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PHARMA SCIENCE MONITOR

AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES

DISPOSITION KINETICS AND IN VITRO PLASMA PROTEIN BINDING OF

ENROFLOXACIN FOLLOWING SINGLE DOSE INTRAPERITONEAL
ADMINISTRATION IN ALBINO RATS
Nitesh Kumar*
Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and A. H., Mhow
453 446 (M. P.), India.

ABSTRACT
Pharmacokinetics of enrofloxacin (Fortius - Virbac Animal Health India Pvt. Ltd.,
Mumbai, India) was studied in five albino rats following intraperitonial (i.p.)
administration (5 mg/kg). Estimation of enrofloxacin in plasma was analyzed by
microbiological assay technique (cylinder plate diffusion method) using E. coli
(ATCC 25922) as the test organism. Kinetic parameter of enrofloxacin was calculated by
using one-compartment open model. Therapeutic concentration of 0.12 g/ml was
maintained up to 72 h and the drug was also detectable up to 72 h. Absorption half life
(t1/2 Ka), elimination half life (t1/2 ), mean residence time (MRT), Volume of distribution
during area under curve (Vdarea) and total body clearance (ClB) of 5.83 1.24 h, 42.84
2.43 h, 66.87 2.48 h, 6.76 0.30 l/kg and 1.87 0.18 ml/kg/min, respectively were
obtained for enrofloxacin in albino rats. The in vitro protein binding percent of
enrofloxacin in albino rats ranged from 37% to 44% with average of 41.23 %. The
AUC/MIC90 for a successful clinical/microbiological outcome of >100125 was achieved
o
at MIC90 of 0.25 g/ml and optimal C p /MIC (>10) was attained at MIC90 of 0.125 g/ml
in albino rats. The highest enrofloxacin MIC90 of bacteria that fulfills the minimum
AUC/MIC ratio (>100) for the present dosage regimen is 0.25 g/ml. To achieve the
o
optimal C p /MIC (>10), the present dosing regimen would allow an MIC90 of 0.125
g/ml for Gram-negative and Gram-positive pathogens. For maintaining therapeutic
concentration of 0.125 g/ml, a loading dose (D*) of around 3 mg/kg and maintenance
dose (D0) of 2 mg/kg may be used at the dosage interval () of 72 h for treating systemic
infections in albino rats.
Key words: Disposition kinetics, in vitro plasma protein binding, enrofloxacin, albino
rats.
INTRODUCTION
Enrofloxacin [1-cyclopropyl-7- (4-ethyl-1-piperazinyl) - 6- fluoro - 1, 4 dihydro
4 oxo 3- quinoline carboxylic acid] is a recent fluorinated quinolone carboxylic acid
derivatives developed exclusively for veterinary use [1]. It effectively penetrates all organs
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and tissues and the distribution pattern is more or less similar in all species. In different
species, enrofloxacin is de-ethylated to ciprofloxacin in vivo
antimicrobial agent used in human medicine

[3]

[2]

, which is also a potent

. Both enrofloxacin and ciprofloxacin are

bactericidal at very low concentrations for a broad spectrum of gram-negative and grampositive bacteria as well as mycoplasmas

[4]

. Pharmacokinetic studies of enrofloxacin in

healthy albino rats was carried out to obtain the detailed pharmacokinetic data and so as
to derive appropriate dosage regimen of enrofloxacin to treat various systemic infections.
MATERIALS AND METHODS
Experimental animals
Five clinically healthy adult albino rats of either sex weighing between 200 to 250
g body weights were used. The rats were kept in colony cage and maintained under
hygienic condition in the department of veterinary pharmacology and toxicology and
provide standard rodent diet as well as ad libitum clean drinking water with the help of
rodent drinking bottle. All animals were kept under the same experimental conditions
with natural day and night cycle. The animals did not receive any drug treatment before
the study. The study was approved by instutional ethical committee of College of
Veterinary Science and Animal Husbandry, Mhow, Madhya Pradesh, India.
Dosage forms
Enrofloxacin (Fortius - 10%) - an injectable single application commercial
preparation containing enrofloxacin in concentration of 100 mg/ml marketed by Virbac
Animal Health India Pvt. Ltd., Mumbai, India was used in the present study.
Enrofloxacin (5 mg/kg, i.p.) was given in each of the five albino rats.
Experimental design
The animals were individually weighed immediately before administering the
drug in order to determine the precise dose. Enrofloxacin (5 mg/kg) was injected
intraperitoneally in each albino rats and blood samples (approx.0.5 ml) were withdrawn
from the infra orbital sinus through an inner medial canthus of eye into heparinised glass
centrifuge tubes before and at 0.083, 0.25, 0.50, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 24, 48 and 72
h post drug administration. Blood samples were centrifuged at 3000 r.p.m. for 15 min at
room temperature in order to separate plasma and kept at - 4C until analysis, which was
usually done on the day of collection.
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Analytical method
The plasma samples were assayed by a standard microbiological assay technique
[5]

