Embedded Scribd iPaper - Requires Javascript and Flash Player

Israel Journal of Veterinary Medicine  Vol. 69 (2)  June 2014 Sadariya, K.A. 68
INTRODUCTION
Non-steroidal anti-inflammatory drugs (NSAIDs) are fre-
quently recommended with antibiotics for the treatment of
various bacterial infections in animals. It is well documented
that concurrently administered drugs as well as the disease
state may alter the pharmacokinetics of one or both drugs
(1). Fluoroquinolones are group of antimicrobials that have
become widely used in veterinary medicine. Moxifoxacin
is a novel fourth generation fuoroquinolone with a broad
spectrum of antibacterial activity against Gram-positive and
Gram-negative bacteria, anaerobes and atypical organisms
such as Mycoplasma and Chlamydia spp. (2). It has the highest
potency against Staphylococcus aureus and Staphylococcus epi-
dermidis compared to gatifoxacin, levofoxacin, ciprofoxacin
and ofoxacin (3). Te drug thus seems to be extremely use-
ful in a variety of infections including those of urinary tract,
respiratory tract, soft tissues, bones and joints of animals.
Ketoprofen is a routinely used non-steroidal anti-infamma-
tory, analgesic and antipyretic agent in veterinary practice (4).
Pharmacokinetics of moxifoxacin has been studied in
Efect of Febrile Condition and Ketoprofen Co-administration
on Pharmacokinetics of Moxifoxacin Following Intravenous
Administration in Sheep
Sadariya, K.A.,
1
* Patel, J.B.,
1
Bhavsar, S.K.
2
and Taker
,
A.M.
1
1
Department of Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, Anand Agricultural
University, Anand-388001, Gujarat, India.
2
Department of Pharmacology and Toxicology, Vanbandhu College of Veterinary Science and Animal Husbandry, Navsari
Agricultural University, Navsari-396450, Gujarat, India.
* Corresponding Author: Dr. K. A. Sadariya, M.V.Sc., Ph.D., Assistant Professor, Department of Pharmacology and Toxicology, College of Veterinary
Science and Animal Husbandry, Anand Agricultural University, Anand-388001, Gujarat (India). Cell. No: 09427180817, Phone & Fax: 02692-261486.
Email: dr_kasadariya@yahoo.co.in.
ABSTRACT
Te present study was planned to determine the efect of intramuscularly administered ketoprofen (3 mg/kg)
and lipopolysaccharide induced febrile condition on pharmacokinetics of moxifoxacin following intravenous
administration (5 mg/kg) in sheep. Moxifoxacin was assayed in plasma by High Performance Liquid
Chromatography. Following intravenous administration of moxifoxacin in normal sheep, apparent volume
of distribution area (Vd
area
), under plasma drug concentration-time curve (AUC
0-∞
), area under frst moment
curve (AUMC), elimination half-life (t
1/2β), total body clearance (Cl
B
) and mean residence time (MRT)
were 4.88 ± 0.20 L/kg, 8.38 ± 0.23 mg.h/mL, 49.52 ± 3.83 mg.h
2
/mL, 5.70 ± 0.37 h, 0.60 ± 0.02 L/h/kg
and 5.87 ± 0.32 h, respectively. Following intravenous administration of moxifoxacin in ketoprofen-treated
sheep, a signifcant increase in mean value of AUC
(0-∞)
and AUMC while signifcant decrease in mean value
of t
½β, Vd
area
, Vd
ss,
Cl
B
and MRT were observed in comparison to respective pharmacokinetic parameters
of moxifoxacin in normal sheep. However, in febrile sheep, the AUC
(0-∞)
and AUMC were signifcantly
increased while Cl
B
and Vd
area
were signifcantly decreased as compared to normal sheep. Febrile condition
and ketoprofen co-administration appears to alter the pharmacokinetics of moxifoxacin in sheep.
Keywords: Pharmacokinetics, moxifoxacin, ketoprofen, febrile condition, sheep.
Israel Journal of Veterinary Medicine  Vol. 69 (2)  June 2014 69 Pharmacokinetics of Moxifoxacin in Sheep
calves (5), bufalo calves (6), lactating ewes (7), goats (8),
camels (9), rats (10) and rabbits (11). Te disposition kinet-
ics of levofoxacin (12), gatifoxacin (13), danofoxacin (14),
marbofoxacin (15) and enrofoxacin (16, 17) has been deter-
mined following intravenous administration in febrile goats.
