J. vet. Pharmacol. Therap. 25, 449–453, 2002.

ANTIINFLAMMATORY DRUGS

Disposition of sodium salicylate, flunixin and meloxicam after intravenous

administration in broiler chickens

K. BAERT &
P. DE BACKER
Department of Pharmacology, Pharmacy
and Toxicology, Faculty of Veterinary
Medicine, Ghent University, Merelbeke,
Belgium
Baert, K., De Backer, P. Disposition of sodium salicylate, flunixin and meloxicam
after intravenous administration in broiler chickens. J. vet. Pharmacol. Therap.
25, 449–453.
Three nonsteroidal anti-inflammatory drugs (NSAIDs) [sodium salicylate,
flunixin (FLU) and meloxicam (MEL)] were administered intravenously to
broiler chickens. Plasma concentrations were determined by high-performance
liquid chromatography methods and pharmacokinetic parameters were calcu-
lated. After intravenous administration of sodium salicylate (50 mg ⁄ kg), FLU
(1.1 mg ⁄ kg) and MEL (0.5 mg ⁄ kg), these drugs were eliminated from plasma
with a mean half-life of 04.04, 05.45 and 03.20 h, respectively. Apparent
volumes of distribution (0.39, 0.08 and 0.12 L ⁄ kg, respectively) indicated that
tissue distribution was limited for the three drugs. Total body clearance was
70 mL ⁄ hÆkg for sodium salicylate and 10 and 25 mL ⁄ kgÆh for FLU and MEL,
respectively. Based on the pharmacokinetic parameters these NSAIDs may offer
possibilities for treatment of various conditions in chickens.
(Paper received 21 June 2002; accepted for publication 30 October 2002)
K. Baert, Department of Pharmacology, Pharmacy and Toxicology, Faculty of
Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke,
Belgium. E-mail: kris.baert@rug.ac.be

INTRODUCTION metabolism of SA, FLU and MEL following a single i.v.

Salicylic acid (SA) is found in some plants and has been used for
more than 2000 years as an anti-inflammatory, antipyretic and
analgesic agent in man and many animal species. Sodium
salicylate, a water soluble salt of SA, is frequently used in the
poultry industry. Possible indications are respiratory diseases,
digestive coccidial and bacterial infections, inadequate intestinal
equilibrium to sustain good weight gain, broiler ascites, heat
stress, locomotor disturbances and stimulation of egg production
and eggshell quality (Thomas et al., 1966; Proudfoot & Hulan,
1983; Balog & Hester, 1991; Jouglar & Bernard, 1992; McDaniel
et al., 1993; Shlosberg et al., 1996; Abd-Ellah et al., 1997;
McGeown et al., 1999; Cristòfol et al., 2000). Also newer anti-
inflammatory agents, such as flunixin (FLU) and meloxicam
(MEL), may offer possibilities for the treatment of various
conditions in chickens. Nonsteroidal anti-inflammatory drugs
(NSAIDs) act as inhibitors of prostaglandin synthesis (Vane &
Botting, 1995). Despite an increasing awareness of animal
suffering and the recognition of medical, traumatic and surgical
conditions causing pain in animals, there are relatively few
pharmacokinetic data on NSAID in poultry. Also significant
species differences in pharmacokinetics of NSAIDs exist (Boothe,
1989). Therefore it is necessary to perform pharmacokinetic
studies in the target animal. Together with the pharmaco-
dynamic information about the drug, a more precise calculation
of dosage and dosing interval can be made. The present study
provides information on the intravenous (i.v.) disposition and
administration in broiler chickens.
MATERIALS AND METHODS
Animals and experimental protocol
The experiments were carried out for each drug in six clinically
healthy broiler chickens weighing 2.2 ± 0.2 kg. The study was
approved by the Ethical Committee of the Faculty of Veterinary
Medicine (Ghent University). The animals were kept in two
groups of three chickens and fed a commercial chicken feed
(Duvo, Wondelgem, Belgium) and tap water was provided
ad libitum. Sodium salicylate, FLU and MEL were administered
by i.v. bolus injection in the wing vein at a dose of 50, 1.1 and
0.5 mg ⁄ kg, respectively. These dosages were selected from
pharmacokinetic experiments of these drugs in other animal
species. Blood samples were collected in heparinized tubes
(Venoject, Terumo Corp., Tokyo, Japan) from the leg vein
before administration (0) and at 5, 10, 20, 30, 40 min, 1, 1.5, 2,
3, 4, 6, 9, 12, 24, 36, 48 and 60 h for the SA study and at 0, 5,
15, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 24 and 32 h for the
MEL and the FLU study. A 2-mL blood sample was taken each
time. This represents a volume of 30 and 34 mL of blood
sampled. If we assume a blood volume of 200 mL, 15–17% of
the blood volume was sampled over a period of 2–3 days. Plasma
was separated by centrifugation (2400 g for 10 min at room

