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Overview of the Pharmacokinetic Properties
of Fluoroquinolones in Companion Animals
M. Kietzmann, Prof Dr med vet
Institute for Pharmacology, Toxicology and Pharmacy, Tierarztliche Hochschule Hannover, Hannover, Germany
Fluoroquinolones represent a relative-
ly new group of potent antimicrobial
agents. Based on the nuclear structure of
nalidixic acid, the first unfluorinated
quinolone introduced to human medicine
in the 1960s, a large number of modifi-
cations on the predecessor molecule
have led to the modern fluoro-
quinolones. The current third-generation
quinolones have much better pharmaco-
kinetic properties, increased spectrum of
activity, relatively low propensity to
induce resistance, and broader safety
margin compared to substances of the
first and second generations.1
In small animal medicine, the era of
fluoroquinolones began with the intro-
duction of enrofloxacin 10 years ago.This
drug plays an important role in the ther-
apy of bacterial infectious diseases and is
firmly established as part of the arma-
mentarium of the small animal practition-
er. Recently, additional fluoroquinolones
have been introduced in some countries.
Because of their excellent efficacy and
the relatively low level of bacterial resis-
tance against them, a responsible use of
this class of antibacterial drug will ensure
their efficacy in the future.
Chemistry
The fluoroquinolones are derivatives
of nalidixic acid, oxolinic acid, flume-
quine, and pipemidic acid. These drugs
are often characterized as first- and sec-
ond-generation quinolones. Figure 1
shows the ground structure of enro-
floxacin, the first modern third-genera-
tion fluoroquinolone introduced in vet-
erinary medicine. Compared to the
parent compounds, such as nalidixic
acid, the most important step in fluoro-
quinolone development was fluorination
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PHARMACOLOGY-
MICROBIOLOGY
in position 6 of the molecule. Addition-
ally, a piperazine substituent was intro-
duced in position 7, which also is an
indispensable property of the fluoro-
quinolones. The amine substituent usu-
ally is a piperazine, which is partially
alkylated, commonly with a methyl or
ethyl group (Table 1).2
Fluoroquinolones currently licensed for
the treatment of small animals are
enrofloxacin, which is registered in all
major countries of the world, and mar-
bofloxacin, difloxacin, and orbifloxacin,
which have been introduced recently in
some countries.3
Mechanism of Action
Fluoroquinolones interfere with bacte-
rial DNA metabolism by inhibition of two
enzymes, topoisomerase II (DNA gyrase)
and topoisomerase IV. The function of
DNA gyrase is the introduction of super-
coils into the linear DNA double helix,
which results in the highly condensed
three-dimensional structure the DNA usu-
ally presents inside the cell. Topoiso-
Figure 1—Chemical structure of enrofloxacin.
merase IV was proposed to be involved in
chromosome partitioning via its decate-
nating activity, but the understanding of
its function is still in its infancy.
Models to explain the activity of
quinolones at the target site currently
exist only for DNA gyrase. During the
supercoiling process, both DNA strands
are cleaved by DNA gyrase at 4-base-pair
staggered sites, forming a “quinolone
binding pocket.” Two quinolone mole-
cules self-assemble inside the pocket in
dimer structure and attach to the gyrase-
DNA complex by electrostatic forces, sta-
bilizing the intermediate status of this
reaction step. Permanent gaps in the
DNA strands induce the synthesis of
repair enzymes (exonucleases), initiating
uncoordinated repair processes, which
result in irreversible damage of the DNA
and, finally, in cell death.
Fluoroquinolones display antimicro-
bial selectivity because their activity
against mammalian topoisomerases asso-
ciated with DNA replication is two orders
of magnitude less than their activity
against bacterial DNA gyrase.4
7
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the administered galenic formulation

TABLE 1 ■ Drug absorption from the site of
administration
Structural Differences of Some 6-Fluoroquinolones ■ Distribution within the organism
■ Metabolism
■ Excretion of the parent compound
and metabolites

