J. vet. Pharmacol. Therap. 39, 40--44. doi: 10.1111/jvp.12239.

Pharmacokinetics of cefuroxime after intravenous, intramuscular, and

subcutaneous administration to dogs
G. A. ALBARELLOS*
L. MONTOYA*
P. M. LORENZINI*

Albarellos, G. A., Montoya, L., Lorenzini, P. M., Passini, S. M., Lupi, M. P.,
Landoni, M. F. Pharmacokinetics of cefuroxime after intravenous,
intramuscular, and subcutaneous administration to dogs. J. vet. Pharmacol.
Therap. 39, 4044.

S. M. PASSINI*
M. P. LUPI* &
M. F. LANDONI
*C
atedra de Farmacolog
a, Facultad de
Ciencias Veterinarias, Universidad de
Buenos Aires, Buenos Aires, Argentina;

C
atedra de Farmacolog
a, Facultad de

Ciencias Veterinarias, Universidad Nacional
de La Plata, Buenos Aires, Argentina

Cefuroxime pharmacokinetic profile was investigated in 6 Beagle dogs after

single intravenous, intramuscular, and subcutaneous administration at a dosage of 20 mg/kg. Blood samples were withdrawn at predetermined times over
a 12-h period. Cefuroxime plasma concentrations were determined by HPLC.
Data were analyzed by compartmental analysis. Peak plasma concentration
(Cmax), time-to-peak plasma concentration (Tmax), and bioavailability for the
intramuscular and subcutaneous administration were (mean
SD) 22.99

7.87 lg/mL, 0.43
0.20 h, and 79.70
14.43% and 15.37
3.07 lg/
mL, 0.99
0.10 h, and 77.22
21.41%, respectively. Elimination half-lives
and mean residence time for the intravenous, intramuscular, and subcutaneous administration were 1.12
0.19 h and 1.49
0.21 h; 1.13
0.13
and 1.79
0.24 h; and 1.04
0.23 h and 2.21
0.23 h, respectively.
Significant differences were found between routes for Ka, MAT, Cmax, Tmax,
t(a), and MRT. T > MIC = 50%, considering a MIC of 1 lg/mL, was 11 h for
intravenous and intramuscular administration and 12 h for the subcutaneous route. When a MIC of 4 lg/mL is considered, T > MIC = 50% for intramuscular and subcutaneous administration was estimated in 8 h.
(Paper received 15 December 2014; accepted for publication 22 April 2015)
Gabriela A. Albarellos, C
atedra de Farmacolog
a, Facultad de Ciencias Veterinarias,
Universidad de Buenos Aires, Chorroar
n 280 (1427), Buenos Aires, Argentina.
E-mail: albarell@fvet.uba.ar

INTRODUCTION
Cefuroxime is a second-generation cephalosporin with a
broader spectrum of activity. It is active against many grampositive (e.g., staphylococci and streptococci), gram-negative
(Enterobacteriaceae), and some anaerobes bacteria (Prescott,
2013). Although there is no information on cefuroxime susceptibility of bacteria isolated from animals, reports from
human medicine indicate that cefuroxime minimum inhibitory
concentration (MIC) could be as low as 0.015 lg/mL (MIC90
for S. pyogenes) (Dohar et al., 2004). However, it is usually
higher for other bacteria (MIC90 for staphylococci: 1 lg/mL
and MIC90 for E. coli: 4 lg/mL) (von Eiff et al., 2005; Lerma
et al., 2008). Susceptibility break point for human isolates is
0.5 lg/mL for Streptococcus pneumoniae and 8 lg/mL for Enterobacteriaceae (CLSI, 2014).
Efficacy of cephalosporins is related to the time that plasma
concentrations exceed the MIC, and a T > MIC of 4060% of
the dosing interval is the best efficacy predictor for assuring

