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Comparative Pharmacokinetics
of Enrofloxacin and Difloxacin
as Well as Their Main Metabolites
in Dogs
Ernst Heinen, Dr med vet
Bayer AG, Animal Health Research, D-51368, Leverkusen, Germany
Fluoroquinolones (FQs) are a class of
chemotherapeutic agents acting on bac-
terial DNA topoisomerases II (gyrase)
and IV.1,2 High bactericidal activity
against a broad spectrum of aerobic
gram-negative and gram-positive bacte-
ria and mycoplasmas,3,4 combined with
excellent pharmacokinetic properties,
makes them most suitable for the treat-
ment of bacterial infections.5,6 Enro-
floxacin, the first FQ developed for vet-
erinary application, is available in several
oral and parenteral formulations for the
treatment of infectious diseases in pets
and livestock. It is approved in dogs and
cats for the treatment of infections, for
example, urinary tract, respiratory tract,
and skin.7 In dogs and other species,
enrofloxacin is de-ethylated to cipro-
floxacin,8 an FQ used in human medi-
cine.9 Although not licensed for animal
use, ciprofloxacin has occasionally been
used experimentally in dogs.10 Two new
FQs (marbofloxacin and orbifloxacin) for
dogs and cats have been introduced in a
number of countries in recent years.11,12
More currently, difloxacin has been
licensed in North America and Europe
for the treatment of skin, soft tissue,
and urinary tract infections in dogs.13
De-methylation of difloxacin to sara-
floxacin, another FQ used in veterinary
medicine for the treatment of poultry,14
has been described.15
In this study, serum concentrations of
enrofloxacin, ciprofloxacin, and difloxa-
cin were compared in dogs, using com-
mercially available tablet formulations to
12 Third International Veterinary Symposium on Fluoroquinolones Proceedings
Quit
estimate therapeutic potentials. Further-
more, the extent to which enrofloxacin
and difloxacin are transformed into
ciprofloxacin and sarafloxacin, respect-
ively, was analyzed by high-performance
liquid chromatography (HPLC) and com-
pared to the total antimicrobial activity
determined in a microbiological assay.
Materials and Methods
Study Design
Eight healthy adult dogs of either sex
(Beagles, Marshall Farms), weighing 11.6
± 0.9 kg (mean ± SD), were used in the
study, following a complete crossover
design. The animals were kept in individ-
ual cages and fed a standard diet, with
ad libitum access to drinking water. All
compounds were used as commercially
available drugs: ciprofloxacin (Ciprobay®
Tablets [Bayer AG]), difloxacin (Dicural®
Palatabs [Fort Dodge Animal Health]),
and enrofloxacin in two different formu-
lations (Baytril® Tablets and Baytril® Taste
Tabs™ [Bayer]). Each FQ was given at a
single oral dose of 5 mg/kg body weight
(bw) in the morning prior to feeding. For
precise dosing, tablets were homoge-
nized and individually weighted into
gelatin capsules. Eight animals were ran-
domly divided into four groups of two
dogs each. During four phases, the
groups received either an enrofloxacin
formulation, ciprofloxacin, or difloxacin.
Between each crossover, an interval of 1
week was added as a washout period. In
an additional trial, the extent of transfor-
mation of difloxacin to sarafloxacin was
assessed. A single dose of difloxacin 5
mg/kg bw was administered to six
healthy adult dogs of either sex (Beagles,
Winkelmann), weighing 15.3 ± 2.7 kg
(mean ± SD). Blood samples were col-
lected by venipuncture of the jugular
vein prior to and at 0.5, 1, 2, 4, 6, 10,
24, 30, and 48 hours after application.
Serum was separated by centrifugation
at 1000g for 10 minutes and stored at
–20˚C until assayed.
Analytical Methods
Antibacterial activities in all samples
were analyzed by a microbiological agar
diffusion assay16 carried out on bioassay
dishes (230 × 230 mm, Nunc) containing
balanced sensitivity test medium (BRL
Difco). On each plate, 6 duplicate stan-
dard and 10 duplicate test samples of
100 µl volume were tested in wells of
9 mm inner diameter (ID). Klebsiella
pneumoniae ATCC 10031 served as the
test organism. Pure ciprofloxacin, diflox-
acin, and enrofloxacin (synthesized at
Bayer AG) diluted in pooled canine
serum served as reference standards.
Plates were incubated at 37˚C for 17 to
20 hours. Inhibition zones were read
with digital calipers. The limits of quan-
tification (LOQ) for ciprofloxacin and
enrofloxacin were 0.015 µg/ml and for
difloxacin, 0.03 µg/ml. The correlation
coefficient of the standard curves of all
three substances was r2 > 0.975. The
interassay and intraassay coefficients of
variation in all standards were <5%.
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Samples from the additional difloxa-
cin study and from eight animals
receiving enrofloxacin (Baytril Tablets)
in the crossover study were processed
by reverse-phase HPLC. Serum speci-
mens were analyzed for enrofloxacin
and its active metabolite, ciprofloxacin,
or for difloxacin and its active metabo-
lite, sarafloxacin, using LC 10 equip-
ment (Shimadzu). The compounds
were detected in an RF 10 AXL fluores-
cence detector operating at excitation
and emission wavelengths of 278 nm
and 446 nm, respectively (enrofloxacin/
ciprofloxacin), or at 275 nm and 446
nm, respectively (difloxacin/sarafloxa-
cin). Separation of enrofloxacin and