 2002 Blackwell Science Ltd 449

450 K. Baert & P. De Backer
temperature) and the samples were stored at )20 C until
assayed.
Drugs and reagents
A 5% sodium salicylate solution in water, used for i.v. injection,
was prepared under sterile conditions. Commercially available
FLU (Finadyne, Schering-Plough n.v., Brussel, Belgium) and
MEL (Metacam, Boehringer Ingelheim s.a., Brussel, Belgium)
were diluted 10-fold with NaCl 0.9% and used for i.v. injection.
Standards for sodium salicylate, SA, saliuric acid (SU), gentisic
acid (GA) and o-anisic acid [OAA, internal standard (IS) for the
SA method] were obtained from Sigma Chemical Co. (St Louis,
MO, USA). Standards of FLU, MEL (IS for the FLU method) and
piroxicam (IS for the MEL method) were a gift from the
manufacturing companies. Solvents of high performance liquid
chromatography (HPLC) grade were obtained from Sigma
(Bornem, Belgium) and Acros (Geel, Belgium) and were used
for HPLC analysis.
Determination of SA and metabolites in plasma
Plasma concentrations of salicyclic acid and the two major
metabolites GA and SU were determined using a HPLC method
with ultraviolet (UV) detection based on those reported by Vree
et al. (1994) and Mallikaarjuin et al. (1989). Plasma samples
were analysed on a Thermo Seperations Product (TSP, Fremont,
CA, USA) HPLC-system using a P-4000 pump, Model AS 3000
autosampler and a Focus Forward scanning UV-detector set at
305 nm. A 250 · 4.6 mm I.D. reversed-phase column (5 lm
Spherisorb ODS-2, Chrompack, Antwerp, Belgium) attached to
an appropriate guard column was used. The injection volume
was 100 lL. The mobile phase comprised 85% water-acetic acid
(99:1, v ⁄ v) and 15% acetonitrile. A gradient solvent programme
was run: 0–4 min: 85 ⁄ 15; 4–20 min: 85 ⁄ 15–60 ⁄ 40; 20.1–
25 min: 85 ⁄ 15. The flow rate was 1 mL ⁄ min.
Samples were prepared by pipetting 0.5 mL plasma into a
15-mL screw-capped tube, followed by the addition of 50 lL of IS
(OAA in methanol, 100 lg ⁄ mL), 150 lL of 1 M HCl and 5 mL of
diethylether. After centrifugation (2400 g for 5 min at room
temperature), the organic layer was transferred to a clean screw-
capped tube and evaporated under nitrogen at room tempera-
ture. The extraction step was repeated and, after evaporation of
the combined organic extracts, the residue was re-dissolved in
250 lL of the mobile phase, briefly vortexed and 100 lL were
injected.
Determination of FLU and MEL in plasma
Plasma concentrations of FLU and MEL were determined using a
HPLC method with UV-detection. The same HPLC system as for
SA was used, except that FLU was detected at 330 nm and MEL
at 355 nm. A 100 · 3 mm I.D. reversed-phase C-18 column
(5 lm Nucleosil, Chrompack, Antwerpen, Belgium) attached to
an appropriate guard column was used. The injection volume
was 50 lL. The mobile phase comprised 65% water–acetic acid
(99:1, v ⁄ v) and 35% acetonitrile. An isocratic elution was