40

therapeutic success (Craig, 1998; Turnidge, 1998; Toutain

et al., 2002; McKellar et al., 2004).
Cefuroxime pharmacokinetics has been studied in humans
(Foord, 1976; Bundtzen et al., 1981), laboratory animals (Ryan
et al., 1976; Ruiz-Carretero et al., 2000; Zhao et al., 2012a),
goats (Abo El-Sooud et al., 2000; Prawez et al., 2001, 2004),
buffalo calves (Chaudhary et al., 1999), calves (Soback et al.,
1989), and dogs (Zhao et al., 2012b). After i.v. administration,
cefuroxime is rapidly and widely distributed into the extravascular fluid, with a fast elimination by renal mechanisms (glomerular filtration and tubular secretion). It has a very short
elimination half-life (1 h) (Soback et al., 1989; Abo El-Sooud
et al., 2000; Ruiz-Carretero et al., 2000; Zhao et al., 2012b),
and therefore, it requires frequent administrations.
In human medicine, cefuroxime is used for the treatment of
lower respiratory tract infections, urinary, and other soft tissue infections caused by susceptible bacteria. Cefuroxime could
be a useful tool for the treatment of similar infections in
companion animals medicine.

2015 John Wiley & Sons Ltd

Cefuroxime pharmacokinetics in dogs 41

Extravascular parenteral administration routes, such as

intramuscular (i.m.) or subcutaneous (s.c.), have in small animal practice some advantages compared to intravascular
routes. They are easier to administer, enabling ambulatory
treatment and, for some antibiotics, could extend plasma concentrations allowing longer dosage intervals.
To authors knowledge, there are no pharmacokinetic studies
on cefuroxime after intramuscular or subcutaneous administration in dogs; therefore, the aim of this study was to describe
cefuroxime pharmacokinetic after i.v., i.m., and s.c. administration in this species.

was separated by centrifugation (15 min at 3500 g) and stored

at 20 C until analysis.
Blood sampling schedule was the same on the three phases
of the study.
Cefuroxime determination

Experimental animals were six adult Beagle dogs, 4 females, and

2 males, weighing 12.50
1.38 kg. All dogs were healthy as
determined by clinical examination, complete blood and serum
biochemical analysis and urinalysis. Animals were housed in
the UBA Faculty of Veterinary Medicine facilities and allowed to
acclimatize for 2 months before the experiment. Access to standard commercial dry food (Purina ProPlan, Nestl
e Argentina
S.A., Buenos Aires, Argentina) and water was ad libitum.
All animal procedures were approved by the Institutional
Animal Care and Use Committee, School of Veterinary, University of Buenos Aires, Argentina.

Plasma cefuroxime concentrations were determined by HPLC

according to the technique described by Al-Said et al.
(2000). Briefly, 0.1 ml of 12.5% trichloroacetic acid was
added to 0.4 ml of sample containing 20 lL of a 1000 lg/mL
cephalexin solution (internal standard). The contents of the
tube were mixed and then centrifuged at 3500 g for
10 min. A 50-lL aliquot was injected onto an HPLC system
comprising an isocratic solvent delivery system (Thermo
Scientific Dionex UltiMate, HPG-3200SD, Sunnyvale, CA,
USA) and a variable UV/Vis detector (UV Visible MultiLength 151, Gilson Inc., WI, USA). The chromatograph consisted of a 125 9 4 mm, 5 lm LiChroCART (Merck KGaA,
Darmstadt, Germany) RP C18 column. The mobile phase
was acetonitrile and 0.05 M potassium dihydrogen phosphate
buffer (pH 4) (10:90). The flow rate was 2.0 mL/min and
detection wavelength 280 nm.
Cefuroxime standard curve was linear between 0.4 and
50 lg/mL, and the low limit of quantification (LLOQ) was
0.4 lg/mL. Intraday and interday LLOQ coefficient of variation
were 1.6% and 2.3%, respectively.

Dosage forms

Pharmacokinetic analysis

An aqueous 10% cefuroxime sodium salt solution (Cefurox

1.5 g; GlaxoSmithKline, Victoria, Buenos Aires, Argentina)
was used. The formulation was prepared according to manufacturers instructions. Cefuroxime was administered i.v., i.m.,
and s.c. at a dosage of 20 mg/mL.