using Escherichia coli (ATCC 25922) as the test organism. The six wells, 8 mm in

diameter, were cut at equal distances into a (120 120 mm) petriplate containing 25 ml
of seeded agar. The test organism was grown in nutrient broth for 1/2 to 1 hour at 37oC
until the growth was seen (turbid by naked eye). Enrofloxacin assay plates were flooded
with the broth containing the organism and excess broth was drained out after some time.
The plates were dried in the incubator at 37oC for a period of about an hour. The wells
were filled with the test samples and/or an enrofloxacin standard solution (prepared from
a commercial solution). Standard curve of enrofloxacin was prepared in pooled
antibacterial-free plasma. The standards and samples were tested in triplicate. The plates
were kept at room temperature for 2 h before being incubating at 37oC for 18 h. The
mean inhibition zone diameters were measured and the concentrations in the plasma
samples were calculated from the standard curve. The standards were included in each
assay plate in order to compensate for any plate-to-plate variations. There was a linear
relationship between the zone of inhibition and the logarithm of the plasma enrofloxacin
concentration with a correlation coefficient of 0.99. The reproducibility of this method
was excellent and the inter-assay variability was < 5%. The limit of quantitation was 0.04
g/ml. A standard curve was considered acceptable if the quality control samples were
within 15% of the nominal concentration.
Pharmacokinetic analysis
The plasma concentration-time profile of enrofloxacin plotted on a semilogarithmic scale after intraperitoneal administration in each animal was used to establish
various disposition kinetic determinants and mean kinetic variables were obtained by
averaging the variables calculated for individual animals.
The log plasma drug concentrations versus time profile for each rat were analyzed
according to the computed least square regression technique. The kinetic parameters were
calculated manually by applying one-compartment open model as described

[6]

. The

concentration of the drug in plasma at any time is obtained by the following formula
(Eqn. 1):
Cp = Be-.t - A'e Ka.t
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(Eqn. 1)
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where, Cp is the plasma level of enrofloxacin at time t and e represents the base of
natural logarithm, A' and B are the extrapolated zero-time intercepts of the absorption
and elimination phases, respectively, Ka and are the absorption and elimination rate
constants, respectively.
The ultimate objective of present disposition study was to compute dosage regimen
of enrofloxacin in albino rats for the treatment of infectious diseases. Appropriate loading
(D*) and maintenance (D0) dose for maintaining minimum therapeutic concentration (Cp
min = MIC) of 0.125, 0.25 and 0.5 g/ml at desired dosage interval () of 24, 48 and 72 h
were also derived[7] as per the following equation (Eqn. 2 & 3):
D* = Cp (min) . Vdarea . (e. )

(Eqn. 2)

D0 = Cp (min) . Vdarea . (e. - 1)

(Eqn. 3)

Protein binding
Drug concentration of 1, 2, 3, 4 and 5 g/mL were added to the plasma of albino
rats and binding of enrofloxacin was determined in vitro based on the diffusion of free
antibiotic into the agar medium[8]. The concentration of enrofloxacin in phosphate buffer
and plasma were estimated by microbiological assay. The differences in the diameters of
the inhibition zones between the solutions of the drugs in the buffer and plasma samples
were calculated.
Pharmacodynamic efficacy / Efficacy predictors
Clinical and microbiological outcomes of enrofloxacin therapy can be predicted
by the site of infection and in terms of pharmacokinetic pharmacodynamic (PK/PD)
relationships based on Cmax : MIC and the AUC : MIC ratio[9]. The pharmacodynamic
o
efficacy of enrofloxacin was determined by calculating C p / MIC90 and AUC/MIC ratios

following i.p. administration of drugs. In order to calculate the PK/PD efficacy predictors
hypothetical MIC values were used. T h e minimum therapeutic concentration (MIC90)
v a l u e o f e n r o f l o x a c i n f o r d i f f e r e n t s p e c i e s o f microorganisms ranged
between 0.001 to 1.0 g/ml[10]. Keeping in mind the synergistic effect of the body
immune system and other in vivo factors as well as to cover most of the susceptible
organisms, the MIC90 of 0.125, 0.25 and 0.5 g/ml are taken into consideration. In the