Despite the great potential for clinical use of moxifoxacin,
the data on its pharmacokinetics in febrile condition and
ketoprofen co-administration in sheep are not available. In
view of this, the present study was undertaken to determine
the efect of ketoprofen and febrile condition on pharmaco-
kinetics of moxifoxacin in sheep.
MATERIALS AND METHODS
Experimental Animals
Te study was conducted on six Patanwadi sheep of 2-3 years
of age weighing between 25 and 30 kilograms. Tey were ex-
amined clinically and to be found healthy. Te animals were
housed in separate pens and provided with standard ration.
Water was provided ad libitum. All necessary managerial
procedures were adopted to keep the animals free from stress.
Te experimental protocol was approved by the
Institutional Animal Ethics Committee (IAEC No. 2010/
VPT/80) and constituted by Committee for Purpose of
Control and Supervision of Experiments on Animals
(CPCSEA), New Delhi (Reg. No. 486/01/A/CPCSEA).
Induction of febrile state
Febrile state in sheep was induced by injecting lipopolysac-
charide (LPS) of Escherichia coli (055:B5) at the dose rate
of 0.2 µg/kg body weight intravenously (13). Tis dose of
LPS caused a rise in body temperature within 30 minutes
and fever persisted for 12 h. Te minimum rise in tempera-
ture (0.84 to 1.12°C) after injection of LPS endotoxin was
considered as the time of the drug administration (18). LPS
was again injected at dose rate of 0.1 µg/kg body weight at
12 h and at dose rate of 0.05 µg/kg body weight after 24 h
of frst dose of LPS respectively to maintain the febrile state
for up to 36 h.
Drugs and Chemicals
Moxifoxacin technical grade pure powder was obtained
from Ms. Zydus Research Centre, Gujarat, India. Ortho-
phosphoric acid, acetonitrile, methanol and water of HPLC
grade were purchased from Merck Limited, Mumbai, India.
Lipopolysaccharide of Escherichia coli (055:B5) was pur-
chased from Sigma Pvt. Ltd., Mumbai, India.
Experimental plan and drug administration
Te study was conducted in a cross-over design with an in-
terval of ffteen days between successive administrations of
the drug. Six healthy sheep were employed to investigate the
efect of intramuscularly administered ketoprofen (3 mg/kg)
and LPS induced febrile condition on pharmacokinetics of
moxifoxacin following intravenous administration (5 mg/
kg) in sheep. Intramuscular (IM) injection was given into
the deep gluteal muscle using 20G × 25mm needle and the
intravenous (IV) injection of the drug was given through
the jugular vein.
Collection of blood samples
Blood samples (2 mL) were collected from an IV catheter
(Venfon, BD, Franklin Lakes, NJ, USA. 22G × 0.9 × 25
mm) fxed into the contralateral jugular vein. Following IV
administration, blood samples were collected in sterile hepa-
rinized vials at 0 minutes (before drug administration), 2, 5,
10, 15, 30 and 45 minutes and at 1, 2, 4, 8, 12, 18, 24 and 36
h. Plasma was separated soon after collection by centrifuga-
tion at 3000 rpm for 10 minutes at 10°C (Eppendorf 5804
R, Germany). Separated plasma samples were transferred to
labeled cryovials and stored at -40°C until assayed for moxi-
foxacin concentration.
Moxifoxacin assay
Moxifoxacin was assayed in plasma by adopting the proce-
dure as reported by Sultana et al. (2010) with minor modi-
fcations (19). Te high performance liquid chromatogra-
phy (HPLC) apparatus of Laballiance (Pennsylvania, USA)
comprising of quaternary gradient delivery pump (model
AIS 2000) and UV detector (model 500) was used for assay.
Chromatographic separation was performed by using reverse
phase C
18
column (PARTISIL 5 ODS-3 RAC-II column;
4.6 ´ 100 mm ID, Whatman, Kent, UK) at room temper-
ature. Te HPLC data integration was performed using
software Clarity (Version 2.4.0.190, Dataapex, Petrzilkova,
Czech Republic, Central Europe). Te mobile phase consist-
ed of a mixture of methanol and water (55:45 v/v), pH ad-
justed to 2.3 with ortho-phosphoric acid. Te mobile phase
was pumped into column at a fow rate of 0.7 ml/min at
ambient temperature. Te efuent was monitored at 296 nm
Research Articles
Israel Journal of Veterinary Medicine  Vol. 69 (2)  June 2014 Sadariya, K.A. 70
wavelength. Te limit of detection was 0.05 mg/ml. Te low-
er limit of quantitation was 0.1 mg/ml.
