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1Department of Obstetrics and Gynaecology, Centre for Reproductive Biology in Uppsala, and 2Department of
Pharmacology and Toxicology, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences,
Uppsala, Sweden, and 3Department of Reproduction and Forensic Medicine, Norwegian College of Veterinary
Medicine, Oslo, Norway.
lease of PG:s (e.g. Fredriksson 1984, Daels et administered into the contralateral jugular
al. 1989). vein). Blood samples (approximately 5 mL)
The aim of this study was to investigate the were harvested at 60, 45, 30, 15 and 5 minutes
pharmacokinetics of flunixin in Norwegian before and at 5, 15, 30, 45, 60, 90, 120, 150 and
dairy goats after oral, intramuscular and intra- 180 minutes and at 4, 5, 6, 8, 10, 12, 16, 22, 24,
venous administrations and to study the inhibi- 26, 28, 30, 32, 34 and 36 h after administration
tion of prostaglandin synthesis. of flunixin.
The blood was collected in heparinized tubes
Materials and methods (Vacutainer, Terumo, Loeven, Belgium). Plas-
Animals ma was separated by centrifugation at 1500 × g,
6 healthy Norwegian dairy goats were used for for 20 min at 20°C within 20 min after collec-
the study. The age of the goats was 3 years and tion. Plasma was withdrawn and stored at
the body weights ranged from 34 to 59 kg. The -20°C until analysed.
goats were fed according to Norwegian stan-
dards. The same 6 animals were used in all Experimental design
studies, i.e. single intravenous administration The study had a crossover design and all the six
(i.v.), single intramuscular administration (i.m.) participating animals received flunixin i.v., i.m.
and single oral administration (p.o.). The ex- and p.o. Drug administration was carried out at
periments were carried out in the post partal pe- three successive periods with a washout time of
riod (9-61 days after parturition). Four of the 10 days between each experiment. At each pe-
goats were lactating and the other two goats had riod, two animals received each of the adminis-
aborted and were non-lactating. The study has trations. The goats were randomly allocated to
been registered and approved by the Norwegian the administration groups.
Animal Research Authority (NARA) (Registra-
tion No. 5/97). Analytical assay
Flunixin was analysed using a high perfor-
Drug administration mance liquid chromatography (HPLC) method
Flunixin meglumine (Finadyne® vet., Schering- adapted from analysis of bovine plasma
Plough, Stockholm, Sweden) was administered (Odensvik & Johansson, 1995). In short, goat
in all experiments at a nominal dose of 2.2 plasma was used for analysis and as an internal
mg/kg body weight. For i.v. administration, Fi- standard, sodium diclofenac (Ciba-Geigy AG,
nadyne® vet. solution for injection, (50 mg/mL) Basel, Schweiz) dissolved in potassium phos-
was given into the V. jugularis externa, and for phate buffer (KH2PO4) pH 3.5 (0.3 M) was
i.m. administration the same formulation was used. For each sample 1 mL of goat plasma was
given into the dorsal muscles of the neck. For used and the internal standard (200 µl) was
oral administration Finadyne® vet granules (25 added to the plasma and mixed. Then flunixin
mg/g) dissolved in a small amount of water was and diclofenac were extracted by an addition of
given via a gastric tube as a gavage. All admin- 5 mL of diethyl ether. After gentle mixture for
istrations were performed at 9 am. 20 min the tube with its contents were put in
methanol, -20°C. When the plasma had frozen
Blood sampling the ether-phase was removed and transferred to
Before each experiment an intravenous catheter a second tube and then evaporated. The residue
was inserted into the jugular vein (flunixin was was dissolved in 200 µL mobile phase and
for PG-metabolite suppression was calculated these assumed distribution phases was seen
and defined as the pre-experimental mean value also after i.m. administration (Fig. 1).
minus two times the standard deviation. Inhibi- Flunixin absorption after oral administration
tion of the prostaglandin synthesis was as- was rapid with two Cmax in all individuals (Fig
sumed to last as long as the PG-metabolite lev- 2). The second Cmax was of the same magnitude
els remained below the cut-off limit. as the first. The terminal phase of the plasma
concentration-time profiles had similar (Krus-
Statistical analyses kal-Wallis, p >0.05) elimination rates indepen-
All pharmacokinetic parameters are expressed dent of route of administration (Fig. 1 and Fig.
