Researchin VeterinaryScience1992,53, 264-266
Pharmacokineties of earprofen administered intravenously to sheep E. M. WELSH, P. BAXTER, A. M. NOLAN, Department of Veterinary Pharmacology, University of Glasgow Veterinary School, Bearsden Road, Bearsden, Glasgow G64 1AN
Carprofen was administered intravenously to sheep at two dose rates (0.7 and 4.0 mg kg-1), and the pharmacokinetics of the drug studied. Plasma concentrations of the drug were measured by high performance liquid chromatography. Carprofen had a small volume of distribution (Vd[area], 95-5 and 118"4 ml kg-1), a prolonged elimination half-life (tl/2[~, 26"1 and 33"7 hours) and a slow body clearance rate (Clb, 2"5 ml kg -1 h-1) in sheep. C A R P R O F E N (+6-chloro-c~-methyl-carbazole-2acetic acid) is a novel non-steroidal anti-inflammatory drug (NSAID)presented in solution as a racemic mixture. In the domestic species, descriptions of its pharmacokinetics have been limited to the dog (McKellar et al 1990), horse (McKellar et al 1991) and lactating cow (Ludwig et al 1989). The NSAIDS,in general, are known to have relatively narrow therapeutic indices which makes it unwise to extrapolate pharmacokinetic data from one species to another. However, although carprofen may induce gastrointestinal ulceration the safety ratio (ulcerogenic dose/anti-inflammatory dose) of this drug, when compared to indomethacin and aspirin, is considerably greater (Randall and Baruth 1976). Of its class, carprofen may therefore prove to be an extremely useful drug in veterinary medicine. The aim of this study was to investigate the pharmacokinetics of carprofen, at two dose rates, when administered intravenously to sheep. Five healthy Suffolk crossbred sheep aged 18 months and weighing 53 to 66 kg were used. They had free access to hay and water during the trial period. Carprofen, as a 5 per cent mixed micelle solution was injected intravenously at 0.7 mg kg -1, and after an interval of not less than 14 days, the drug was again administered intravenously at a dose rate of 4.0 mg kg -1. Blood samples were collected from the contralateral jugular vein immediately before drug administration, and at 0.083, 0.5, 1, 2, 4, 6, 8, 12, 24, 32, 48, 56 and 72 hours after administration. Blood was collected into hcparinised tubes (Sarstedt) and centrifuged at 1500 g for 15 minutes. The plasma was then decanted and stored at ~ 0 ° C until analysis. Carprofen was extracted from the plasma using a method developed from that described by Iwakawa
et al (1989). Briefly, to 0.25 ml of plasma, 62.5 gl of citrate phosphate buffer (pH 3) and 4 ml of ethyl acetate were added. The mixture was inverted on a slow rotating mixer for 10 minutes and then the organic layer was transferred to a second tube and evaporated to dryness under nitrogen gas at 50°C. Another 4 ml of ethyl acetate was added to the residue of the first tube and the process repeated. When the organic layer had completely dried, the second tube was washed down using approximately 1 ml ethyl acetate and evaporated to dryness under nitrogen gas at 50°C. The sample was reconstituted in 150 gl of methanol and 15 to 20 pl of the solution was injected on to the column. Analysis was by high performance liquid chromatography (HPLC). The chromatographic equipment consisted of a Gilson 302 pump, Shandon column 100 