For extraction of moxifoxacin from plasma, 100 ml (0.1
mL) of plasma sample was taken in micro-centrifuge tube
(2.0 mL capacity). Acetonitrile (200 ml) was added in order
to precipitate plasma proteins. Te mixture was vortexed for 1
minute and centrifuged at 10000 rpm for 5 minutes at 10°C.
Te supernatant was decanted in clean sterile microcentrifuge
tubes and 20 ml supernatant was injected into the loop in-
jector. A standard curve of moxifoxacin was prepared using
drug-free sheep plasma. Te assay was found to be sensitive,
reproducible and its linearity was observed from 0.1 to 50
mg/mL with mean correlation coefcient (r
2
) > 0.999. Non-
compartmental pharmacokinetic analysis was performed
using software PK solution (version 2.0, Summit Research
Services, Colorado, USA) to calculate various pharmacoki-
netic parameters from plasma concentrations of moxifoxacin.
Statistical analysis
Moxifoxacin plasma concentrations and pharmacokinet-
ic parameters of diferent treatment groups were compared
by students’ “t” test using SPSS software (version 12.0.1).
Statistical diferences were considered at p≤0.05 and p≤0.01.
Te pharmacokinetic parameters were expressed in terms of
Mean ± Standard Error (S.E.).
RESULTS
All animals remained in good health throughout the accli-
matization and study period. Plasma moxifoxacin concen-
trations at diferent time intervals following IV injection
alone, co-administered intramuscularly with ketoprofen and
under a febrile state in sheep are presented as a semi loga-
rithmic plot in Figure 1.
Te intravenous administration of a single dose of moxi-
foxacin alone in sheep resulted in plasma concentrations of
8.48 ± 0.21 mg/mL at 2 minutes, which declined rapidly to
1.20 ± 0.03 mg/mL at 1 h and the drug concentration of 0.17
± 0.01 mg/mL was detected up to 12 h. Plasma drug con-
centrations were signifcantly higher (p≤ 0.01) in ketoprofen-
treated sheep as compared to normal sheep. A plasma drug
concentration of 16.47 ± 0.71 mg/mL observed at 2 minutes
in febrile sheep which declined to 2.09 ± 0.06 mg/mL at 1 h
and was signifcantly higher (p≤ 0.01) as compared to plasma
drug concentration found at 1 h in normal sheep. Plasma
drug concentrations observed were signifcantly higher (p≤
0.01) from 2 minutes to 18 h in febrile than normal sheep.
Comparison of pharmacokinetic parameters (mean ± SE) of
moxifoxacin after IV administration (5 mg/kg) in normal,
ketoprofen-treated (3 mg/kg) and febrile sheep are depicted
in Table 1.
Following IV administration of moxifoxacin in ketopro-
Figure 1: Semilogarithmic plot
of moxifoxacin concentration
in plasma versus time following
intravenous administration (5
mg/kg) in normal, ketoprofen
treated (3 mg/kg) and febrile
sheep. Each point represents
mean and standard error of six
animals.
Research Articles
Israel Journal of Veterinary Medicine  Vol. 69 (2)  June 2014 71 Pharmacokinetics of Moxifoxacin in Sheep
fen-treated sheep, a signifcant increase in the mean value of
various pharmacokinetic parameters such as Cp
0
(p≤ 0.05),
β (p≤ 0.05), AUC
(0-∞)
(p≤ 0.01) and AUMC (p≤ 0.01) along
with signifcant decrease in mean values of t
½β
(p≤ 0.05),
Vd
area
(p≤ 0.01), Vd
ss
(p≤ 0.01)
,
Cl
B
(p≤ 0.01) and MRT (p≤
0.05) were observed as compared to respective pharmacoki-
netic parameters of moxifoxacin in normal sheep. Following
IV administration of moxifoxacin in febrile sheep, signif-
cant increases (p≤ 0.01) in mean values of Cp
0
, α, AUC
(0-∞)
and AUMC, whereas signifcant decreases (p≤ 0.01) in mean
value of t
½α, Vd
area
, Vd
ss
and
Cl
B
were observed as compared
to respective pharmacokinetic parameters of moxifoxacin
in normal sheep.