Individual cefuroxime plasma concentration vs. time curves

was analyzed with a computer software (Phoenix WinNonlin 6.3, 20052012, Certara, L.P., Princeton, NJ, USA). Initial
estimates were determined using the residual method (Gibaldi
& Perrier, 1982) and refitted by nonlinear regression.
The number of exponents needed for i.v., i.m., and s.c.
administration data was determined by applying the Schwartz
(Schwartz, 1978) and Akaike criterions (Yamaoka et al.,
1978), and the residual distribution around the estimated concentrations.
Most pharmacokinetic parameters were calculated using
classic equations associated with compartmental analysis (distribution half-life, t(d); elimination half-life, t; absorption halflife, t(a); microrate constants; intercepts; and rate constants)
and noncompartmental methods (total body clearance, ClB;
area under the curve from time 0 to time, AUC(0t); area under
the curve from time 0 to infinity, AUC(0-); mean residence
time (MRT); mean absorption time (MAT); volume of distribution of the area during the elimination phase, Varea; volume of
distribution at the steady-state, V(d(ss); maximum plasma concentration, Cmax; time of maximum plasma concentration,
Tmax) (Gibaldi & Perrier, 1982).
Cefuroxime bioavailability for extravascular administrations
(F) was calculated by relating intramuscular and subcutaneous
AUC to the intravenous one:

MATERIALS AND METHODS

Experimental animals

Experimental design
A three-period, three-treatment crossover design was used. As
a result, each animal received cefuroxime i.v., i.m., and s.c. in
a randomized sequence.
For i.v. administration, cefuroxime was given via bolus (over
a 2 min period) through a catheter placed in the left cephalic
vein. For the i.m. route, the dose was administered in the dorsal lumbar muscles, and for the s.c. administration, the dose
was injected under the lateral ribcage skin. A 2-week washout
period elapsed between each phase.
Blood sampling
Samples (2.5 mL) were collected through a catheter placed in
the right cephalic vein prior antibiotic administration and at 5,
10, 20, 30, 45 min and at 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 h.
Samples were taken with heparinized syringes, placed into
tubes, mixed, and kept on ice until plasma separation. Plasma

2015 John Wiley & Sons Ltd

42 G. A. Albarellos et al.

F% AUCEV =AUCiv  100;

Statistical analysis
Pharmacokinetic parameters are expressed as mean
standard deviation. Main estimated pharmacokinetic parameters
were statistically compared for the different administration
routes, applying an ANOVA test (AUC(0t), AUC(0), t, MRT) or
a t test (ka, t(a), MAT, Tmax, Cmax, F) (GraphPad Prism,
GraphPad Software, version 5.00, 2007, San Diego, CA, USA).
Results were considered significant when P < 0.05.

IV
IM
SC

Plasma concentration ( g/mL)

where AUCEV and AUCiv are the areas under the concentration
time curves for the extravascular routes (i.m. or s.c.) and the
i.v. administration, respectively.

100

10

MIC = 4 g/mL

MIC = 1 g/mL

0.1

PK/PD integration
Time above the minimum inhibitory concentration (T > MIC)
for the three studied administration routes was estimated by
visual approximation from the plasma concentration vs. time
curve. The MIC value applied was based on human reports
(staphylococci MIC90 = 1 lg/mL; E. Coli MIC90 = 4 lg/mL)
(von Eiff et al., 2005; Lerma et al., 2008).

RESULTS
No adverse effects were recorded by physical examination in
any of the dogs during or after cefuroxime administration.
The applied blood sample withdrawal schedules after i.v.,
i.m., and s.c. cefuroxime administration allowed a proper
description of the plasma concentrations vs. time curves as
shown in Fig. 1. Estimated pharmacokinetic parameters are
shown in Table 1.
Cefuroxime plasma concentrations after intravascular and
extravascular administrations were best fitted to a bicompartmental (i.v.) and a monocompartmental (with first-order input)
model (i.m. and s.c.).
After i.v. administration, cefuroxime showed a rapid distribution, reflected by the rate constant of the process (k1
10.73
8.25 h1) and its short half-life (T(d) 0.10

0.06 h). However, the extent of distribution was moderate,
with a volume of distribution (V(d(ss))) of 0.49
0.03 L/kg.
After i.v. administration, cefuroxime was rapidly eliminated
from the body as reflected by the high body clearance (ClB)
(0.34
0.04 L/hkg), short elimination half-life (T)
(1.12
0.19 h), and short mean residence time (MRT)
(1.49
0.21 h). Cefuroxime blood concentrations remained
above the LLOQ for 4 h in only three dogs.
Cefuroxime absorption was much slower after s.c. than after
i.m. administration, and this was evident (P < 0.05) when
parameters associated with this process (ka, T(a), Tmax, and
Cmax) were compared. However, extent of absorption was the
same for both extravascular routes, with a bioavailability of

Time (h)

Fig. 1. Mean and SD cefuroxime plasma concentrationtime profile

after intravenous (i.v.) (), intramuscular (i.m.) (), and subcutaneous
(s.c.) () administration to dogs at a dosage of 20 mg/kg (n = 6).

