fentanyl,
10 lg kg)1 IV, was followed by a CRI at
10 lg kg)1 hour)1 maintained for 1 (group B), 3
(group C) or 4 (group D) hours. The combination of
a 10 lg kg)1 loading dose and a CRI of
10 lg kg)1 hour)1 investigated in this study was
based upon pharmacokinetic variables reported by
Holley & van Steennis (1988) previously. The blood-
sampling interval in dogs receiving CRIs depended
on the infusion time. In group A, 2.5 mL blood was
collected before the loading dose, 1, 5, 10, 20, 40
and 60 minutes after the start of infusion, and 2, 5,
10, 30, 45, 60, 120, 240, 360 and 480 minutes
after the end of infusion. In the 3-hour infusion
group, blood was collected at 80, 100, 120, 150
and 180 minutes after the start of infusion in
addition to those times listed for group B. In group
D, blood was also collected 210 and 240 minutes
after the start of infusion in addition to those times
listed for group C.
Blood samples were collected into heparinized
tubes and centrifuged at 1560 g for 10 minutes.
Plasma was harvested, placed in cryogenic storage
vials and frozen at )80
C until analysis.
267
Pharmacokinetics of fentanyl after single IV injection T Sano et al.
Fentanyl assay
Plasma fentanyl concentration was analysed using
high-performance liquid chromatography–mass
spectrometry (HPLC/MS). Each plasma sample
(400 lL) was applied to an Extraction Disk C18
cartridge (Empore; 3M Co. Ltd, Tokyo, Japan) pre-
treated with methanol, water and 20 mM ammo-
nium acetate (pH 4.8). After washing the column
with 3 mL of 20 mM ammonium acetate, fentanyl
was eluted with 1 mL of methanol and the elute
was evaporated under reduced pressure. The
residue was dissolved in 40 lL of mobile phase
and then 5 lL of this solution was injected into
the HPLC system. In this study an HPLC system
(L-8000 Hitachi, Tokyo, Japan) connected to a
mass spectrometer computer system (M-7000 Hi-
tachi, Tokyo, Japan) through the SSI interface
(L-8000 Hitachi; Tokyo, Japan) was used. The
chromatographic separation was carried out on
an ODS column of hydrosphere (YMC-Pack Pro
semi micro column; 150 · 146 mm ID, Kyoto,
Japan) using methanol:20 mM ammonium acetate
(60:40) as the mobile phase. The system was
operated at ambient temperature at a flow of
0.2 mL minute)1. The drift voltage of SSI was
60 V, and the shield temperature and sampling
aperture were 200 and 110
C respectively. The
lowest limit of this assay system for detection of
fentanyl was 50 pg mL)1.
Pharmacokinetic analysis
Plasma pharmacokinetic estimates were obtained
by plotting plasma concentrations versus time data
and by fitting the change in concentration to a
pharmacokinetic model. Curve fitting was per-
formed with an interactive least–squares approach,
using the computer program MULTI (free software
based on the Microsoft Excel; provided by Graduate
school of Pharmaceutical Sciences, Faculty of
Pharmaceutical Sciences, Kyoto University, Kyoto,
Japan) (Yamaoka et al. 1981). Area under the
curve (AUC) was calculated using the log-trapezoi-
dal method and adding the estimated terminal
portion of the curve. Clearance, distribution volume
and microdistribution rate constants were calcula-
ted on the basis of the AUC and the variables for the
aforementioned equation.
In the CRI groups, clearance and volume of
distribution were calculated by moment-analysis
using MULTI.
268
Statistical analysis
Values are expressed as the mean ± standard devi-
ation. One-way factorial analysis of variance (one-
factor ANOVA) was performed for comparison of
pharmacokinetic variables among the infusion
groups. When a statistically significant difference
was detected, these variables were analysed using
the Bonferroni’s/Dunn method. Values of p < 0.05
were considered statistically significant.
Results
Bolus administration
Plasma fentanyl concentrations of 5.0 ng mL)1
which were achieved approximately 2.5 minutes
after IV injection, rapidly decreased for the first
20 minutes and more slowly thereafter. The plasma
concentration–time curve was derived from two
exponential functions (Fig. 1). The data were best
fitted to a two-compartment open model using the
formula:
t t
Ct ¼ Ae
a þ Be
b
where Ct is the plasma concentration at time t, A the
intercept, a the rate constant for the initial steep
(disposition) portion of the curve, B the intercept
and b the rate constant for the terminal (elimin-
ation) portion of the curve. The pharmacokinetic
variables of a single fentanyl injection (10 lg kg)1)
are shown in Table 1. The decrease in plasma
fentanyl concentration was rapid, with a distribu-
tion half-time (t1/2a) of 1.9–6.2 minutes (mean
4.5 minutes) and an elimination half-time (t1/2b)
of 30.6–55.2 minutes (mean 45.7 minutes). The
distribution volumes expressed as V1 (volume of
distribution at central compartment) and Vdb
(volume of distribution at elimination phase) were
870–1940 mL kg)1 (mean 1500 mL kg)1) and
3835–6186 mL kg)1 (mean 4939 mL kg)1)
respectively. Total body clearance (TBCL)
was 48.1–110.3 mL minute)1 kg)1 (mean
77.9 mL minute)1 kg)1).
Constant rate infusion
Changes in plasma fentanyl concentration are
shown in Figs 2–4 and the pharmacokinetic varia-
bles in the CRI group are shown in Table 2. In
group D, the IV administration of fentanyl caused
an initial rise in plasma concentration after which
 2006 Association of Veterinary Anaesthetists, 33, 266–273
 Pharmacokinetics of fentanyl after single IV injection T Sano et al.