DISCUSSION
Te pharmacokinetics of moxifoxacin (5 mg/kg) was studied
following IV administration of moxifoxacin alone, co-ad-
ministered with ketoprofen (3 mg/kg) and in a febrile state.
Following IV administration of moxifoxacin in ketoprofen-
treated and febrile sheep, the peak plasma levels of drug were
higher (p< 0.05) than normal sheep (8.48 ± 0.21 µg/mL). Te
plasma moxifoxacin concentration was detected for up to 12
hrs in the moxifoxacin treated group, whereas in ketoprofen
treated and febrile group it was detected up to 18 hrs. Te
LPS induced febrile state produced a significant increase in
the plasma levels of moxifoxacin following IV administration
in sheep. Similarly, signifcant increases in plasma levels of en-
rofoxacin (16), marbofoxacin (15) and danofoxacin (14) fol-
lowing IV administration has been observed in febrile goats.
In the present study, signifcant increases in mean values
of Cp
0
, β, AUC
(0-∞)
and AUMC, whereas signifcant de-
crease in mean values of t
½β, Vd
area
, Vd
ss,
Cl
B
and MRT were
observed in ketoprofen-treated sheep as compared to respec-
tive pharmacokinetic parameters of moxifoxacin in normal
sheep. Similarly, co-administration of paracetamol (50 mg/
kg, IM) or meloxicam (0.5 mg/kg, SC) altered the pharma-
cokinetics of levofoxacin (4 mg/kg, IV) in crossbred calves
(20, 21). Te values of AUC
(0-∞)
of levofoxacin (12.7 ± 0.12
µg.h/mL) following co-administration with paracetamol was
higher as compared to levofoxacin alone (7.66 µg.h/mL)
treated calves. Similar to fnding as presented in this study,
t
½β of levofoxacin (1.38 h) following co-administration with
paracetamol was shorter than levofoxacin alone (3.67 h) in
treated calves (20, 22). A signifcant increase in t
½β and a
signifcant decrease in the C
max
of enrofoxacin were found
following co-administration with funixin meglumine com-
pared to enrofoxacin alone treated dogs (23). Concomitant
IM administration of meloxicam (0.5 mg/kg) altered the
disposition of moxifoxacin (5 mg/kg) in female rats (10).
Table 1: Comparison of pharmacokinetic parameters (mean ± SE) of moxifoxacin after intravenous administration
(5 mg/kg) in normal, ketoprofen-treated (3 mg/kg) and febrile sheep (n=6).
Pharmacokinetic
parameter
Unit Sheep
Normal/Healthy Ketoprofen-treated Febrile
Cp
0
mg/mL 7.00 ± 0.23 9.43 ± 0.78* 18.41 ± 1.54**
α h
-1
0.22 ± 0.03 0.29 ± 0.04 3.00 ± 0.43**
β h
-1
0.12 ± 0.01 0.17 ± 0.01* 0.12 ± 0.01
t
½a
h 3.55 ± 0.56z 2.63 ± 0.42 0.25 ± 0.03**
t
½b
h 5.70 ± 0.37 4.08 ± 0.25* 5.70 ± 0.16
AUC
(0 - ¥)
mg.h/mL 8.38 ± 0.23 17.55 ± 0.25** 14.88 ± 0.39**
AUMC mg.h
2
/mL 49.52 ± 3.83 84.14 ± 1.96** 88.82 ± 4.38**
Vd
area
L/kg 4.88 ± 0.20 1.67 ± 0.09** 2.76 ± 0.04**
Vd
ss
L/kg 3.49 ± 0.11 1.37 ± 0.02** 2.00 ± 0.03**
Cl
B
L/h/kg 0.60 ± 0.02 0.29 ± 0.01** 0.34 ± 0.01**
MRT h 5.87 ± 0.32 4.79 ± 0.07* 5.95 ± 0.15
* Significant at P<0.05, ** significant at P<0.01 when compared with respective values of normal sheep. Cp
0
:
Concentration at time 0; α: Exponential coefcient of distribution; β: Exponential coefcient of elimination; t
½α:
Distribution half life, t
½β: Elimination half life, AUC
(0-∞)
: Area under the curve, AUMC: Area under frst moment
curve, Vd
area
: Apparent volume of distribution, Vd
ss
: Volume of distribution at steady-state; Cl
B
: Total body
clearance; MRT: Mean residence time.