mm x 5 mm with ODS Hypersil 5 ~m packing and a Spectraphysics Ultra-violet Detector. The HPLC solvent was methanol : H20, 75:25, with 50 gl of 1:55 v/v perchloric acid : H20 added. Detection was at 254 nm. Blank plasma samples were spiked with known amounts of carprofen and were included in each assay to produce a standard concentration curve from which the concentration in the unknown samples was assessed. The coefficient of variation for this assay was 5-84. The limit of detection achieved using this method was 0.10 gg m ~ 1 or better. This was based on twice background noise of the chromatogram. The plasma concentration versus time data from each individual animal given carprofen intravenously were analysed using a curve stripping computer program (CSTRIP)(Sedman and Wagner 1976). The area under the plasma concentration time curve (AUC(0_72)) was calculated using the trapezoidal rule. Results are quoted as mean values + standard error of the mean
(SZM). The decline in the plasma concentration of carprofen with time at both 0.7 and 4.0 mg kg -I in all animals was best fitted by a biexponential equation. The mean plasma concentrations of carprofen following a single intravenous injection of 0.7 mg kg -1 bodyweight are shown in Fig 1. The plasma disposition and pharmacokinetic characteristics for each of the five sheep are shown in Table 1. These indicate a small volume of distribution, Vd(-area), 95.5 + 6-0 ml kg-1, a slow body
264
Carprofen in sheep
265
TABLE 1 : PharmacokineUc parameters after administration of carprofen (0.7 and 4.0 mg kg-1) intravenously to a group of five adult sheep Animal number Dose (mg kg-1)
1 0.7
t1/21~(h) 26.3 Vc (ml kg-1) 64-7 Vd(area) (m[ kg-1) 114.0 Vd(ss) (ml kg 1) 110.0 kel (h-1) 0.05 CIb (ml kg-lh -1) 3.0
2 0.7
3 0.7
21.9 50.4 78.8 76.0 0.05 2-5
4 0.7
5 0.7
28.5 26.0 27.7 45-6 44-6 48-5 90.6 91.7 102.6 88.9 88.2 100.2 0.05 0.06 0.05 2-2 2-4 2.6
Mean
SEM
26.1 50.8 95.5 92-7 0.05 2.5
1-14 3.63 5.95 5-77 0-002 0.1
clearance rate, Clb, 2.5 + 0.1 ml kg-1 h q and an elimination half-life (h/2~) of 26.1 _+ 1.1 hours. Fig 1 also illustrates the mean plasma concentration of carprofen following a single intravenous injection of 4.0 mg kg -1 bodyweight to five animals. The plasma disposition and kinetic characteristics for the individual sheep are given in Table 1. Again these indicate a small volume of distribution, 118.4 + 3.5 ml kg-% a slow body clearance rate, 2-5 + 0-3 ml k T 1 h -1 and an elimination half-life of 33.7 + 3-1 hours. The mean AUC(0_72) for the animals given 4.0 mg k g -I carprofen intravenously was approximately 5.7 times greater than the AUC(0.72) for those animals administered 0.7 mg kg q, indicating that, between these two dose rates, plasma levels are directly proportional to the dose rate. The high drug concentration of carprofen in the plasma, at both dose rates, may be explained by the small volume of distribution, 95.5 _+ 6.0 and 118.4 _+ 3.5 ml kg q, which illustrates that carprofen is not widely distributed throughout the body. The result is consistent with that seen in the horse (McKellar et al 1991), dog (McKellar et al 1990) and cow (Ludwig et al 1989), and is probably related to the high degree of protein binding seen with carprofen (Baruth et al 1986) as with most other NSAIDS.
E
100 k
•
I ~
~
4.0 mg kg-1 0-7mgkg -1
Q.