79.70
14.43% and 77.22
21.41% for the i.m. and s.c.
administration, respectively.
Cefuroxime elimination after i.m. and s.c. administration
was rather similar, with identical body clearance (0.34

0.04 L/hkg) and similar elimination half-life (1.13
0.13 h,
i.m.; 1.04
0.23 h, s.c.). However, significant differences
were found when MRT values were compared. As body clearances were identical for the three routes, observed MRT differences should be consequence of an absorption delay after
extravascular administrations.
Cefuroxime blood concentration was above 0.40 lg/mL
(LLOQ) for 6 h after i.m. (5/6 dogs) and s.c. (6/6 dogs) administration.
Cefuroxime plasma concentrations above the MIC are shown
in Fig. 1. After i.m. and s.c. administration, T > MIC for more
susceptible bacteria (MIC 1 lg/mL) was 5.56 h, while for
less susceptible micro-organisms (MIC 4 lg/mL), this time
was 3.54 h.

DISCUSSION
Cefuroxime could be a good option to treat susceptible bacteria
causing infections in dogs. However, the lack of pharmacokinetic information makes impossible the design of a rational
administration schedule.
The results obtained on this study would be useful to optimize cefuroxime parenteral use in dogs.
Observed cefuroxime pharmacokinetic profile after i.v.
administration was the expected for a beta-lactam and similar
to that reported for dogs, goats, calves, and buffalo calves
(Soback et al., 1989; Chaudhary et al., 1999; Abo El-Sooud

2015 John Wiley & Sons Ltd

Cefuroxime pharmacokinetics in dogs 43

Table 1. Mean (
SD) pharmacokinetic parameters of cefuroxime after
intravenous, intramuscular, and subcutaneous administration to dogs
at a dosage of 20 mg/kg

Pharmacokinetic
Parameter
C1 (lg/mL)
C2 (lg/mL)
Cp(0) (lg/mL)
k1 (h1)
k2 (h1)
AUC(0t)
(lgh/mL)
AUC(0)
(lgh/mL)
K12 (h1)
K21 (h1)
K12/k21
T(d) (h)
Varea (L/kg)
V(d(ss)) (L/kg)
ka (h1)
T(a) (h)
MAT (h)
Tmax (h)
Cmax (lg/mL)
ClB (L/hkg)
T (h)
MRT (h)
F (%)

Intravenous
administration
(mean
SD)

Intramuscular
administration
(mean
SD)

Subcutaneous
administration
(mean
SD)

45.93
8.50

43.69
8.33

47.56
8.17*

45.52
9.01*

8.43

0.13

0.31

0.43

22.99

0.34

1.13

1.79

79.70

1.47

0.50

0.72

0.99

15.37

0.34

1.04

2.21

77.22

38.15
34.94
73.09
10.73
0.63
52.29

22.87
4.26
23.62
8.25
0.11
6.69

60.13
6.91
4.95

5.16

0.81

0.10

0.53

0.49

0.34

1.12

1.49

5.45
2.68
0.54
0.06
0.04
0.03

0.04
0.19
0.21

6.39
0.09
0.37
0.20
7.87
0.04
0.13
0.24
14.43

0.38
0.14
0.32
0.10
3.07
0.04
0.23
0.23
21.41

*Significantly different (P < 0.05) i.v. vs i.m. and s.c.

Significantly different (P < 0.05) i.m. vs s.c.

ClB corrected by F.

Significantly different (P < 0.05) i.v. vs s.c.