performed. The flow rate was 0.7 mL ⁄ min.
Samples were prepared by pipetting 0.5 mL plasma into a
15-mL screw-capped tube, followed by the addition of 50 lL of IS
(MEL in methanol, 10 lg ⁄ mL: FLU method or piroxicam in
methanol, 10 lg ⁄ mL: MEL method), 150 lL of 1 M HCl and
5 mL of diethylether. After centrifugation (2400 g for 5 min at
room temperature), the organic layer was transferred to a clean
screw-capped tube and evaporated under nitrogen at a tempera-
ture of 40 C. The residue was re-dissolved in 200 lL of the
mobile phase, briefly vortexed and 50 lL were injected.
Validation of the HPLC methods
The methods were validated prior to the start of the analysis. The
selectivity of the methods was shown as no interfering peaks
from endogenous compounds were observed with the same
retention time as SA, GA, SU, FLU, MEL and their respective IS in
the chromatograms of blank samples. Calibration curves were
prepared by spiking blank plasma with known concentrations of
SA, GA, SU, FLU and MEL. Correlation coefficients were ‡0.99
for all components. The limit of detection was determined as
three times the signal to noise ratio at the time of elution of the
analyte and was: 0.025 lg ⁄ mL (FLU), 0.01 lg ⁄ mL (MEL),
0.15 lg ⁄ mL (SA), 0.1 lg ⁄ mL (GA), and 0.1 lg ⁄ mL (SU). The
limit of quantification was calculated as two times the LOD and
was: 0.05 lg ⁄ mL (FLU), 0.02 lg ⁄ mL (MEL), 0.3 lg ⁄ mL (SA),
0.2 lg ⁄ mL (GA), and 0.2 lg ⁄ mL (SU). The accuracy and
precision fell within ranges specified by Heitzman (1994).
Analysis of data
Analyses were performed for each data set independently. The
pharmacokinetic parameters (elimination constant, kel; elimini-
ation half-life, t1 ⁄ 2; volume of distribution, Vd(area); area under
the curve from zero to infinity fi , AUC0 fi ¥; clearance, Cl) were
calculated with a computer program (M ⁄ W PHARM, Ver. 3.15,
Groningen, The Netherlands). The pharmacokinetic parameters
were determined with open compartmental models. The follow-
ing equations were used to describe the concentration–time
curves of the three NSAIDs after i.v. administration C ¼ C(0)e–kt
(a one compartmental model); C ¼ A1e–at + A2e–bt (a two
compartmental model), where C is the plasma concentration,
C(0) is the extrapolated initial concentration, k is the elimination
rate constant, A1 and A2 are zero time intercepts, a is the
distribution rate constant, b is the elimination rate constant and
t is the time.
RESULTS AND DISCUSSION
The mean plasma concentrations of SA and GA, FLU and MEL
were plotted on a semilogarithmic scale as a function of time and
are shown in Figs 1–3, respectively. No SU was found in the
plasma of the salicylate treated chickens, but GA was detected at
low concentrations. Sodium salicylate was best described as a
 2002 Blackwell Science Ltd, J. vet. Pharmacol. Therap. 25, 449–453