8 E n
12
24
36 Time (h)
48
60
72
FIG 1: Mean plasma concentration-time curves for carprofen given by intravenous injection to sheep at two dose rates (0.7 and 4-0 mg kg 1)
1 4-0
2 4,0
3 4.0
4 4.0
5 4.0
30.3 24-6 33.8 36.4 43-5 57~6 67.9 62.7 61.2 52.5 115.4 125.9 127.4 113.7 109-4 115.0 124.5 125.6 112-6 108-8 0.05 0.05 0.04 0-04 0-03 2.6 3.5 2-6 2.2 1.7
Mean
SEM
33.7 60.4 118.4 117.3 0.04 2-5
3.14 2-57 3-53 3.31 0-004 0-3
Fig 1 shows that at the dose rate of 4.0 mg kg -~ there appears to be a small rise in plasma concentration of carprofen between six and eight hours after drug administration. Although the results shown are mean values, this rise occurred in four of the five animals sampled. It is possible that this rise represents an enterohepatic circulation for carprofen in sheep. Enterohepatic circulation of carprofen has been described in man (Ray and Wade 1982) and, although initially there was no evidence (Rubio et al 1980), McKellar et al (1990) suggested that it may occur in the dog. The elimination half-life of carprofen in sheep was 26.1 +_1.1 and 33-7 + 3.1 hours for animals administered 0.7 and 4.0 mg kg~1 intravenously, respectively. This is similar to that observed in the horse and pony at 3-5 mg kg-1 intravenously (21.9 +-2-3 hours) (McKellar et al 1991). In the lactating cow the plasma elimination half-life ranged from 44-5 to 64.6 hours (Ludwig et al 1989), which is considerably more prolonged than that observed in the sheep and over three times longer than observed by McKellar et al (1990) in dogs administered 0-7 mg k ~ 1 carprofen intravenously (8.0 + 1-2 hours). It is possible that the existence, or differences, in the degree of enterohepatic circulation of carprofen between species could account for the wide margin of values seen. The mean body clearance rates ofcarprofen in sheep were 2.5 ml kg~1 h -I at both dose rates, similar to those reported in cattle (Ludwig et al 1989), but lower than those reported in the dog (McKellar et al 1990) and horse (McKellar et al 1991). This may be a result of sheep clearing carprofen more slowly than other species. This is supported by the fact that sheep also clear flunixin meglumine, another NSAID, at a slower rate than other species (Welsh et al 1992). Recently, Lees et al (1991) described the pharmacokinetics of the carprofen enantiomers in the horse. They showed that there were marked differences in the pharmacokinetic disposition of the individual enantiomers, although the reasons for this were not established. In the dog, although there is no chiral inversion of the enantiomers, different pharmacokinetic profiles are seen (Q. A. McKellar, personal communication). The present authors have not analysed the individual
266
E. M . Welsh, P. B a x t e r , A. M . N o l a n
e n a n t i o m e r c o n c e n t r a t i o n s o f c a r p r o f e n in sheep, b u t it w o u l d be o f value to d o so w i t h any f u r t h e r investigations o f t h e analgesic and, or, a n t i - i n f l a m m a t o r y efficacy o f the drug. S c h a t z m a n et al (1990) h a v e o b s e r v e d t h a t p l a s m a levels o f >1.5 btg ml -I o f c a r p r o f e n are r e q u i r e d to p r o v i d e analgesia in the horse. F r o m F i g 1, f o l l o w i n g a d m i n i s t r a t i o n o f 4.0 m g kg 1 c a r p r o f e n i n t r a v e n o u s l y to sheep, p l a s m a levels o f the d r u g are m a i n t a i n e d well a b o v e this level f o r at l e a s t 72 h o u r s . A d m i n i s t r a t i o n o f 0.7 m g k ~ 1 o f c a r p r o f e n intrav e n o u s l y results in p l a s m a levels o f _>1-5 ~tg m1-1 f o r u p to 48 h o u r s , a n d if this level p r o v e s analgesic in sheep, the d r u g w o u l d be a useful aid for alleviating p a i n in this species. T h e p r e s e n t a u t h o r s are c u r r e n t l y i n v e s t i g a t i n g the analgesic effects o f c a r p r o f e n in sheep at 0.7 m g kg -1.
Acknowledgements This w o r k was s u p p o r t e d b y the A g r i c u l t u r a l a n d F o o d R e s e a r c h Council. C a r p r o f e n s o l u t i o n for this s t u d y was p r o v i d e d by B o r d e r R e s e a r c h .