C1, C2, y-axis intercept terms; Cp(0), plasma concentration at 0 time;
k1, distribution rate constant; k2, elimination rate constant; AUC(0t),
area under the plasma concentration vs time curve from 0 to time;
AUC(0), area under the plasma concentration vs time curve from 0
to infinite; K12, rate constant for passage from central to peripheral
compartment; K21, rate constant for passage from peripheral to central
compartment; t(d), distribution half-life; Varea, volume of distribution
of the elimination phase; V(d(ss)), volume of distribution at steady-state;
Ka, absorption rate constant; t(a), absorption half-life; MAT, mean
absorption time; Tmax, time of maximum concentration; Cmax, maximum concentration; ClB, body clearance; t, elimination half-life; MRT,
mean residence time; F, bioavailability.

et al., 2000; Zhao et al., 2012b) characterized by a fast distribution into the extracellular fluid and a relatively rapid renal
excretion.
The distribution process was rapid but, moderate in its
extension (high rate constant, short half-life, and moderate volume of distribution). These pharmacokinetic parameters
resulted rather similar to those reported for buffalo calves
(Chaudhary et al., 1999), goats (Abo El-Sooud et al., 2000),
and dogs (Zhao et al., 2012b). Also, pharmacokinetic parameters evaluating elimination process (high clearance, short halflife, and MRT) were very similar in the other studied species.
Zhao et al. (2012b) studied cefuroxime disposition in dogs at
2015 John Wiley & Sons Ltd

three intravenous doses (20, 40, and 80 mg/kg) demonstrating a linear pharmacokinetic. They report values of ClB of
0.31 L/hkg, t of 1.50 h, and MRT of 1.86 h, for the 20 mg/kg
dosage. These values are slightly different than those found in
the present study. Cefuroxime elimination lasted longer in the
study of Zhao et al. (2012b); this difference is modest and
could be explained by the more sensitive analytical method
(triple-quadrupole tandem mass spectrometer) used by these
authors.
Cefuroxime ClB (0.34 L/hkg) was higher than glomerular
filtration rate in dogs (0.24 L/hkg) (Baggot, 2001), indicating
that other mechanisms (e.g., renal tubular secretion) are
implicated in cefuroxime elimination as reported for humans
and other species (Foord, 1976; Soback et al., 1989; Tsuji,
2006).
Moderated pain was observed after i.m. administration,
although no reaction at the injection site (intramuscular or
subcutaneous) was clinically observed in any of the dogs.
After i.m. administration, cefuroxime absorption was faster
and Cmax higher than after s.c. administration. Moreover, after
s.c. administration, cefuroxime remained in the plasma longer
than after i.m. administration. These findings could be
explained through the flip-flop phenomenon, where terminal
T is reflecting the ka rather than the k. This pharmacokinetic
phenomenon would have clinical implications as it would prolong dosage intervals.
The most common cause for retardation of drugs absorption,
mainly after s.c. administration, is a local tissue reaction (irritation and inflammation) (Py
or
al
a et al., 1994). In fact, for
sodium cefuroxime a mild irritation, after subcutaneous administration to dogs, has been reported (Glaxo Laboratories,
1986).
Cefuroxime bioavailability after both extravascular administration routes was equally high (i.m., 79.70% and s.c.,
77.22%) without significant differences between them. The relatively longer permanence of cefuroxime in plasma when
administered extravascularly (especially subcutaneously) could
bring a bit more desirable plasma concentration profile in dogs
than after intravenous administration.
For beta-lactams, a T > MIC 50% of the dose interval has
been established as optimal for bactericidal action. At the dose
used in this study, a dose interval of 11 h (i.v., i.m.) or 12 h
(s.c.) would be effective for treating bacteria with a MIC value
of 1 lg/mL. However, for less susceptible bacteria (e.g.,
MIC 4 lg/mL), the dose interval should be shorter (8 h)
(i.m., s.c.).
More pharmacokinetic and pharmacodynamic studies are
necessary to support the present results. Furthermore, clinical
controlled trials are mandatory to establish proper cefuroxime
dosing schedules in dogs.

ACKNOWLEDGMENTS
The authors wish to thank to the personnel of Caniles, FCV,
and UBA for the technical assistance with the dogs employed

44 G. A. Albarellos et al.

in this study. This work was supported by a Research Project

UBACyT (Grant Numbers 20020100100745, 20112014 and
20020130100400, 20142017) of Secretar
a de Ciencia y
T
ecnica, Universidad de Buenos Aires, Argentina.

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