Research Articles
Israel Journal of Veterinary Medicine  Vol. 69 (2)  June 2014 Sadariya, K.A. 72
Similarly, it has been reported that concomitant intravenous
use of naproxen or diclofenac (20 mg/kg) signifcantly altered
the pharmacokinetics of tetracycline (5 mg/kg) as compared
to tetracycline alone treated rats (24). In contrast, it has been
described that diclofenac sodium (1 mg/kg, I/M) did not
alter signifcantly the pharmacokinetic profles of enrofoxa-
cin in calves (5 mg/kg, I/V) and in bufalo calves (4 mg/kg,
I/V) (25, 26).
Following IV administration of moxifoxacin in febrile
sheep, the AUC (14.88 ± 0.39 mg.h/mL) and AUMC (88.82
± 4.38 mg.h
2
/mL) were signifcantly higher as compared to
normal sheep. Signifcant decreases in Vd
area
(2.76 ± 0.04 L/
kg), Vd
ss
(2.00 ± 0.03 L/kg), Cl
B
(0.34 ± 0.01 L/h/kg) and
t
1/2α
(0.25 ± 0.03 h) of the drug were observed in febrile
compared to normal sheep. In the present study, Vd
area
was
signifcantly decreased from 4.88 ± 0.20 L/kg to 2.76 ± 0.04
L/kg in febrile compared to normal sheep.
Te acute phase response induced by fever includes syn-
thesis of acute phase hepatic proteins, including a
1
-acid gly-
coprotein, which binds some drugs and which may produce
a decrease in their volume of distribution. However, it should
be noted that this contributes only a minor degree to the de-
cline of moxifoxacin volume of distribution because of its
low degree of protein binding (27).
After administration of the lipopolysaccharide, the slow-
er elimination of the drug may be the result of renal and/or
hepatic modifications caused by the toxin. Endotoxin can
possibly impair the excretion process of organic anions in
the liver at the stage of transport from intracellular storage
to bile via the canalicular membrane (28). Furthermore, it is
possible that a decrease in the glomerular filtration rate in-
duced by endotoxin plays an important role in the decrease of
body clearance of drugs which are widely eliminated by the
renal route. Moreover, it has been reported that endotoxin
produces an increase in tubular reabsorption and a decrease
in tubular secretion of some drugs including moxifoxacin
(28, 29).
Findings of the present study agree with previous fnd-
ings of signifcant increase in AUC (2.368 ± 0.18 to 4.26 ±
0.4 mg.h/mL), AUMC (9.93 ± 0.65 to 33.2 ± 1.9 mg.h
2
/
mL) and MRT (4.196 ± 0.3 to 8.3 ± 0.6 h) and decrease in
Cl
B
(0.58 ± 0.031 to 0.31 ± 0.02 L/h/kg) following IV ad-
ministration of danofoxacin in febrile compared to normal
goats (14). Approximating our fndings, there was highly sig-
nifcant increase in absorption half life, α, β, AUC
(0-∞)
and
C
max
whereas there was signifcant decrease in t
1/2α
and t
1/2β
in febrile rabbits as compared to normal rabbits following
oral administration of ciprofoxacin (30). Similarly, a signif-
cant rise in AUMC and a signifcant reduction in b, t
1/2β and
Vd
area
were reported in experimentally induced febrile state as
compared to normal rabbits (31). Additionally, the fndings
have been well supported by observing similar alterations in
pharmacokinetics following IV administration of enrofoxa-
cin (16), marbofoxacin (15) and gatifoxacin (13) in febrile
goats, levofoxacin in febrile calves and febrile sheep (32, 33).
In conclusion, co-administration of ketoprofen and LPS
induced febrile conditions causing alterations in pharma-
cokinetics of moxifoxacin in sheep. It would be prudent to
raise the awareness regarding pharmacokinetics in febrile
animals and the potential drug-to-drug interaction between
moxifoxacin and ketoprofen.
AKNOWLEDGEMENT
Te authors express their sincere gratitude to Dean, College of
Veterinary Science and A.H., Anand Agricultural University,
Anand (India) for providing all the facilities required for this re-
search work.