ciprofloxacin was achieved on Nucleosil
C18 analytic columns (5-µm particle,
250 mm × 4 mm ID [Machery-Nagel,
Dueren, Germany]) kept at 40˚C. For
separation of difloxacin and sara-
floxacin, Nucleosil C8 columns (5 µm,
125 mm × 4 mm ID [Machery-Nagel]),
protected by a precolumn (LiCrospher
100 RP-18, 5 µm, 4 × 4 mm [Merck,
Darmstadt, Germany]) were used. The
mobile phase consisted of 90% (v/v) of
a solution of 1 g tetrabutylammonium
hydrogen sulfate and 1 ml phosphoric
acid (85%, v/v) in 1 L demineralized
water and 10% (v/v) acetonitrile (enro-
floxacin/ciprofloxacin) or 10% (v/v)
methanol (difloxacin/sarafloxacin). The
flow rates were 1 ml/minute for enro-
floxacin/ciprofloxacin and 1.5 ml/
minute for difloxacin/sarafloxacin.
C18 disposable extraction columns
(Bakerbond SPE [Baker]) were condi-
tioned with 2 ml of acetonitrile followed
by 10 ml of potassium dihydrogen phos-
phate (8.75 mg/L), adjusted to pH 2.1
with orthophosphoric acid (85%, v/v).
Serum samples (0.5 ml) were diluted
with 10 ml of the potassium dihydrogen
phosphate solution, poured on the car-
tridge, and rinsed with 2 ml of the same
solution. After drying, substances were
eluted with 4 ml of methanol. The eluate
was evaporated to dryness and the
residue dissolved in 1 ml of the mobile
phase (enrofloxacin/ciprofloxacin) or in
0.5 ml methanol/water at equal volumes
(difloxacin/sarafloxacin). The injection
volume was 12 µl for enrofloxacin/
ciprofloxacin or 10 µl for difloxacin/
sarafloxacin. Pure substances of all four
drugs served as standards. Mean recov-
eries were >74%. The LOQ were
0.002 µg/ml for ciprofloxacin and
enrofloxacin and 0.005 µg/ml for
difloxacin and sarafloxacin. The methods
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High
bactericidal
activity against
a broad
spectrum of
aerobic gram-
negative and
gram-positive
bacteria and
mycoplasmas
makes
fluoroquinolones
most suitable for
the treatment
of bacterial
infections.
were linear between LOQ and 1 µg/ml (r2
> 0.98). The interassay coefficients of
variation in standards were <5%.
Data Analysis
Data were computed using Excel
(Microsoft) and PlotIt software (Scientif-
ic Programming Enterprises). Pharmaco-
kinetic parameters were calculated from
individual data sets of the crossover
study following bioassay analysis using
noncompartmental methods (Kincalc
[Bayer AG]). This software extrapolates
the terminal half-life (t1/2) after log trans-
formation of the concentration curve.
The area under the concentration-time
curve (AUC) was determined by apply-
ing the mixed log–linear rule. The rela-
tive bioavailability of the enrofloxacin
formulations was assessed by calculat-
ing the AUC0–24 ratios.
Results
The mean antimicrobial serum con-
centrations following an oral dose of
ciprofloxacin, difloxacin, or enrofloxa-
cin 5 mg/kg bw are presented in Figure
1 (see also Table 1). Both enrofloxacin
tablet formulations achieved mean
peak antimicrobial activities (Cmax) of
1.85 to 1.90 µg/ml approximately 1 to
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1.6 hours after administration (Table 2).
Thereafter, the compound was elimi-
nated at a t1/2 of approximately 3.5
hours. After 24 hours, concentrations
had decreased to the LOQ. The mean
AUC0–24 ratios of the enrofloxacin for-
mulations were 0.98 (Tablet/Taste Tabs)
and 1.10 (Taste Tabs/Tablet).
Ciprofloxacin attained its Cmax of 0.52
µg/ml after 1.5 hours. Its t1/2 was 3.5
hours and the extrapolated AUC0–24 was
2.63 mg × hours/L. After 24 hours, the
concentrations had fallen below LOQ.
Difloxacin concentration reached its
mean Cmax of 1.11 µg/ml after Tmax of
2.75 hours. It was eliminated at t1/2 of
7.3 hours, leading to a serum concen-
tration of 0.12 µg/ml after 24 hours.
Antimicrobial activity was detected up
to 48 hours postadministration. The
AUC0–24 of difloxacin and enrofloxacin
were within the same order of magni-
tude of approximately 8.5 mg ×
hours/L. Bioassay and corresponding
HPLC concentrations of enrofloxacin
and its metabolite ciprofloxacin are
shown in Figure 2; those of difloxacin
and its metabolite sarafloxacin are
shown in Figure 3. The sum of the
HPLC concentrations of ciprofloxacin
plus enrofloxacin was 20% to 30%
below the corresponding bioassay val-
ues (Table 3). In six of eight dogs,
ciprofloxacin was found after 0.5 hour.
The mean ciprofloxacin concentration
increased over time, reaching similar
concentrations as enrofloxacin after 10
hours. The average Cmax was 0.28
µg/ml for ciprofloxacin and 1.16 µg/ml
for enrofloxacin, whereas the mean
bioassay result was 1.87 µg/ml.
Enrofloxacin, but not ciprofloxacin, was
still detected by HPLC in three dogs
after 48 hours. For difloxacin, only mar-
ginal differences between bioassay
results and HPLC concentrations were
measured (Table 4). The mean Cmax of
difloxacin was 1.18 µg/ml as deter-
mined by HPLC, compared to 1.06
µg/ml determined by bioassay. Metab-
olism of difloxacin to sarafloxacin 0.5
hour after administration was observed
in only one animal. The mean sara-
floxacin fraction increased from 1%
after 1 hour to 7% after 30 hours. The
maximum concentration of 0.033
µg/ml was reached after 4 hours.
Discussion
In this study, all FQs were dosed at 5
mg/kg bw, the recommended dosage
13
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were nearly twice as high after