as median (range). Differences between differ- 2). The median (range) r2 for the linear regres-
ent routes of administration regarding the and sion of the terminal phase of the curve was 0.98
the effect duration were statistically evaluated (0.87-0.99) and the fraction of AUC extrapo-
using the Kruskal-Wallis test by the use of lated beyond the last sampling time point was
Minitab for Windows 95, release 12 (Mininc, less than 6%. The main pharmacokinetic pa-
State College, PA, USA). P<0.05 was consid- rameters for flunixin are presented in Table 1.
ered as the level of significance.
Suppression of PG-metabolite levels
Results Pre-experimental levels of the PG-metabolite
Pharmacokinetic parameters were high – 775 pmol/L (499-865) – in 2 goats
Flunixin was detected in the plasma samples ir- (on 1 and 2 occasions, respectively) where the
respective of route of administration at all time experiments were performed within 20 days af-
points up to 22 (12-26) hours (median (range)). ter parturition (during the early postpartal pe-
The plasma concentrations of flunixin after i.v. riod). In the remaining goats the pre-experi-
administration declined rapidly with two dis- mental levels were 66 pmol/L (43-99).
tinct phases prior to the -phase. The latter of In all goats and for all routes, with one excep-
Figure 1. Mean values of the plasma concentrations Figure 2. Mean values of the plasma concentra-
obtained after intramuscular administration of flu- tions obtained after oral administration of flunixin to
nixin to goats (n=6). Data after intravenous adminis- goats (n=6). Data after intravenous administration
tration are shown as a reference. are shown as a reference.
Table 1. Pharmacokinetic parameters (median (range)) in plasma following flunixin meglumine (2.2 mg/kg)
given intravenously, intramuscularly and orally to 6 Norwegian dairy goats.
Route of administration
parameter unit i.v. (n=6) i.m. (n=6) p.o. (n=6)
AUC = area under the concentration time curve extrapolated to infinity, CL = total body clearance, Vdss = apparent volume of
distribution at steady state, = elimination rate constant, Vd = volume of distribution based on the terminal phase, MRT =
mean residence time, t1⁄2 = half-life of the terminal phase, Cmax = maximum concentration, Tmax = time for Cmax, F = bioavail-
ability.
sorption due to binding of flunixin to ruminal cattle where puerperal cows need flunixin ad-
contents. Flunixin binds to hay and this influ- ministration several times per day for a more
ences the absorption in the horse (Welsh et al. sustained inhibition of the prostaglandin syn-
1992). thesis (Odensvik & Fredriksson 1993).
There were no statistical differences in efficacy In conclusion flunixin administered at a dose of
between the different routes of administration. 2.2 mg/kg orally, intramuscularly or intra-
This is in agreement with findings in heifers venously, suppressed prostaglandin synthesis in
(Odensvik 1995) where oral and intramuscular goats. The systemic exposure of flunixin in
administration of flunixin was as efficient as in- goats was similar to that in cattle given the same
travenous administration. This suggests that the dose per kg bw (which is the therapeutic dose in
same dose could be used even though the this species). Together these findings indicate
bioavailability was only 79% and 58% after in- that 2.2 mg/kg bw is likely to be be an appro-
tramuscular and oral administration to goats, priate dose for clinical use also in goats.
respectively.
Prostaglandins and tromboxanes are often used Acknowledgement
as bio-markers for COX-inhibition. As the half- This study was supported by the Swedish Council for
lives of these compounds are very short, quan- Forestry and Agricultural Research and the Swedish
Farmers Foundation for Agricultural Research. The
tification of metabolite concentrations are used authors would like to thank the staff at the Depart-
instead of the parent compounds. The use of a ment of Reproduction and Forensic Medicine, Nor-
PG-metabolite connected to the reproductive wegian College of Veterinary Medicine, Oslo, Nor-
system allowed estimation of a pharmacody- way and Schering-Plough, Stockholm, Sweden for
kind contributions.
namic effect in healthy animals not subjected to
inflammation or pain. This protocol had advan- References
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