REFERENCES
1. Hardman, J. G. and Limbird L. E.: Goodman and Gilman’s-
Te Pharmacological Basis of Terapeutics, Mc Graw Hill, New
York, 2001.
2. Brown, S.A.: Fluorquinolones in animal health. J. Vet. Pharma-
col. Ter. 19: 1-14, 1996.
3. Kowalski, R.P., Dhaliwal, D.K. and Karenchak, L.M.: Gatifoxa-
cin and moxifoxacin: an in vitro susceptibility comparison to lev-
ofoxacin, ciprofoxacin and ofoxacin using bacterial keratitis iso-
lates. Am. J. Ophthalmol. 136: 500-505, 2003.
4. Boothe, D. M.: Te analgesic, antipyretic, anti-infammatory
drugs. In: Adams, R.: Veterinary Pharmacology and Terapeu-
tics. Iowa State University Press. Ames IA, pp. 433-451, 2001.
5. Goudah, A. and Hasabelnaby, S.: Pharmacokinetics and bioavail-
ability of moxifoxacin in calves following diferent routes of ad-
ministrations. Chemotherapy. 56: 26-31, 2010.
6. Pathania, R. and Sharma, S.K.: Pharmacokinetics and bioavail-
ability of moxifoxacin in bufalo calves. Res. Vet. Sci. 88: 108-
112, 2010.
7. Goudah, A.: Disposition kinetics of moxifoxacin in lactating
ewes. Vet. J. 178: 282-287, 2007.
8. Carceles, C.M., Villamayor, L., Escudero, E., Marín, P. and Fer-
nandez-Varon, E.: Pharmacokinetics and milk penetration of
moxifoxacin after intramuscular administration to lactating
goats. Vet. J. 173: 452-455, 2007.
9. Abdelaty, A. M., Goudah, A., Shah, S. S., Shin, H.C., Shimoda,
M. and Shim, I.H.: Pharmacokinetic variables of moxifoxacin in
Research Articles
Israel Journal of Veterinary Medicine  Vol. 69 (2)  June 2014 73 Pharmacokinetics of Moxifoxacin in Sheep
healthy male camels following intravenous and intramuscular ad-
ministration. J. Vet. Pharmacol. Ter. 30: 586-591, 2007.
10. Sadariya, K.A., Gothi, A.K., Patel, S.D., Patel, H.V., Bhavsar,
S.K. and Taker, A.M.: Pharmacokinetic interaction of moxifox-
acin and meloxicam following intramuscular administration in
rats. Pharma Science Monitor. 1: 27-34, 2010.
11. Carceles, C. M., Serrano, J. M., Marín, P., Escudero, E. and Fernan-
dez-Varon, E.: Pharmacokinetics of moxifoxacin in rabbits after in-
travenous, subcutaneous and a long-acting poloxamer 407 gel for-
mulation administration. J. Vet. Med. Series A. 53: 300-304, 2006.
12. Mishra, V.K. and Roy, B.K.: Pharmacokinetics of levofoxacin af-
ter single intravenous administration in healthy and febrile goats.
J. Vet. Pharmacol. Toxicol. 6: 19-21, 2007.
13. Verma, D.K. and Roy, B.K.: Milk kinetics of gatifoxacin after
single dose intravenous administration in healthy and febrile
goats. Indian J. Pharmacol. 38: 366-367, 2006.
14. Ismail, M.: A pharmacokinetic study of danofoxacin in febrile
goats following repeated administration of endotoxin. J. Vet.
Pharmacol. Terap. 29: 313–316, 2006.
15. Waxman, S., Sanandres, M. D., Gonzalez, F., De lucas, J. J., San-
andres, M. I. and Rodriguez, C.: Infuence of Escherichia coli en-
dotoxin-induced fever on the pharmacokinetic behavior of mar-
bofoxacin after intravenous administration in goats. J. Vet. Phar-
macol. Terap. 26: 65–69, 2003.
16. Rao, G.S., Ramesh, S., Ahmad, A.H., Tripathi, H.C., Sharma,
L.D. and Malik, J.K.: Efects of endotoxin-induced fever and
probenecid on disposition of enrofloxacin and its metabolite
ciprofloxacin after intravascular administration of enrofloxacin in
goats. J. Vet. Pharmacol. Terap. 23: 365–372, 2000.
17. Kumar, U., Sinha, S. P. and Jayachandran, C.: Comparative phar-
macokinetics and dosage regimen of enrofoxacin in febrile and
afebrile goats. Indian J. Anim. Sci. 72: 954-956, 2002.