Figure 1—Serum antimicrobial activity after single oral administration of FQ 5 mg/kg bw
as determined by bioassay (mean, n = 8).
of difloxacin and enrofloxacin for dogs.
The serum pharmacokinetics after a
single oral administration of enro-
floxacin is characterized by rapid
absorption, resulting in high peak con-
centrations and by an elimination rate
justifying a single daily dosing. Com-
pared to ciprofloxacin and difloxacin,
the maximum antimicrobial activities
after administration of enrofloxacin
difloxacin and fourfold higher after
ciprofloxacin application. Moreover,
enrofloxacin and ciprofloxacin achieved
their maximum antimicrobial activity 1
to 1.5 hours earlier than did difloxacin.
Because of a longer elimination half-
life of difloxacin, its AUC0–24 was similar
to that of enrofloxacin. Notably, the
mean AUC0–24 of ciprofloxacin was 2.5
times lower than that of enrofloxacin
and difloxacin. The different enro-
floxacin formulations were equivalent.
Based on pharmacokinetic and sus-
ceptibility studies, several pharmacody-
namic predictors of antimicrobial effi-
cacy of FQs, including the AUC:MIC
ratio, the AUC above MIC (AUCeff),
time above MIC (Teff), and the Cmax:MIC
ratio, have been examined in recent
years.17–19 These relationships are highly
variable, depending on the compound
used, the bacterial species involved,
and the type of study performed, such
as clinical trial, experimental infection,
or in vitro killing experiments. A defini-
tive and reliable predictor for describ-
ing FQ activity is lacking. However, FQs
are considered to act in a concentra-
tion-dependent manner. Hence, Cmax:

TABLE 1
Serum Antimicrobial Activity after Single Oral Application
of Fluoroquinolone 5 mg/kg bw as Determined by Bioassay

Antimicrobial Activity (µg/ml) at Sampling Time (hours)

Compound 0 0.5 1 2 4 6 10 24 30 48

Enrofloxacin meana <b 0.70 1.64 1.51 0.93 0.45 0.22 0.01 < <
(Baytril SEMc 0.24 0.27 0.14 0.09 0.03 0.02
Tablets) min < < 0.11 0.80 0.45 0.28 0.13 < < <
max < 1.90 2.30 2.20 1.30 0.53 0.27 0.03 < <

Enrofloxacin mean < 0.84 1.53 1.50 1.05 0.49 0.26 0.02 0.01 <
(Baytril SEM 0.28 0.27 0.12 0.13 0.04 0.04 0.01 0.01
Taste Tabs) min < < 0.12 1.00 0.58 0.32 0.13 < < <
max < 2.00 2.40 2.20 1.80 0.67 0.50 0.09 0.05 <

Ciprofloxacin mean < 0.15 0.50 0.51 0.31 0.20 0.08 < < <
(Ciprobay SEM 0.05 0.16 0.11 0.04 0.03 0.01
Tablets) min < 0.02 0.09 0.27 0.17 0.09 0.03 < < <
max < 0.35 1.55 1.00 0.50 0.34 0.12 0.02 < <

Difloxacin mean < 0.40 0.77 1.01 0.79 0.60 0.30 0.12 0.06 0.01
(Dicural SEM 0.13 0.14 0.06 0.06 0.07 0.03 0.04 0.02 0.01
Palatabs) min < < 0.29 0.80 0.55 0.39 0.20 0.02 < <
max < 0.98 1.35 1.22 0.98 0.93 0.43 0.29 0.16 0.06
aMean, n = 8.
bBelow LOQ.
cStandard error of the mean.

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TABLE 2
Pharmacokinetic Parameters after Single Oral Application
of Fluoroquinolone 5 mg/kg bw as Determined by Bioassay

Cmax Tmax t1/2 Mean Residence Time (MRT) AUC0–24

Compound (µg/ml) (hours) (hours) (hours) (mg × hours/L)

Enrofloxacin meana 1.90 1.63 3.42 5.14 8.34

(Baytril SEMb 0.17 0.38 0.12 0.32 0.48
Tablets) min 1.00 1.00 3.13 4.23 6.37
max 2.30 4.00 4.11 6.53 9.86