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present investigation, a MIC90 of 0.125 g/ml of enrofloxacin was taken into

consideration for discussion.
RESULTS
Clinical examination of all animals before and after each trial did not reveal any
abnormalities. No serious adverse events of enrofloxacin were observed throughout the
study. The plasma concentrations (g/ml) of enrofloxacin at different time interval in
albino rats following single intraperitoneal administration of enrofloxacin (5 mg/kg,
b.wt.) were depicted in Figure 1. Enrofloxacin concentrations were present in plasma
from 0.083 to 72 h. The mean peak plasma concentration of enrofloxacin was observed
2.66 0.03 g/ml at time intervals of 1 h and plasma concentrations gradually declined
up to 72 h. The minimum therapeutic concentration ( 0.125 g/ml) of enrofloxacin was
maintained throughout from 0.083 to 72 h.

Figure 1
Plasma concentrations (g/ml) of enrofloxacin in albino rats
The values of different kinetic parameters of enrofloxacin such as the absorbtion
rate constant (Ka) and absorbtion half - life (t1/2 Ka) of enrofloxacin was noted to be
0.157 0.05 h-1 and 5.83 1.24 h, respectively and the elimination rate constant (),
elimination half life (t1/2 ), area under curve (AUC), area under first moment curve

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(AUMC), mean residence time (MRT), volume of distribution at area under curve
(Vdarea) and total body clearance (ClB) of enrofloxacin were depicted in Table 1.
Table 1: shows kinetic parameters of enrofloxacin in albino rats calculated by one
compartment open model following single intraperitoneal (i.p.) dose @ 5 mg/kg
b.wt.
PK parameters (Unit)

Enrofloxacin

A (g/ml)

0.49 0.05

B (g/ml)

0.82 0.01

Cp0 (g/ml)

1.31 0.04

Ka (h-1)

0.157 0.05

t 1/2 Ka (h)

5.83 1.24

(h-1)

0.016 0.001

t 1/2 (h)

42.84 2.43

AUC (g/ml.h)

46.44 4.39

AUMC (g/ml.h2)

3141.93 396.79

MRT (h)

66.87 2.48

K12 (h-1)

0.039 0.01

K21 (h-1)

0.110 0.04

Kel (h-1)

0.024 0.002

Fc

0.691 0.01

TP

0.465 0.03

VdC (L/kg)

3.83 0.14

VdB (L/kg)

6.08 0.07

Vdarea (L/kg)

6.76 0.30

VdSS (L/kg)

5.21 0.17

CIB (ml/kg/min)

1.87 0.18

Where, A = zero time intercept for distribution phase; B = zero time intercept for
elimination phase; C0p (g/ml) = theoretical zero time concentration (A+B); Ka =
absorption rate constant; t 1/2 Ka = absorption half life; = elimination rate constant; t 1/2
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= elimination half life; AUC = total area under plasma drug concentration curve; AUMC
= area under first moment curve; MRT = mean residential time; K12 = rate constant of
drug transfer from central compartment to peripheral compartment; K21 = rate constant of
drug transfer from peripheral to central compartment; Kel = rate constant of drug
elimination from central compartment; Fc = fraction of drug available for elimination
from central compartment; T P = approximate tissue to plasma concentration ratio; Vd
area

= apparent volume of distribution; VdSS = volume distribution at steady state; ClB =

total body clearance.

The dosage regimen to maintain the different levels of therapeutic concentrations
in plasma for i.p. route in albino rats at different dosage intervals are presented in Table
2. For maintaining CP min of 0.125 g/ml, the loading doses (D*) were calculated to be
1.87 0.16 and 2.80 0.30 mg/kg while maintenance doses (D0) were calculated to be
1.03 0.12 and 1.96 0.26 mg/kg at dosage interval () of 48 and 72 h, respectively.
Like wise, D*s and D0s were derived for maintaining CP min of 0.25 and 0.5 g/ml at
of 48 and 72 h (Table 2).
Table 2: shows calculated dosage regimens of enrofloxacin in albino rats for
intraperitoneal route.