Fig. 1. Mean salicylic acid (SA, r) and gentisic acid (GA, j) concen-
trations (±SD) in plasma from broiler chickens after a single intravenous
administration of a dose of 50 mg ⁄ kg BW (n ¼ 6).
Fig. 2. Mean flunixin (FLU) concentrations (±SD) in plasma from
broiler chickens after a single intravenous administration of a dose of
1.1 mg ⁄ kg BW (n ¼ 6).
Fig. 3. Mean meloxicam (MEL) concentrations (±SD) in plasma from
broiler chickens after a single intravenous administration of a dose of
0.5 mg ⁄ kg BW (n ¼ 6).
one compartmental open model, FLU and MEL as two compart-
mental open models. The pharmacokinetic parameters obtained
for SA, FLU and MEL are presented as the mean ± SD (n ¼ 6) in
Table 1.
The plasma concentration of SA above which effective
antipyretic, anti-inflammatory and analgesic activity can be
achieved, has been reported to be 50 lg ⁄ mL for several species
(Lees & Higgins, 1985; Lees et al., 1991a). After a single i.v. dose
 2002 Blackwell Science Ltd, J. vet. Pharmacol. Therap. 25, 449–453
Antiinflammatory drugs in chickens 451
of 50 mg ⁄ kg, the duration for which the plasma SA concentra-
tion exceeds 50 lg ⁄ mL is approximately 5 h. When given in the
drinking water, this therapeutic level is reached at a concentra-
tion of 1.25 g sodium salicylate per litre of drinking water
(Moutafchieva et al., 1993). Effective levels for FLU and MEL
have not been reported, but anti-inflammatory effects are
probably more related to exudate levels than plasma levels.
These exudate levels are maintained longer than the plasma
levels in ponies (Higgins et al., 1986).
Comparative pharmacokinetic parameters of the three mol-
ecules in different mammalian species are summarized in
Table 2. The volume of distribution of salicylate was low but
larger in chickens than in rabbits, dogs, cattle and goats (Short
et al., 1990a,b; Waters et al., 1993). Chickens cleared SA more
slowly than cattle and goats, and of the same magnitude as
rabbits and dogs. Consequently, the biological half-life of SA
was longer in chickens, rabbits and dogs than in goats and
cattle. Metabolism of SA can occur through conjugation with
glycine to produce SU, oxidation to 2,5-dihydroxybenzoic acid
(GA), glucuronide formation and the formation of some minor
metabolites. In most species (man, horse, cattle, goat and rat),
SU is the major metabolite (Short et al., 1990b). In rabbits it is
a minor metabolite and the only metabolite detectable in
plasma. In our experiment in broiler chickens, however, no SU
was found in the plasma. This could be because rabbits and
chickens are deficient in their ability to conjugate SA with
glycine, relative to other species. Only GA could be detected in
the chicken plasma at low concentrations. In chickens, this is
probably a minor metabolic pathway, as i.v. administration of
GA in one chicken resulted in a plasma-half-life of approxi-
mately 3 h. No other metabolites were found in the plasma, but
this analytical method did not detect glucuronide conjugates, as
there was no b-glucuronidase treatment during the sample
preparation. In other species glucuronide formation seems to be
only a minor pathway. In goats and cattle, no glucuronide
conjugates were found, in humans glucuronide formation is
around 10% of the excreted dose, in horses it is only 2%. For
humans, there are reports that formation seems to be highly
variable, ranging from 0.8 to 40% of the excreted dose (Short
et al., 1990a).
The volume of distribution of FLU was lower in chickens than
in camels, horses, cattle, sheep and dogs (Hardie et al., 1985;
Welsh et al., 1993; Landoni & Lees, 1995; Odensvik, 1995;
Wasfi et al., 1998). However, chickens cleared FLU more slowly
than camels, horses, sheep, cattle and dogs. As a result, the
biological half-life of FLU was of a similar magnitude in chickens
as in camels, horses, sheep, cattle and dogs. Metabolism of FLU
can occur through oxidation and glucuronidation of either the
parent molecule or the oxidized FLU. In camels and dogs
glucuronidation of the parent molecule seems to be the major
metabolic pathway (Brady et al., 1998; Wasfi et al., 1998). In
horses an hydroxy metabolite is formed and conjugation
reactions have been suggested (Jaussaud et al., 1987).
The volume of distribution of MEL was lower in chickens than
in horses and humans (Lees et al., 1991b; Schmid et al., 1995).
Chickens cleared MEL more slowly than horses and humans. The
452 K. Baert & P. De Backer