Enrofloxacin mean 1.85 1.06 3.45 5.29 8.99

(Baytril SEM 0.12 0.22 0.28 0.41 0.91
Taste Tabs) min 1.40 0.50 2.73 4.17 6.09
max 2.40 2.00 5.16 7.59 14.89

Ciprofloxacin mean 0.52 1.56 3.51 5.65 2.63

(Ciprobay SEM 0.08 0.39 0.25 0.35 0.39
Tablets) min 0.30 0.50 2.60 4.01 1.36
max 0.89 4.00 4.47 6.67 4.48

Difloxacin mean 1.11 2.75 7.28 11.03 8.73

(Dicural SEM 0.06 0.62 1.07 1.69 0.58
Palatabs) min 0.91 1.00 3.94 5.74 6.88
max 1.35 6.00 11.65 17.65 11.71
aMean, n = 8.
bStandard error of the mean.

pharmacokinetic properties. Compared

Figure 2—Serum concentrations of enrofloxacin and its metabolite ciprofloxacin com-
pared to bioassay activities after single oral administration of enrofloxacin 5 mg/kg bw
(mean, n = 8).
MIC and AUC:MIC ratios seem to be
the best parameters for predicting
antimicrobial effect and comparing dif-
ferent quinolones.20, 21
Although better in vitro activity has
been reported,22 for example, against
Pseudomonas aeruginosa, ciprofloxa-
cin compared to enrofloxacin might
offer no advantages for treating infec-
tions in dogs because of its inferior
to difloxacin, superior Cmax:MIC and
AUC:MIC ratios for enrofloxacin result
from higher Cmax and similar AUC val-
ues of enrofloxacin, combined with its
reported lower MICs and minimum
bactericidal concentrations (MBCs).23
Regardless of the absolute figures, a
better antimicrobial effect of enro-
floxacin can be postulated. However,
additional clinical studies should be
undertaken to confirm these predic-
tions. Based on the pharmacodynam-
ics, the possibility of a successful treat-
ment, even of bacteria with elevated
MICs, may be improved by using high-
er dosages.24 The recently approved
professional flexible labeling of
enrofloxacin for dogs in the United
States offers the veterinarian the
option of following these concepts.
Results of bioassays represent the
total antimicrobial activity and may be
different from concentrations of the
parent substance determined by HPLC
if the parent compound is metabolized
to molecules that are active against the
test organism.
Generally, sarafloxacin exhibits high-
er in vitro activity than its parent com-

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due to the main metabolite, cipro-

Figure 3—Serum concentrations of difloxacin and its metabolite sarafloxacin compared to
bioassay activities after single oral administration of difloxacin 5 mg/kg bw (mean, n = 6).
pound, difloxacin; for example, it is four
times as active against Klebsiella pneu-
moniae.25 The discrepancy between
bioassay and HPLC was small, however,
probably because of the low metabo-
lism rate. Only when the sarafloxacin
fraction exceeded 5% were the bioassay
values slightly above the HPLC concen-
trations. Therefore, difloxacin concen-
tration results of either analytical
method may be used for pharmacoki-
netic and pharmacodynamic evaluations
in dogs.
A marked difference between
bioassay and HPLC results was found
after administration of enrofloxacin. A
considerable part of the antimicrobial
activity after enrofloxacin application is
floxacin.8 In this study, ciprofloxacin
achieved equal or higher concentra-
tions of enrofloxacin after 10 hours,
which parallels previous results.26,27 The
combined activity is simply additive.28
The HPLC concentrations of enro-
floxacin plus ciprofloxacin, however,
achieved approximately only 70% of
the bioassay values. This difference
may be partially explained by the slight-
ly higher activity of ciprofloxacin against
the test organism (data not shown).
Significant quantities of other active
metabolites contributing to the bio-
assay results may exist.29 Additionally,
methodological factors like the totally
different analytical procedure as well as
sample preparation influence the
results and make direct comparison of
data difficult. Further studies are need-
ed to identify and verify all biasing fac-
tors to allow proper evaluation.
Bioassay data still seem to be appro-
priate if the pharmacokinetics of total
antimicrobial activities of different
drugs are directly compared and de-
scribed. For pharmacodynamic evalua-
tions and estimations of the treatment
success, these results are most useful if
the metabolite has at least similar or
even better antimicrobial activities than
the parent compound, as is the case of
enrofloxacin and ciprofloxacin.3