The pharmacokinetic disadvantage of

R1 R2
Enrofloxacin -H - cyclopropyl
Ciprofloxacin -H - cyclopropyl
Marbofloxacin - O - CH2 - N(CH3) -
Difloxacin -H - 4-fluorophenyl
Norfloxacin -H - ethyl
Antimicrobial Activity
The first prerequisite for any success-
ful antibacterial treatment is the selection
of drugs capable of sufficient activity
against the bacteria in question. Here the
actual situation of bacterial sensitivity
toward antimicrobials must be taken into
consideration.
Fluoroquinolones are well known for
their excellent efficacy. In general, a low
level of resistance against these drugs is
being assessed. However, as the issue of
quinolone resistance is of utmost impor-
tance, prudent and responsible use of
this class of antimicrobial drug is required
to limit the emergence and dissemination
of resistance and to ensure that this class
remains effective in the future.1
Fluoroquinolones possess a broad spec-
trum of activity against the majority of bac-
teria relevant to small animal infectious dis-
ease with low MICs and favorable killing
kinetics. They are rapidly bactericidal
against replicating as well as dormant bac-
teria, which makes them well suited for the
treatment of immunocompromised pa-
tients suffering from chronic relapsing dis-
eases and those that have previously
undergone therapy with corticoids or cyto-
toxic agents. Resistance against fluoro-
quinolones develops slowly and is not plas-
R3
- 4-ethyl-piperazinyl
- piperazinyl
- 4-methyl-piperazinyl
- 4-methyl-piperazinyl
- piperazinyl
mid mediated. It occurs either by changes
in cell wall permeability or by chromosomal
alterations of the binding site for
quinolones. Bacterial enzymes degrading
quinolones, such as beta-lactamases for
penicillin derivatives, are not known.
Although gyrase inhibitors do not show
cross-resistance to other classes of anti-
microbials, cross-resistance exists among
the fluoroquinolones.1,2,4
Current fluoroquinolones have poor
activity against anaerobic organisms,
although these mechanisms are barely
understood. For facultative aerobic bacte-
ria growing under anaerobic conditions,
however, enrofloxacin has been demon-
strated to show similar killing behavior
when compared to bacteria growing under
aerobic conditions. Lack of activity against
anaerobes may also be beneficial, because
the commensal intestinal flora, composed
of different anaerobic species of bacteria, is
much less affected in animals undergoing
treatment with quinolones than with other
classes of antiinfectives.
Pharmacokinetics
Pharmacokinetics describes the fol-
lowing:
■ Release of the active compound from
older quinolones, such as nalidixic or
oxolinic acid, is a high degree of binding to
plasma proteins (>95%), resulting in mod-
est tissue penetration and rapid and com-
plete metabolism and elimination. Suffi-
cient drug concentrations, therefore, are
achieved only in the kidneys and urine of
treated animals. Research has led to the
modern fluoroquinolones, in which these
disadvantages have been compensated by
the molecular modifications previously de-
scribed. Both fluorination in position 6 of
the molecule and the piperazine sub-
stituent enhance antimicrobial activity,
increase the antibacterial spectrum, and
optimize the pharmacokinetic properties of
these drugs.1
6-Fluoroquinolones possess a car-
boxylic acid in position 3 and a basic
amine functional group in position 1 of
the molecule. Therefore, the compounds
are amphoteric and zwitterionic (pH
dependent). In a pH range between 6
and 8, the fluoroquinolones are suffi-
ciently lipophilic to penetrate cell mem-
branes and therefore achieve high intra-
cellular concentrations in tissues and in
phagocytes, as recently shown for
enrofloxacin.1,2,6
Absorption
As described previously, the fluoro-
quinolones are well suited for oral and
parenteral administration. As shown for
enrofloxacin, plasmakinetics after oral
administration is similar to that after sub-
cutaneous injection (Figure 2).7
Following oral application, absorption
from the intestines (duodenum, jejunum)
is nearly complete. Compared to other
quinolones, norfloxacin and flumequine
are absorbed to a lower degree. It has also
been demonstrated that fluoroquinolone
absorption is best after administration on
an empty stomach. Various studies con-
firm the excellent bioavailability of modern
fluoroquinolones such as enrofloxacin
after oral and parenteral administra-
tion.1,2,8–10
In addition to the maximum plasma
concentration (Cmax) and the time of peak
concentration (Tmax), the area under the