10

log fentanyl concentration (ng ml–1)

1

0.1

Figure 1 Plasma fentanyl concentra- 0.01

0 20 40 60 80 100 120 140 160 180 200 220 240
tion changes after rapid IV injection
of 10 lg kg)1 in conscious dogs. Time after administation (minutes)

Table 1 Pharmacokinetic parameters of fentanyl after cantly different in any CRI group, but TBCL was
rapid intravenous injection (10 lg kg)1) in conscious dogs significantly higher in group B compared with those
in groups C and D.
A (ng mL)1) zero-time intercept of distribution 5.6 ± 2.2
phase adjusted by method of residuals
B (ng mL)1) zero-time intercept of elimination 1.5 ± 0.2
Discussion
phase
In this study, plasma fentanyl concentrations
a (minute)1) distribution phase rate-constant 0.18 ± 0.09
b (minute)1) elimination phase rate-constant 0.02 ± 0.004
decreased rapidly for approximately 20 minutes
V1 (mL kg)1) apparent volume of the central 1500.0 ± 400 after IV administration and then more gradually.
compartment Plasma fentanyl concentrations best fitted a two-
Vdb (mL kg)1) apparent volume of distribution 4939.2 ± 859 compartment open model consisting of two lines, in
at the b phase
which the initial rapid decrease in plasma concen-
AUC (ng mL)1 minute)1) area under the blood 137.9 ± 41.9
concentration versus time curve
tration is caused mainly by drug redistribution from
t1/2a (minutes) half-life of distribution phase 4.5 ± 1.5 the central to the peripheral compartment, with
t1/2b (minutes) half-life of elimination phase 45. ± 8.6 subsequent changes resulting from drug redistri-
TBCL (mL minute)1 kg)1) total body clearance 77.9 ± 22.3 bution and elimination from the body. It has been
of fentanyl
reported elsewhere that the pharmacokinetics of
k12 0.09 ± 0.026
k21 0.05 ± 0.007
fentanyl are best fitted to two-compartment models
kel 0.05 ± 0.029 in rats and three-compartment models in humans,
dogs and cats (Murphy et al. 1979; McClain & Hug
Values are given as mean ± SD. 1980; Hug & Murphy 1981, Shafer & Varvel 1991,
Kxy (minute)1) microrate constant (rate of drug transfer from Lee et al. 2000). However, the number of com-
compartment x to y). partments involved also depends on the frequency
of blood sampling (Adam et al. 1980). The distri-
the level decreased until 60 minutes after the start bution volume (Vd) of fentanyl in group A was
of infusion. The concentration then remained rel- relatively large and similar to that reported else-
atively stable, increasing slightly for 3 hours until where in dogs (Murphy et al. 1979, 1983, ). This
the end of infusion. During that period, plasma large value indicates that fentanyl diffuses rapidly
fentanyl concentration remained between 0.8 and throughout body tissues or binds to tissues other
1.5 ng mL)1 (mean 1.0–1.3 ng mL)1). In groups B than plasma. Distribution half-time (t1/2a) in group
and C, the changes in plasma fentanyl concentra- A was short and similar to times previously repor-
tions were similar to those in group D until the end ted in dogs (Murphy et al. 1979, 1983), humans
of infusion, when the fentanyl concentration de- (Bovill & Sebel 1980) and rats (Hug & Murphy
creased rapidly for a short while before decreasing at 1981). The short t1/2a indicates that fentanyl dis-
a more gradual rate in all the CRI groups. Compared appears rapidly from the effect site after rapid IV
with group A, t1/2a, t1/2b and Vdss were not signifi- injection.

 2006 Association of Veterinary Anaesthetists, 33, 266–273 269

Pharmacokinetics of fentanyl after single IV injection T Sano et al.