References BARUTH, H., BERGER, L, BRADSHAW, D., COSTIN, C. H., COFFEY, J. W., GUPTA, N, KONIKOFF, J., ROBERTS, N. A. & WYLER-PLANT, R. (1986) Carprofen: In: Anti-inflammatory and Anti-rheumatic Drugs, Volume II. Newer Anti-inflammatory Drugs, Ed K.D. Rainsford. Boca Raton CRC Press, pp119-127 IWAKAWA, S., TOSHIYUKI, S., SHII-FUENG, L., HILDEGARD, S., LESLIE, B. Z. & EMIL, L.T. (1989) Direct determination of diastereometric carprofen glucuronides in human plasma and urine and preliminary measurements of stereoselectivemetabolic
and renal elimination after oral administration of carprofen in man. Drug Metabolism and Disposition 17, 414-418 LEES, P., DELATOUR, P., BENOIT, E. & FOSTER, A. P. (1991) Pharmacokinetics of carprofen enantiomers in the horse. Acta Veterinaria Seandinavica Supplementum 87, 249-251 LUDWIG, B., JORDAN, J. C., REHM, W. F. & THUN, R. (1989) Carprofen in veterinary medicine. 1. Plasma disposition, milk excretion and tolerance in milk producing cows. Schweizer Arehiv fiir Tierheilkunde 131, 99-106 McKELLAR, Q. A., BOGAN, J. A., von FELLENBERG, R.-L., LUDWIG, B. & CAWLEY, G.D. (1991) Pharmacokinetic, biochemical and tolerance studies on carprofen in the horse. Equine Veterinary Journal 23, 280- 284 MeKELLAR, Q. A., PEARSON, T., BOGAN, J.A., GALBRAITH, E. A., LEES, P., LUDWIG, B. & TIBERGHIEN, M. P. (1990) Pharmacokinetics, tolerance and serum thromboxane inhibition of carprofen in the dog. Journal of Small Animal Practice 31, 443448 RANDALL, L. O. & BARUTH, H. (1976) Analgesic and anti-inflammatory activity of 6-chloro-alpha-methyl-carbazole-2-acetic acid (C-5720). Archives Internationales de Pharmacodynamie 220, 94114 RAY, J. E. & WADE, D. N. (1982) The pharmacokinetics and metabolism of 14C-carprofen in man. Biopharmaeeuties and Drug Disposition 3, 29 RUBIO, F., SEAWALLS, S, POCELINKO, R., De BARBIERI, B., BENZ, W., BERGER, L., MORGAN, L., PAO, J., WILLIAMS, T. H. & KOECHLIN, B. (1980) Metabolism of carprofen: a uonsteroidal anti-inflammatory drug in rats, dogs and humans. Journal of Pharmaceutical Science 69, 1245-1253 SCHATZMAN, U., GUELMANN, M., Von CRANACH, J, LUDWIG, B. M. & REHM., W. F. (1990) Pharmacodynamic evaluation of the peripheral pain inhibition by carprofen and flunixin in the horse. Schweizer Arehiv fiir Tierheilkunde 132, 497-504 SEDMAN, A. J. & WAGNER, J. G. (1976) CSTRIP, A Fortran IV computer program for obtaining initial polyexponential parameter estimates. Journal of Pharmaceutical Science 65, 1006-1010 WELSH, E. M., McKELLAR, Q. A. & NOLAN, A. N. (1992) The pharmacokinetics of flunixin meglumine in the sheep. Journal of Veterinary Pharmacology and Therapeutics (in press) Received February 11, 1992 Accepted May 7, 1992
Pharmacokineties of earprofen administered intravenously to sheep E. M. WELSH, P. BAXTER, A. M. NOLAN, Department of Veterinary Pharmacology, University of Glasgow Veterinary School, Bearsden Road, Bearsden, Glasgow G64 1AN
Carprofen was administered intravenously to sheep at two dose rates (0.7 and 4.0 mg kg-1), and the pharmacokinetics of the drug studied. Plasma concentrations of the drug were measured by high performance liquid chromatography. Carprofen had a small volume of distribution (Vd[area], 95-5 and 118"4 ml kg-1), a prolonged elimination half-life (tl/2[~, 26"1 and 33"7 hours) and a slow body clearance rate (Clb, 2"5 ml kg -1 h-1) in sheep. C A R P R O F E N (+6-chloro-c~-methyl-carbazole-2acetic acid) is a novel non-steroidal anti-inflammatory drug (NSAID)presented in solution as a racemic