8 Third International Veterinary Symposium on Fluoroquinolones Proceedings

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Figure 2—Plasma concentration of enrofloxacin (sum of enrofloxacin and its metabolite
ciprofloxacin) in dogs after a single oral treatment with 5.8 mg/kg body weight as Baytril ®
Tablets.5
time-concentration curve (AUC) is an
important pharmacokinetic parameter in
characterizing bioavailability of the
drugs. For fluoroquinolones, the ratio
(AUCparenteral:AUCIV × 100) or (AUCoral:AUCIV
× 100) is in the range of 90% to 100%,
which means nearly complete bioavail-
ability.1,9,10 This may also be the reason
that the oral route of administration
(tablets) is used most frequently in dogs
and cats. In dogs, intestinal absorption is
quite variable. For example, the oral dose
of enrofloxacin is 100% bioavailable in
dogs, whereas the oral dose of cipro-
floxacin is variably absorbed and the oral
therapeutic dose may be up to five times
higher than the parenteral dose.11 How-
ever, injectable formulations for small
animals, available only for enrofloxacin
and two other fluoroquinolones, are well
suited to initiation of therapy or for treat-
ment of very sick animals.
Distribution
The favorable chemical properties of
the quinolones (lipid solubility, ampho-
teric structure) ensure a rapid and excel-
lent extracellular and intracellular distribu-
tion in the patient.1 It has been
demonstrated in a number of studies that
high tissue concentrations are achieved
with enrofloxacin. In most organs, includ-
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ing all relevant target tissues, tissue con-
centrations considerably exceed plasma
concentrations (Table 2).2,6,12
Excellent tissue distribution is also
documented by a large volume of distrib-
ution (Vd) exceeding 1 L/kg body weight
for all fluoroquinolones.1,2,7,9,10 Although
compounds with a Vd in the range of 0.2
L/kg are distributed to extracellular fluid
only, compounds such as the fluoro-
quinolones with a Vd of more than 1 L /kg
are enriched in major tissue compart-
ments. Similar to macrolides, fluoro-
quinolones achieve high tissue concen-
trations and penetrate cell membranes.
In contrast to the former, which are
sequestered in subcellular compartments
(lysosomes), fluoroquinolones concen-
trate mainly in the cytoplasm, where they
remain unbound and active. It has been
shown that high intracellular concentra-
tion of enrofloxacin is achieved also in
phagocytic cells, exceeding plasma con-
centrations by a factor of nearly 100. In
this way, intracellular or intraphagocytic
bacteria, which may survive therapy with
conventional antibiotics such as beta-
lactams and may later cause recurrence
of the infection, can be combated with
fluoroquinolones.6,13,14
Phagocytic cells (macrophages and
neutrophilic granulocytes), attracted by
chemotactic stimuli, migrate to the site of
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infection. In a drug-free environment, the
active drug readily diffuses out of the
cells, following the concentration gradi-
ent. Phagocytes have therefore been pro-
posed to act as transport media to the
site of infection.15
Additionally, it has been demonstrat-
ed that enrofloxacin reaches about 2.5
times the concentration in inflamed skin
of dogs with pyoderma compared to
dogs with healthy skin (ratio of pyoderma
to healthy skin is 1:8; ratio of deep to
superficial pyoderma is 2:5).12 In addition
to pH-dependent effects, as well as
increased blood perfusion, the migration
of phagocytic cells into the inflamed skin
tissue may contribute to these findings.
Confirming enrofloxacin’s excellent
suitability in the treatment of various bac-
terial infections in small animal practice,
tissue drug concentrations after oral
treatment with enrofloxacin are shown in
Table 2. Significantly higher concentra-
tions than the MICs of the most relevant
bacteria for small animal practice were
found in all tissues examined.
Although some data exist on the con-
centrations of enrofloxacin in the major
target tissues, only one study on bone
concentrations has been published to
date.16 To examine enrofloxacin distribu-
tion in canine bone tissue, an additional
study was performed. In healthy dogs,
enrofloxacin concentrations of 1 µg/ml
plasma and nearly 1 µg/g bone tissue
were found 4 hours after a single admin-
istration of 10 mg/kg enrofloxacin sub-
cutaneously. Similar concentrations were
achieved in dogs that were treated with
enrofloxacin at the same dose for 3 con-
secutive days.17 The relatively low plasma
concentration can be explained by the
fact that the plasma peak occurs approx-
imately 2 hours after drug administration
and that preexisting plasma levels are in
the declining phase.
Metabolism
Fluoroquinolones are metabolized in
various phase I and phase II reactions. N-
dealkylation is a very important phase I
reaction of most fluoroquinolones.
Enrofloxacin is dealkylated to cipro-
floxacin, which has similar antibacterial
activity.2 Additionally, oxidation at the
piperazine structure and hydroxylation
take place. The most important phase II
reaction is a glucuronidation of the car-
boxylic acid in position 3. Additionally,
sulfoxidation and acetylation occur. After
glucuronidation, a significant amount of
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the drug is excreted via the bile. Because

TABLE 2 of hydrolysis by β-glucuronidases in the
gastrointestinal tract, which allows reab-
Concentration of Enrofloxacin in Tissues sorption of the parent compound,
of Dogs and Cats after Oral Treatment9–11, 21 enterohepatic recirculation occurs.18