10
log fentanyl concentration (ng ml )
–1

0.1

Fentanyl
Figure 2 Plasma fentanyl concentra-
infusion tion changes in conscious dogs
after rapid intravenous injection of
0.01
0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440 460 480 500 520 540 10 lg kg)1 followed by infusion
Time after administration (minutes) (10 lg kg)1 hour)1) for 1 hour.

10
log fentanyl concentration (ng ml–1)

0.1

Figure 3 Plasma fentanyl concentra-

Fentanyl infusion tion changes in conscious dogs
0.01 after rapid intravenous injection of
0 40 80 120 160 200 240 280 320 360 400 440 480 520 560 600 640 10 lg kg)1 followed by infusion
Time after administration (minutes) (10 lg kg)1 hour)1) for 3 hours.

10
log fentanyl concentration (ng ml–1)

0.1

Figure 4 Plasma fentanyl concentra-

Fentanyl infusion
tion changes in conscious dogs
0.01
after rapid intravenous injection of
0 40 80 120 160 200 240 280 320 360 400 440 480 520 560 600 640 680 720 10 lg kg)1 followed by infusion
Time after administration (minutes) (10 lg kg)1 hour)1) for 4 hours.

Total body clearance is an important pharmaco- (10 mL kg)1 minute)1) in dogs. This indicates that
kinetic parameter that represents the body’s ability fentanyl may be metabolized in extra hepatic sites
for drug elimination. In this study, fentanyl TBCL in and eliminated by extra renal routes in addition to
group A was approximately 80 mL kg)1 minute)1, hepatic metabolism through N-dealkylation and
which exceeds the sum total of hepatic hydroxylation (Clotz & Nahata 1991; Rajan et al.
(40 mL kg)1 minute)1) and renal blood flow 1998). A first pass by pulmonary uptake (approxi-