mixture. In the domestic species, descriptions of its pharmacokinetics have been limited to the dog (McKellar et al 1990), horse (McKellar et al 1991) and lactating cow (Ludwig et al 1989). The NSAIDS,in general, are known to have relatively narrow therapeutic indices which makes it unwise to extrapolate pharmacokinetic data from one species to another. However, although carprofen may induce gastrointestinal ulceration the safety ratio (ulcerogenic dose/anti-inflammatory dose) of this drug, when compared to indomethacin and aspirin, is considerably greater (Randall and Baruth 1976). Of its class, carprofen may therefore prove to be an extremely useful drug in veterinary medicine. The aim of this study was to investigate the pharmacokinetics of carprofen, at two dose rates, when administered intravenously to sheep. Five healthy Suffolk crossbred sheep aged 18 months and weighing 53 to 66 kg were used. They had free access to hay and water during the trial period. Carprofen, as a 5 per cent mixed micelle solution was injected intravenously at 0.7 mg kg -1, and after an interval of not less than 14 days, the drug was again administered intravenously at a dose rate of 4.0 mg kg -1. Blood samples were collected from the contralateral jugular vein immediately before drug administration, and at 0.083, 0.5, 1, 2, 4, 6, 8, 12, 24, 32, 48, 56 and 72 hours after administration. Blood was collected into hcparinised tubes (Sarstedt) and centrifuged at 1500 g for 15 minutes. The plasma was then decanted and stored at ~ 0 ° C until analysis. Carprofen was extracted from the plasma using a method developed from that described by Iwakawa
et al (1989). Briefly, to 0.25 ml of plasma, 62.5 gl of citrate phosphate buffer (pH 3) and 4 ml of ethyl acetate were added. The mixture was inverted on a slow rotating mixer for 10 minutes and then the organic layer was transferred to a second tube and evaporated to dryness under nitrogen gas at 50°C. Another 4 ml of ethyl acetate was added to the residue of the first tube and the process repeated. When the organic layer had completely dried, the second tube was washed down using approximately 1 ml ethyl acetate and evaporated to dryness under nitrogen gas at 50°C. The sample was reconstituted in 150 gl of methanol and 15 to 20 pl of the solution was injected on to the column. Analysis was by high performance liquid chromatography (HPLC). The chromatographic equipment consisted of a Gilson 302 pump, Shandon column 100 mm x 5 mm with ODS Hypersil 5 ~m packing and a Spectraphysics Ultra-violet Detector. The HPLC solvent was methanol : H20, 75:25, with 50 gl of 1:55 v/v perchloric acid : H20 added. Detection was at 254 nm. Blank plasma samples were spiked with known amounts of carprofen and were included in each assay to produce a standard concentration curve from which the concentration in the unknown samples was assessed. The coefficient of variation for this assay was 5-84. The limit of detection achieved using this method was 0.10 gg m ~ 1 or better. This was based on twice background noise of the chromatogram. The plasma concentration versus time data from each individual animal given carprofen intravenously were analysed using a curve stripping computer program (CSTRIP)(Sedman and Wagner 1976). The area under the plasma concentration time curve (AUC(0_72)) was calculated using the trapezoidal rule. Results are quoted as mean values + standard error of the mean