18. Agrawal, A.K., Singh, S.D. and Jayachandran, C.: Comparative
pharmacokinetics and dosage regimen of amikacin in afebrile and
febrile goats. Indian J. Pharmacol. 34: 356-360, 2002.
19. Sultana, N., Arayne, M.S., Akhtar, M. Shamim, S., Gul, S. and
Khan, M.M.: High-performance liquid chromatography assay
for moxifoxacin in bulk, pharmaceutical formulations and se-
rum: application to in-vitro metal interactions. J. Chin. Chem.
Soc. 57: 1-10, 2010.
20. Dumka, V.K.: Disposition kinetics and dosage regimen of lev-
ofoxacin on concomitant administration with paracetamol in
crossbred calves. J. Vet. Sci. 8: 357-360, 2007.
21. Dumka, V.K., Singh, H. and Srivastava, A.K.: Disposition kinet-
ics and urinary excretion of levofoxacin on concomitant admin-
istration with meloxicam in cross-bred calves. Environ. Toxic.
Pharmacol. 26: 56–60, 2008.
22. Dumka, V.K. and Srivastava, A.K.: Disposition kinetics, urinary
excretion and dosage regimen of levofoxacin formulation follow-
ing single intravenous administration in crossbred calves. Vet.
Res. Commun. 31: 873–879, 2006.
23. Ogino, T., Mizuno, Y., Ogata, T. and Takahashi, Y.: Pharma-
cokinetic interactions of funixin meglumine and enrofoxacin in
dogs. Am. J. Vet. Res. 66: 1209-1213, 2005.
24. Oh, Y.H. and Han, H.K.: Pharmacokinetic interaction of tetracy-
cline with non steroidal anti-infammatory drugs via organic ani-
on transporters in rats. Pharmacol. Res. 53: 75-79, 2006.
25. Kumar, N., Singh, S.D. and Jayachandran, C. : Pharmacokinetics
of enrofloxacin and its active metabolite ciprofloxacin and its in-
teraction with diclofenac after intravenous administration in buf-
falo calves. Vet. J. 165: 302-306, 2003.
26. Ahmed, F.A., Mohan, P., Barua, C.C. and Dutta, D.J.: Efect of
intramuscular diclofenac sodium on pharmacokinetics of intra-
venous enrofoxacin in calves. Indian J. Pharmacol. 37: 189-190,
2005.
27. Bregante, M.A., De Jong, A., Aramayona, J.J., Garcia, M.A.,
Solans, C. and Rueda, S.: Protein binding of fluoroquinolones
applied to livestock and companion animals. J. Vet. Pharmacol.
Ter. 23:16, 2000.
28. Hasegawa, T., Takagi, K. and Kitaichi K.: Efects of bacterial en-
dotoxin on drugs pharmacokinetics. Nagoya J. Med. Sci. 62: 11-
28, 1999.
29. Jernigan, A. D., Hatch, R. C., Wilson, R. C., Brown, J. and Crow-
ell W. A.: Pathologic changes and tissue gentamicin concentra-
tions after intravenous gentamicin administration in clinically
normal and endotoxemic cats. Am. J. Vet. Res. 49, 613-617, 1988.
30. Bashir, S. Jamshaid, M. Iqbal, J. and Bukhari, I.: Pharmacokinet-
ics of ciprofoxacin in normal rabbits and changes observed in
experimentally induced febrile condition. Pak. J. Pharmacol. 25:
1-6, 2008.
31. Ahmad, M., Raza, H., Murtaza, G. and Akhtar, N.: Pharmacoki-
netic variations of ofoxacin in normal and febrile rabbits. Paki-
stan Vet. J. 28: 181-185, 2008.
32. Kumar, S., Roy, B.K., Kumar, V. and Vishakha, S.: Pharmacoki-
netics of levofoxacin after intravenous bolus in healthy and fe-
brile calves. Online J. Pharmacol. Pharmacokin. 5: 54-64, 2009.
33. Patel, U.D., Patel, J.H., Varia, R.D, Patel, H.B. Bhavsar, S.K. and
Taker, A.M.: Disposition kinetics of levofoxacin in experimen-
tally induced febrile model of sheep. J. Pharmacol.Toxicol. 7: 11-
19, 2012.
Research Articles