Enrofloxacin Elimination
Concentration Hours Dosage
after (mg/kg body Fluoroquinolones are excreted via the
Tissue Dog Cat Treatment weight) bile and the urine, mainly by glomerular
filtration and, to a lesser extent, by active
Heart 3.1 µg/g 5.0 µg/g 1 5
tubular secretion. In an experimental
Uterus 3.8 µg/g — 1 2.5 study on ciprofloxacin, probenecid, a
— 2.2 µg/g 1 5
blocker of tubular secretion, was used. It
Cerebrospinal fluid 0.9 µg/ml 0.9 µg/ml 1 5 was demonstrated that probenecid did
Lung 2.5 µg/g 4.5 µg/g 1 5 not produce a significant accumulation
of the drug within the organism, which
Bronchial fluid 4.8 µg/ml — 4 5
led to the conclusion that tubular secre-
Alveolar macrophages 54.3 µg/g — 4 7.5 tion is of less importance in fluoro-
Kidney 3.5 µg/g 5.4 µg/g 1 5 quinolone excretion. In dogs, only 30%
to 40% of the enrofloxacin is excreted via
Liver 5.8 µg/g 6.5 µg/g 1 5
the renal route, whereas 70% is eliminat-
Spleen 2.8 µg/g 3.0 µg/g 1 5 ed via the bile (glucuronidation).1
Skin (healthy) 1.1 µg/g — 3 5 The existence of a correlation between
half-life, volume of distribution, and total
Skin (inflamed) 2.9 µg/g — 3 5
clearance must be considered. If the total
Fat 1.4 µg/g 1.3 µg/g 1 5 clearance is constant, a shortened half-life
Muscle 2.3 µg/g 2.8 µg/g 1 5 results from a decreased volume of distri-
bution. A prolonged half-life may be
Brain 0.4 µg/g 1.6 µg/g 1 5
caused by an enlarged volume of distrib-
Plasma 1.6 µg/ml — 1.4 5 ution or a low excretion rate (clearance)
1.5 µg/ml 1
via bile or urine. In a marbofloxacin study,
Urine 34.5 µg/ml 31.0 µg/ml 6 5 it was demonstrated that the clearance
Bile 30.0 µg/ml 39.0 µg/ml 1 5 was slightly enhanced in dogs suffering
from nephroses (1.6 versus 1.4 ml/kg/
Saliva 5.8 µg/ml — 1 5
minute in healthy dogs).19
Bone 0.8 µg/g — 4 10
Clinical Relevance of
Pharmacokinetic
Properties
Table 3 summarizes pharmacokinetic
parameters for enrofloxacin in dogs and
TABLE 3 cats. These data confirm the previously
described favorable pharmacokinetic
Pharmacokinetic Parameters of properties of quinolones. The high
Enrofloxacin in Dogs and Cats5,8,11 bioavailability and the excellent extra-
cellular and intracellular tissue distribu-
Parameter Dog Cat tion are documented by an AUC ratio
(AUCoral:AUCIV × 100) of nearly 100%, a
Maximum plasma concentration, Cmax (µg/ml)a 1.7 1.8 maximum plasma concentration (Cmax) of
Time of maximum plasma concentration, Tmax (hr) 2 0.5–2 1.7 µg/ml in dogs (1.8 µg/ml in cats),
Area under the curve, AUC (µg•hr/ml) 10.4 10.4 which is achieved in 0.5 to 2 hours (Tmax),
and a high Vd (3.7 L/kg in dogs, 4.0 L/kg
Volume of distribution (steady state), Vdss (L/kg) 3.7 4.0
in cats) as well.1,7,9,10
Half-life, t1/2 (hr) 3.8 6.2 Those favorable pharmacokinetic
Protein binding (%) <30 properties allow efficient therapeutic
Bioavailability, oral (%) 95 100
strategies. Based on current knowledge,
treatment regimens providing high peak
aSum of enrofloxacin and ciprofloxacin, dosage 5 mg/kg orally. concentrations in plasma and tissues
appear to be best for successful therapy.
Fluoroquinolones were found to exhibit

10 Third International Veterinary Symposium on Fluoroquinolones Proceedings

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concentration-dependent antibacterial
activity against the relevant bacteria
occurring in small animal practice. In
addition, a postantibiotic effect (1–3
hours for enrofloxacin),20 with no visible
bacterial growth on culture, could be
shown experimentally after withdrawal
of active drug.
Based on these findings, a single
application of the total daily dose rather
than division of the dose into two or
more applications has been recommend-
ed for concentration-dependent drugs,
such as the fluoroquinolones. Additional-
ly, once daily dosing simplifies administra-
tion of the drug, significantly increasing
owner and patient compliance.
Conclusion
The 6-fluoroquinolones, such as
enrofloxacin, are antimicrobials with a
broad antibacterial spectrum and a favor-
able antibacterial efficacy. High bioavail-
ability and excellent extracellular and
intracellular distribution, especially into
inflamed tissues and phagocytes, make
them well suited even for the treatment
of chronic relapsing bacterial infections.
Excretion via the renal system and the
bile ensures very high concentrations in
the urinary and intestinal tracts.
The 6-fluoroquinolones are one of the
most useful classes of antibacterial
agents. Their outstanding antimicrobial
activity and their excellent pharmaco-
kinetic properties make them well suited
to effective therapy. Responsible clinical
use considering the pharmacokinetic and
pharmacodynamic properties and careful
instructions to the animal owner about
the correct administration of those drugs
will ensure the usefulness of fluoroquino-
lones in the future.
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