TABLE 3
Serum Concentrations of Enrofloxacin and Its Metabolite Ciprofloxacin Determined by HPLC
Compared to Bioassay Activities after Single Oral Application of Enrofloxacin 5 mg/kg bw

Concentration (µg/ml) at Sampling Time (hours)

0 0.5 1 2 4 6 10 24 30 48

Enrofloxacin meana <b 0.426 1.061 0.850 0.436 0.209 0.074 0.006 0.004 0.003
(HPLC) SEMc 0.151 0.204 0.077 0.063 0.032 0.010 0.001 0.001 0.000
min < 0.006 0.060 0.548 0.192 0.105 0.024 0.004 0.002 <
max < 1.086 1.882 1.205 0.761 0.375 0.104 0.011 0.007 0.004

Ciprofloxacin mean < 0.081 0.194 0.246 0.233 0.172 0.091 0.008 0.002 <
(HPLC) SEM 0.029 0.036 0.021 0.029 0.022 0.010 0.001
min < < 0.016 0.142 0.133 0.098 0.048 0.004 < <
max < 0.224 0.304 0.315 0.390 0.283 0.130 0.014 0.004 <

Total activity mean < 0.70 1.64 1.51 0.93 0.45 0.22 0.01 < <
(Bioassay) SEM 0.24 0.27 0.14 0.09 0.03 0.02
min < < 0.11 0.80 0.45 0.28 0.13 < < <
max < 1.90 2.30 2.20 1.30 0.53 0.27 0.03 < <
aMean, n = 8.
bBelow LOQ.
cStandard error of the mean.

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TABLE 4
Serum Concentrations of Difloxacin and Its Metabolite Sarafloxacin Determined by HPLC
Compared to Bioassay Activities after Single Oral Application of Difloxacin 5 mg/kg bw

Concentration (µg/ml) at Sampling Time (hours)

0 0.5 1 2 4 6 10 24 30 48

Difloxacin meana <b 0.155 0.591 0.946 1.021 0.419 0.186 0.125 0.066 0.023
(HPLC) SEMc 0.068 0.202 0.167 0.106 0.037 0.034 0.051 0.036 0.008
min < < 0.057 0.403 0.699 0.313 0.107 0.021 0.014 0.008
max < 0.383 1.259 1.321 1.344 0.531 0.317 0.312 0.239 0.048

Sarafloxacin mean < < 0.006 0.020 0.033 0.024 0.012 0.007 0.005 <
(HPLC) SEM 0.002 0.004 0.005 0.003 0.002 0.003 0.002
min < < < 0.006 0.022 0.010 0.005 < < <
max < 0.003 0.012 0.033 0.056 0.034 0.017 0.020 0.016 0.005

Total activity mean < 0.19 0.57 0.95 0.95 0.51 0.23 0.12 0.07 0.02
(Bioassay) SEM 0.09 0.15 0.12 0.02 0.02 0.03 0.04 0.03 0.01
min < < 0.10 0.51 0.89 0.44 0.15 0.03 < <
max < 0.52 1.00 1.30 1.05 0.59 0.32 0.24 0.21 0.06
aMean, n = 6.
bBelow LOQ.
cStandard error of the mean.

Acknowledgments bials: Structure, antimicrobial activity,

I thank Claudia Heyder, Josef
Langenohl, Angelika Seinsche-Genster,
Angela Schulten, and Claudia Wolf for
technical assistance. The critical review
of the manuscript by my colleagues
Rollo Daube, Anno de Jong, Markus
Edingloh, Kerstin Heeschen, and Heinz-
Georg Wetzstein is kindly acknowl-
edged.
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