Table 1. Pharmacokinetic parameters of sali-

SA FLU MEL
Pharmacokinetic cylic acid (SA), flunixin (FLU) and meloxicam
parameters i.v. SD i.v. SD i.v. SD (MEL) in plasma after intravenous adminis-
tration of 50 mg ⁄ kg of SA, 1.1 mg ⁄ kg FLU
AUC0 fi ¥ (mgÆh ⁄ L) 1047.7 672.7 118.6 37.9 20.2 2.9 and 0.5 mg ⁄ kg MEL (n ¼ 6, mean ± SD)
ke (1 ⁄ h) 0.17 0.05 0.13 0.03 0.22 0.04
t1 ⁄ 2b (h) 4.04* 5.45* 3.20*
Vd(area) (L ⁄ kg) 0.390 0.130 0.084 0.038 0.117 0.010
Cl (mL ⁄ hÆkg) 70 27 10 3 25 4
MRT (h) 4.59 0.68 6.66 1.91 4.41 0.84

*Harmonic mean.

Table 2. Major pharmacokinetic parameters

Vd(area) (L ⁄ kg) Cl (mL ⁄ hÆkg) t1 ⁄ 2 (h) Authors
of salicylic acid, flunixin and meloxicam in
SA Rabbits 0.249 43 4.29 Short et al. (1990b) different animal species
Dogs 0.285 41 4.49 Waters et al. (1993)
Cattle 0.176 253 0.48 Short et al. (1990a)
Goats 0.138 193 0.50 Short et al. (1990a)
FLU Camels 0.489 89 3.76 Wasfi et al. (1998)
Horses 0.317 58 3.37 Landoni and Lees (1995)
Sheep 0.166 60 3.82 Welsh et al. (1993)
Cattle 0.782 115 5.2 Odensvik (1995)
Dogs 0.348 64 3.75 Hardie et al. (1985)
MEL Horses 0.160 42 2.7 Lees et al. (1991b)
Humans 0.190 11 13.7 Schmid et al. (1995)

biological half-life of MEL was of similar magnitude in chickens
and horses. Other data on half-lives of MEL in several species
indicates a large variation: cattle (13 h), rat (11 h), dog
(12–36 h), human (20–50 h), minipig (4 h) (Lees et al.,
1991b). Metabolism of MEL can occur through oxidation of
the parent molecule and further oxidation of the metabolites
(Schmid et al., 1995). The MEL is eliminated partly in urine and
partly in faeces of humans and rats. Only traces of the parent
drug can be recovered from excreta.
Excretion studies of urine and faeces metabolites could further
elucidate the metabolism and excretion patterns of SA, FLU and
MEL in chickens. Experimental work on this topic is currently
being undertaken in our laboratory.
All NSAIDs may induce undesirable side-effects. Most adverse
reactions reflect the inhibitory effects on prostaglandin activity
with manifestations most often being gastrointestinal in nature.
Salicylates cause local damage because of ‘backdiffusion’ of
acid, which causes injury to mucosal cells and submucosal
capillaries (Boothe, 1989). Other side-effects can occur in the
haematopoetic or the renal systems. In this study, no side-
effects were observed. Further research could characterize the
effects of multiple or continuous administration in feed or
drinking water.
Based on the pharmacokinetic parameters of sodium salicy-
late, FLU and MEL after i.v. administration, one may conclude
that these NSAIDs offer possibilities for treatment of various
conditions in chickens. This information should be the starting
point of further research to the pharmacokinetics, metabolic
profile, pharmacodynamics and side-effects of NSAIDs in
chickens.
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