270  2006 Association of Veterinary Anaesthetists, 33, 266–273

 Pharmacokinetics of fentanyl after single IV injection T Sano et al.
Table 2 Pharmacokinetic properties
of fentanyl in conscious dogs receiv-
ing single fentanyl injection
(10 lg kg)1 IV) (group A) followed t1/2a (minutes)
by a controlled rate infusion t1/2b (minutes)
(10 lg kg)1 hour)1) for 1 (group Total body clearance
B), 3 (group C) or 4 hours (group D) (mL minute)1 kg)1)
End-infusion plasma
fentanyl concentration
(ng mL)1).
Vdss (mL kg)1)
Values are given as mean ± SD.
*Statistical significance (p < 0.05) was observed compared with group A; †Statistical
significance (p < 0.05) was observed compared with group B.
mately 75% of administered fentanyl) has been
reported in humans. A small amount of unchanged
fentanyl is eliminated in the urine and faeces in rats
(Hug & Murphy 1981; Mather 1983; Roerig et al.
1987).
The elimination half-time (t1/2b) in group A was
relatively short and similar to times previously
reported in dogs (Murphy et al. 1979, 1983),
humans (Bovill & Sebel 1980) and rats (Hug &
Murphy 1981). The t1/2b is related to drug
elimination from the body and is mainly influenced
by the rate of elimination or TBCL. The result
obtained here suggests that fentanyl is excreted in a
comparatively short time after IV administration in
dogs.
In group B, plasma fentanyl concentrations did
not reach stable levels, while in groups C and D,
they were relatively stable and remained between
0.2 and 1.8 ng mL)1 (mean 0.9–1.3 ng mL)1)
from about 80 minutes after the start of CRI until
the end of infusion. The optimal plasma fentanyl
concentration for analgesia has been reported to be
0.9–2.0 ng mL)1 in humans and dogs (Holley &
van Steennis 1988; Varvel et al. 1989; Robinson
et al. 1999). The combination of a 10 lg kg)1
loading dose followed by a CRI of 10 lg kg)1
investigated in this study might be a guideline for
a CRI dose of fentanyl during general anaesthesia to
provide analgesia in dogs. Because of its large
distribution volume, loading doses of fentanyl are
necessary for establishing early effective and stable
plasma levels. The loading dose used in this study
was much greater than that used in humans (Holley
& van Steennis 1988). The optimal fentanyl level
described above in humans was established by using
loading doses of 1.0–4.0 lg kg)1 followed by CRIs
of 1.0 lg kg)1 hour)1. One study showed that dogs
 2006 Association of Veterinary Anaesthetists, 33, 266–273
Group A Group B Group C Group D
4.5 ± 1.5 30.5 ± 24.3 51.6 ± 35.5* 41.1 ± 32.2*
45.7 ± 8.6 151.1 ± 61.0* 182.1 ± 68.1* 157.1 ± 87.5*
77.9 ± 22.3 61.9 ± 4.6 46.9 ± 7.5† 47.9 ± 16.4†
1.01 ± 0.7 1.11 ± 0.4 1.25 ± 0.7
4774.0 ± 253.8 4382.5 ± 385.5 4040.4 ± 260.3
are less sensitive to opioid analgesics than humans
(Murphy et al. 1979). In addition, the analgesic
plasma concentration required depends on the
surgery to be performed. Further investigations
including the pharmacokinetic changes caused by
drugs given concomitantly are required to deter-
mine the optimal dose of fentanyl in dogs under-
going surgery.
In this study, the plasma fentanyl concentration
remained relatively stable during CRI for the first
4 hours. It has been reported that plasma fentanyl
concentration increases rapidly after CRI exceeding
3 hours in humans, even at low infusion rates
(Hughes et al. 1992). Fentanyl accumulation is
thought to account for this (Hughes et al. 1992). In
contrast, plasma fentanyl concentration remained
stable and Vdss did not change significantly even
after CRI for 4 hours in this study. Fentanyl is
widely distributed to peripheral tissues even after
prolonged infusions in dogs, although concentra-
tions increased gradually, even in this study.
Target-controlled infusion using a computer system
(Saijo et al. 2001) may be a more suitable way
of obtaining more stable plasma fentanyl levels
rapidly.
After the cessation of CRI in groups B, C and D,
values for t1/2a were greater than that in group A.
The t1/2a indicates the rate of fentanyl disappear-
ance from the effect site and depends on clearance
and distribution volume. In this study, the volume
of distribution did not change statistically in any
CRI group, but the TBCL changed in the 3- and
4-hour CRI groups. This indicates that analgesia
may be sustained for longer periods after CRI
discontinuation when infusion doses of
10 lg kg)1 hour)1 are administered for more than
3 hours.
271
Pharmacokinetics of fentanyl after single IV injection T Sano et al.
Total body clearance in the 3- and 4-hour CRI
groups was significantly lower than that found in
Groups A and B. Hepatic metabolism, which is the
principal determinant of clearance, depends on
hepatic blood flow and hepatic enzyme activity
(Clotz & Nahata 1991; Rajan et al. 1998). However,
extra hepatic factors contribute to falling plasma
concentrations. Reduced hepatic blood flow occurs
during cumulative administration of fentanyl in
dogs (Hayashi 1998). In this study, hepatic blood
flow may have been reduced during 3 and 4 hours
of infusion. Values for TBCL obtained in this
study were larger than those reported previously
in dogs (Murphy et al. 1979) even in group D. The
pharmacokinetic data reported previously were
obtained under general anaesthesia with enflurane,
which reduces arterial blood pressure and cardiac
output in dogs (Mutoh et al. 1997) and which may
reduce hepatic blood flow and therefore, drug
metabolism. Fentanyl is used to provide additional
analgesia during the administration of volatile
agents. Further investigation is needed to elucidate
the effects of anaesthetics on fentanyl metabolism
in dogs.
The t1/2b in each of the CRI group was longer
than that in group A. The t1/2b is strongly related to
drug elimination and can be predicted from the
TBCL. Although other pharmacokinetic factors such
as Vd and drug accumulation might have affected
t1/2b in the CRI groups in the current study, the
most important factor was considered to be changes
in TBCL.
This study confirms previous accounts of fenta-
nyl’s pharmacokinetic properties after IV adminis-
tration and CRI in dogs. Changes in plasma
concentration after IV administration were best
fitted to a two-compartment model. Pharmaco-
kinetic variables like short half-times, large distri-
bution volumes and clearances were similar to those
previously reported. The study demonstrates that
fentanyl is excreted in a comparatively short time
after IV injection which indicates that alternative
administration methods, e.g. repeated administra-
tion and/or CRI must be used to achieve prolonged
analgesia. Plasma fentanyl concentrations re-
mained relatively stable in the CRI groups, which
indicates the suitability of this technique. However,
plasma fentanyl concentration increased gradually
and pharmacokinetic variables were influenced by
the duration of infusion. The optimum plasma
fentanyl concentration for true satisfactory anal-
gesia has not been established in dogs. Further
272
research is needed to determine how these levels
may be achieved and the influence of other varia-
bles, e.g. co-administered drugs.
Acknowledgements
The authors thank professor N. Sasaki and associate
professor R. Nishimura and co-workers in Labora-
tory of Veterinary Surgery, Graduate School of
Agricultural and Life Sciences, the University of
Tokyo and associate professor H. Kanazawa and
assistant Y. Nagata and co-workers in Laboratory
of Physical Pharmaceutical Chemistry, Kyoritsu
College of Pharmacy.
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