(SZM). The decline in the plasma concentration of carprofen with time at both 0.7 and 4.0 mg kg -I in all animals was best fitted by a biexponential equation. The mean plasma concentrations of carprofen following a single intravenous injection of 0.7 mg kg -1 bodyweight are shown in Fig 1. The plasma disposition and pharmacokinetic characteristics for each of the five sheep are shown in Table 1. These indicate a small volume of distribution, Vd(-area), 95.5 + 6-0 ml kg-1, a slow body
264
Carprofen in sheep
265
TABLE 1 : PharmacokineUc parameters after administration of carprofen (0.7 and 4.0 mg kg-1) intravenously to a group of five adult sheep Animal number Dose (mg kg-1)
1 0.7
t1/21~(h) 26.3 Vc (ml kg-1) 64-7 Vd(area) (m[ kg-1) 114.0 Vd(ss) (ml kg 1) 110.0 kel (h-1) 0.05 CIb (ml kg-lh -1) 3.0
2 0.7
3 0.7
21.9 50.4 78.8 76.0 0.05 2-5
4 0.7
5 0.7
28.5 26.0 27.7 45-6 44-6 48-5 90.6 91.7 102.6 88.9 88.2 100.2 0.05 0.06 0.05 2-2 2-4 2.6
Mean
SEM
26.1 50.8 95.5 92-7 0.05 2.5
1-14 3.63 5.95 5-77 0-002 0.1
clearance rate, Clb, 2.5 + 0.1 ml kg-1 h q and an elimination half-life (h/2~) of 26.1 _+ 1.1 hours. Fig 1 also illustrates the mean plasma concentration of carprofen following a single intravenous injection of 4.0 mg kg -1 bodyweight to five animals. The plasma disposition and kinetic characteristics for the individual sheep are given in Table 1. Again these indicate a small volume of distribution, 118.4 + 3.5 ml kg-% a slow body clearance rate, 2-5 + 0-3 ml k T 1 h -1 and an elimination half-life of 33.7 + 3-1 hours. The mean AUC(0_72) for the animals given 4.0 mg k g -I carprofen intravenously was approximately 5.7 times greater than the AUC(0.72) for those animals administered 0.7 mg kg q, indicating that, between these two dose rates, plasma levels are directly proportional to the dose rate. The high drug concentration of carprofen in the plasma, at both dose rates, may be explained by the small volume of distribution, 95.5 _+ 6.0 and 118.4 _+ 3.5 ml kg q, which illustrates that carprofen is not widely distributed throughout the body. The result is consistent with that seen in the horse (McKellar et al 1991), dog (McKellar et al 1990) and cow (Ludwig et al 1989), and is probably related to the high degree of protein binding seen with carprofen (Baruth et al 1986) as with most other NSAIDS.
E
100 k
•
I ~
~
4.0 mg kg-1 0-7mgkg -1
Q.
8 E n
12
24
36 Time (h)
48
60
72
FIG 1: Mean plasma concentration-time curves for carprofen given by intravenous injection to sheep at two dose rates (0.7 and 4-0 mg kg 1)
1 4-0
2 4,0
3 4.0
4 4.0
5 4.0
30.3 24-6 33.8 36.4 43-5 57~6 67.9 62.7 61.2 52.5 115.4 125.9 127.4 113.7 109-4 115.0 124.5 125.6 112-6 108-8 0.05 0.05 0.04 0-04 0-03 2.6 3.5 2-6 2.2 1.7
Mean
SEM
33.7 60.4 118.4 117.3 0.04 2-5
3.14 2-57 3-53 3.31 0-004 0-3
Fig 1 shows that at the dose rate of 4.0 mg kg -~ there appears to be a small rise in plasma concentration of carprofen between six and eight hours after drug administration. Although the results shown are mean values, this rise occurred in four of the five animals sampled. It is possible that this rise represents an enterohepatic circulation for carprofen in sheep. Enterohepatic circulation of carprofen has been described in man (Ray and Wade 1982) and, although initially there was no evidence (Rubio et al 1980), McKellar et al (1990) suggested that it may occur in the dog. The elimination half-life of carprofen in sheep was 26.1 +_1.1 and 33-7 + 3.1 hours for animals administered 0.7 and 4.0 mg kg~1 intravenously, respectively. This is similar to that observed in the horse and