Cp min

(h)

Dose (mg/kg)

Enrofloxacin

(g/ml)
48
0.125
72
48
0.25
72
48
0.50
72

D*
D0
D*
D0
D*
D0
D*
D0
D*
D0
D*
D0

1.87 0.16
1.03 0.12
2.80 0.30
1.96 0.26
3.75 0.32
2.06 0.25
5.60 0.59
3.91 0.52
7.50 0.64
4.12 0.49
11.21 1.19
7.83 1.05

Where,
D* = Loading dose, D0 = Maintenance dose, = Dosage interval, C
p min = Minimum therapeutic
concentration in plasma (MIC).

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The individual PK/PD ratios for the assumed MIC90 values for enrofloxacin are
summarized

in

Table

3.

The

threshold

AUC/MIC90

for

successful

clinical/microbiological outcome of >100125 was achieved at MIC90 of 0.25 g/ml and

o
optimal C p /MIC (>10) was attained at MIC90 of 0.125 g/ml in albino rats. The highest

enrofloxacin MIC90 of bacteria that fulfills the minimum AUC/MIC ratio (>100) for the
o
present dosage regimen is 0.25 g/ml. To achieve the optimal C p /MIC (>10), the

present dosing regimen would allow an MIC90 of 0.125 g/ml for Gram-negative and
Gram-positive pathogens.
o
Table 3: depicts efficacy predictors ( C p /MIC and AUC/MIC) estimated for

enrofloxacin in albino rats using different MIC values.

MIC 0.125 (g/ml)

MIC 0.25 (g/ml)

MIC 0.5(g/ml)

o
C p /MIC

10.48

5.24

2.62

AUC/MIC

371.52

135.76

32.88

o
For calculations the applied values were: C p = 1.31 g/ml, AUC = 46.44 g/ml.h in
albino rats.
DISCUSSION

In the current investigation, we measured the residual concentrations of

enrofloxacin in the plasma of albino rats using the microbial inhibition test. The reasons
that we selected the bioassay are: (a) the bioassay measures the total activity, which could
be more useful for pharmacodynamic evaluations than HPLC [11]; (b) congruent results
between the data determined by the microbiological assay and those determined by
HPLC

[12]

; and (c) the bioassay method is precise, reproducible, and does not require

specialized equipment or toxic solvents

[13]

. For these reasons, the application of

microbiological assay for measuring enrfloxacin concentration is suitable [14].

The minimum inhibitory concentration (MIC90) values of enrofloxacin for
different species of microorganisms ranged between 0.001 to 1.0 g/ml [10]. Hence, in the
present investigation, the dosage regimen of enrofloxacin was calculated at three different
therapeutic levels (0.125, 0.25 and 0.5 g/ml) and at two dosage intervals (48 and 72 h).

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As compared to the present study, a shorter t1/2 of 2.82 0.33 h in goat[15], 2.5
h[16] & 2.19 h[17] in rabbit and 2.4 h[18] & 3 h[19] in dog were reported after i.v.
administration of enrofloxacin. However, a very lower

t1/2 of 0.734 h (enrofloxacin)

and 0.934 h (ciprofloxacin)[20], 0.734 h[21] and 1.7 h[22] were noted in cows after i.v.
administration of enrofloxacin. A very lower t1/2 of 1.97 0.23 h was noted in buffalo
bulls[23] and very lower value of 0.74 h (enrofloxacin) and 1.38 h (ciprofloxacin) in goats
were noted[24]. The much higher t1/2 of 42.84 2.43 h obtained in the present study
indicate comparatively the much slower removal of enrofloxacin from the body of albino
rats as compared to above noted species. This is further supported by very lower value of
rate constant of drug elimination from central compartment (Kel) obtained for
enrofloxacin in albino rats (0.024 0.002 h-1).
A volume of distribution of 0.6 L/kg[20,21] and 1 L/kg[22] in cows, 0.61 0.13 L/kg
in buffalo bulls[23], 2 L/kg[25], 0.77 0.11 to 1.22 0.07 L/kg[26] and 2.3 L/kg[27] in
horses, 2.49 0.43 L/kg in foals[28], 3.02 0.22 L/kg in sheep[29] and 2.34 0.54 L/kg in
goats[15] were reported while a very high volume of distribution (Table 2) was noted in
the present study. This may suggest that enrofloxacin may be distributed well in body
tissues and fluids in albino rats than all above noted species, which may also be beneficial
for treating systemic microbial infections in albino rats.
ClB values of enrofloxacin were noted to be 1.87 0.18 ml/kg/min in the present
study. More or less similar ClB values of 1.73 ml/kg/min in foals