pony at 3-5 mg kg-1 intravenously (21.9 +-2-3 hours) (McKellar et al 1991). In the lactating cow the plasma elimination half-life ranged from 44-5 to 64.6 hours (Ludwig et al 1989), which is considerably more prolonged than that observed in the sheep and over three times longer than observed by McKellar et al (1990) in dogs administered 0-7 mg k ~ 1 carprofen intravenously (8.0 + 1-2 hours). It is possible that the existence, or differences, in the degree of enterohepatic circulation of carprofen between species could account for the wide margin of values seen. The mean body clearance rates ofcarprofen in sheep were 2.5 ml kg~1 h -I at both dose rates, similar to those reported in cattle (Ludwig et al 1989), but lower than those reported in the dog (McKellar et al 1990) and horse (McKellar et al 1991). This may be a result of sheep clearing carprofen more slowly than other species. This is supported by the fact that sheep also clear flunixin meglumine, another NSAID, at a slower rate than other species (Welsh et al 1992). Recently, Lees et al (1991) described the pharmacokinetics of the carprofen enantiomers in the horse. They showed that there were marked differences in the pharmacokinetic disposition of the individual enantiomers, although the reasons for this were not established. In the dog, although there is no chiral inversion of the enantiomers, different pharmacokinetic profiles are seen (Q. A. McKellar, personal communication). The present authors have not analysed the individual
266
E. M . Welsh, P. B a x t e r , A. M . N o l a n
e n a n t i o m e r c o n c e n t r a t i o n s o f c a r p r o f e n in sheep, b u t it w o u l d be o f value to d o so w i t h any f u r t h e r investigations o f t h e analgesic and, or, a n t i - i n f l a m m a t o r y efficacy o f the drug. S c h a t z m a n et al (1990) h a v e o b s e r v e d t h a t p l a s m a levels o f >1.5 btg ml -I o f c a r p r o f e n are r e q u i r e d to p r o v i d e analgesia in the horse. F r o m F i g 1, f o l l o w i n g a d m i n i s t r a t i o n o f 4.0 m g kg 1 c a r p r o f e n i n t r a v e n o u s l y to sheep, p l a s m a levels o f the d r u g are m a i n t a i n e d well a b o v e this level f o r at l e a s t 72 h o u r s . A d m i n i s t r a t i o n o f 0.7 m g k ~ 1 o f c a r p r o f e n intrav e n o u s l y results in p l a s m a levels o f _>1-5 ~tg m1-1 f o r u p to 48 h o u r s , a n d if this level p r o v e s analgesic in sheep, the d r u g w o u l d be a useful aid for alleviating p a i n in this species. T h e p r e s e n t a u t h o r s are c u r r e n t l y i n v e s t i g a t i n g the analgesic effects o f c a r p r o f e n in sheep at 0.7 m g kg -1.
Acknowledgements This w o r k was s u p p o r t e d b y the A g r i c u l t u r a l a n d F o o d R e s e a r c h Council. C a r p r o f e n s o l u t i o n for this s t u d y was p r o v i d e d by B o r d e r R e s e a r c h .
References BARUTH, H., BERGER, L, BRADSHAW, D., COSTIN, C. H., COFFEY, J. W., GUPTA, N, KONIKOFF, J., ROBERTS, N. A. & WYLER-PLANT, R. (1986) Carprofen: In: Anti-inflammatory and Anti-rheumatic Drugs, Volume II. Newer Anti-inflammatory Drugs, Ed K.D. Rainsford. Boca Raton CRC Press, pp119-127 IWAKAWA, S., TOSHIYUKI, S., SHII-FUENG, L., HILDEGARD, S., LESLIE, B. Z. & EMIL, L.T. (1989) Direct determination of diastereometric carprofen glucuronides in human plasma and urine and preliminary measurements of stereoselectivemetabolic
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