[28]

and 1.50 2.33

ml/kg/min in horses [26] were noted for enrofloxacin. However, a very longer ClB value of
27.1 ml/kg/min in dogs[18], 22.8 6.8 mL/kg/min in rabbits[17], 9.27 2.40 ml/kg/min in
sheep[29] and 9.40 1.36 ml/kg/min in goats[15] were obtained after i.v. administration of
enrofloxacin.
Variation among species, breed, sex, age and different methods for estimation of
drugs may contribute to the wide discrepancies in kinetic parameters as suggested by
various workers [30].
The major objective of the present study was to calculate and modify the dosage
regimen of enrofloxacin. Enrofloxacin may be routinely used at the dose rate of 2.8
mg/kg as loading dose (D*) and 2 mg/kg as maintenance dose (D0) for maintaining MIC
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of 0.125 g/ml at the dosage interval () of 72 h for treating septicemia and any other
systemic infections in albino rats. For treating severe infections (MIC = 0.25 and 0.5
g/ml), the suggested D* and D0 may be used (Table 3).
The in vitro protein binding percent of enrofloxacin in albino rats ranged from
37% to 44% with average of 41.23 %. The extent of binding of enrofloxacin to the
plasma proteins of albino rats (41.23 %) in the present study was in accordance to the
corresponding values of 36-45% for enrofloxacin[22] in cattle, 24-38% for levofloxacin in
man[31] and 17.0 1.2% in calves for levofloxacin[32] as well as 26% for danofloxacin[33],
17- 24 % for orbifloxacin in horses[34] and 34.5% for moxifloxacin in lactating ewes[35]
have been recorded. The drug was mainly bound to albumin, and the binding was fully
reversible. This low degree of protein binding will not inhibit distribution of the drug to
the interstitial fluid (the site of action for most antibacterial drugs), and interstitial fluid
drug concentrations are expected to equal the plasma concentrations [34].
There is general consensus that the clinical and microbiological outcomes of
fluoroquinolone treatment are favourable and selection of a mutant subpopulation is
preventable if an AUC/MIC 100125 and a Cmax,/MIC of 10 are achieved in Gramnegative infections[36,37]. For Gram-positive pathogens, the minimum required Cmax,/MIC
is also 10, while the optimum AUC/MIC target values are still a topic of debate[36]. An
AUC/MIC of 3050 is claimed to be optimal in numerous studies performed mainly in in
vitro or animal models

[38]

. Other studies conducted on different patient populations

suggested a minimum AUC/MIC of 87-125 to achieve a favourable outcome and to avoid

development of resistance regardless of whether the organism is Gram-positive or Gramnegative[37].
o
Considering the AUC/MIC90 and C p /MIC90 ratios obtained in the present study,

it can be stated that enrofloxacin administered intraperitoneally in the dosing schedule

applied is efficacious against bacteria with MIC90 values under 0.125 g/ml in albino
o
rats. The high value of AUC/MIC90 (371.52) and C p /MIC90 (10.48) obtained in the

present study, provides support for excellent clinical and bacteriological efficacy of
enrofloxacin in albino rats. In agreement with the present results, a Cmax/MIC ratio of
more than 10 has been reported following subcutaneous administration of both
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danofloxacin and enrofloxacin in calves [39]. The AUC/MIC ratio was higher in present
study than the values of 76.6 reported for levofloxacin administered intramuscularly in
calves [32] and for other fluoroquinolones, 40.7 for marbofloxacin in cows [40]. However, it
is necessary to note that the numerical values of AUC/MIC90 and Cmax/MIC90 used as a
surrogate marker to predict optimal dosage, have been generated in experimental
infections in laboratory animals or in human clinical trials [41].
CONCLUSION
In conclusion, the fact that general adverse reactions were not observed in any
albino rats and favourable pharmacokinetic properties of enrofloxacin, such as long halflife and high bioavailability with wide penetration into different body fluids and tissues
o
from blood, were found. Based on the calculated AUC/MIC90 and C p /MIC90, a dosage

of 3 mg/kg could be effective in albino rats MIC90 > 0.125g/ml following

intraperitoneal route.
ACKNOWLEDGEMENT
The author is thankful to Virbac Animal Health India Pvt. Ltd., Mumbai, India for
providing gift samples of enrofloxacin (Fortius).
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For Correspondence:

Dr. Nitesh Kumar

Assistant Professor and I/C Head
Department of Pharmacology and Toxicology
College of Veterinary Science and A. H., Mhow 453 446 (M. P.), India
Mob. No. 09039 170494
Fax No. 07324-275655
E-mail: drnitesh_kumar01@yahoo.co.in

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