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1.
The disposition kinetics and systemic availability of phenylbutazone were studied in healthy dairy cows. The same dose (6mg/kg) of phenylbutazone was administered by the i.v., i.m. and oral routes. The elimination half time after intravenous administration ranged from 32.4 to 60.8h. The result suggested that the distribution of phenylbutazone in cows can be described by a two-compartment open model. Total body clearance of the drug had a mean value of 0.0016 ml/kg-h. The overall tissue to plasma level ratio (k12/k21-β), after distribution equilibrium had been attained was 0.64. Phenylbutazone was shown, by an equilibrium dialysis method, to be highly bound to plasma proteins (93%) at serum levels of 100 μ/ml. The systemic availability of phenylbutazone was 69% and 89% when administered orally and intramuscularly respectively. Animals receiving half the dose of phenylbutazone (3 mg/kg) intravenously did not differ from cows receiving 6 mg/kg in elimination half-life and other distribution and elimination kinetic parameters. Based on the experimental data obtained, a dosage regimen is proposed, consisting of a priming oral dose of 9 mg/kg and maintenance doses of 4.5 mg/kg of phenylbutazone orally administered at 48 h intervals. The relatively long half-life in cattle, however, complicates the use of phenylbutazone because of the drug residue problem.  相似文献   

2.
Phenylbutazone was administered intravenously (i.v.) to a group of four lactating cows at a dosage of 6 mg/kg body weight. Whole plasma, protein-free plasma and milk were analysed for phenylbutazone residues. Pharmacokinetic parameters of total and free phenylbutazone in plasma were calculated using a non compartmental method. In regards to whole plasma data, the mean volume of distribution at steady state ( V ss), was 147 mL/kg body weight, with a mean (± SEM) terminal elimination half-life ( t 1/2) of 40 ± 6 h. The mean clearance ( Cl ) was 3 mL/h/kg body weight. The V ss as determined from the protein-free plasma fraction was 50 021 mL/kg body weight. This larger V ss of free phenylbutazone compared to total plasma phenylbutazone was attributed to a high degree of plasma protein binding, as well as the greater penetration of free phenylbutazone into tissues. The mean t 1/2 of free phenylbutazone was 39 ± 5 h. This similarity to the t 1/2 estimated from total plasma phenylbutazone data is attributed to an equilibrium between free and plasma phenylbutazone during the terminal elimination phase. Mean t 1/2 as determined from milk, applying a urinary excretion rate model, was 47 ± 4 h. Milk clearance of phenylbutazone was 0.009 mL/h/kg body weight, or about 0.34% of total body clearance. Furthermore, evidence suggests that phenylbutazone either binds to milk proteins, or is actively transported into milk, as its concentration in milk was greater than that predicted due to a simple partitioning from plasma into milk.  相似文献   

3.
Phenylbutazone was administered intravenously and intramuscularly at a dosage rate of 4.4 mg/kg to a group of 6 female camels in a two-period crossover study. After intravenous (i.v.) administration, disposition was characterised by a two-compartment open model, with a low volume of distribution (0.174 l.kg–1), and distribution and elimination half-lives of 0.43 and 12.51 h, respectively. After intramuscular (i.m.) dosing absorption was relatively rapid with absorption half-time and time of maximal concentration values of 1.14 and 3.95 h, respectively. Plateau concentrations of phenylbutazone in plasma were obtained between 2 and 12 h and mean bioavailability was 97%, although this was subject to wide inter-animal differences. Plasma concentrations of the phenylbutazone metabolite, oxyphenbutazone, were low after iv dosing and generally undetectable after im administration, indicating that it is unlikely to contribute significantly to the pharmacological effects produced by phenylbutazone administration. An indication was obtained that phenylbutazone inhibited the ex vivo synthesis of serum thromboxane B2 (TxB2) for 24 h after i.v. dosing, but this finding requires confirmation.  相似文献   

4.
This study evaluated potential alterations to the pharmacokinetics of salicylate by concurrently administered ceftiofur sodium. The trial design was a crossover using 10 non-lactating, non-pregnant dairy cows. In the first period each cow received intravenously (IV) 26 mg/kg of DL-lysine acetyl salicylate (aspirin) followed immediately by 2 mg/kg ceftiofur sodium. In the second period each cow received 26 mg/kg of aspirin IV. Plasma samples were harvested for determination of salicylate concentration by HPLC. The data best fitted a single compartment open model, using weighted non-linear regression. No alterations to the pharmacokinetic parameters of salicylate in cattle by concurrently administered ceftiofur sodium were detected ( P <0.05). Using 90% confidence intervals, and testing for changes of > 20%. control values, elimination half-life ( t 1/2), apparent volume of distribution ( V d), area under the plasma concentration versus time curve ( AUC ) and mean residence time ( MRT ) were not altered. For control animals the elimination rate constant ( k el) and total body clearance ( Cl ) were 1.35/pm0.43 h−1 and 20.2/pm6.1 ml/h.kg respectively (mean/pmSD). Since ceftiofur sodium did not affect the pharmacokinetics of salicylate, dose regimens for aspirin in cattle need not be altered when ceftiofur sodium is administered concurrently.  相似文献   

5.
The pharmacokinetics of thiamphenicol were investigated in 10 calves and six lactating cows. It was found that this drug is rapidly absorbed (1 5 min) following intramuscular injection with an absorption rate constant and a bioavailability of 8.7 h-1 and 84%, respectively. The drug appears to be widely distributed into various body fluids, yielding a volume of distribution (Vd(area)) of approximately 0.9 l/kg. The micro-rate constants indicated that the antibiotic rapidly diffuses into the peripheral compartment (k12 > k21). Elimination from plasma is relatively rapid, with a biological half-life of about 1.75 h. Thiamphenicol appears shortly in milk (15 min) after its intravenous administration, and gives milk to plasma concentration ratios greater than one between 4 and 12 h.  相似文献   

6.
The pharmacokinetics of furosemide were investigated in anaesthetized horses with bilateral ureteral ligation (BUL) with ( n  = 5) or without ( n  = 5) premedication with phenylbutazone. Horses were administered an intravenous (i.v.) bolus dose of furosemide (1 mg/kg) 6090 min after BUL. Plasma samples collected up to 3 h after drug administration were analysed by a validated high performance liquid chromatography method. Median plasma clearance ( CL p) of furosemide in anaesthetized horses with BUL was 1.4 mL/min/kg. Apparent steady state volume of distribution ( V dss) ranged from 169 to 880 mL/kg and the elimination half life ( t ½) ranged from 83 min to 209 h.   No differences in plasma concentration or kinetic parameter estimates were observed when phenylbutazone was administered before furosemide administration. BUL markedly reduces the elimination of furosemide in horses and models the potential effects that severe changes in kidney function may have on drug kinetics in horses.  相似文献   

7.
The pharmacokinetics and pharmacodynamics of meloxicam in piglets (16–23 days old) were studied using a stratified parallel group design. One group ( n  = 13) received 0.4 mg/kg meloxicam intravenously, while the other group ( n  = 12) received physiological saline solution. A carrageenan-sponge model of acute inflammation was used to evaluate the effects of meloxicam. The plasma clearance was low (0.061 L/kg/h), the volume of distribution was low (0.19 L/kg) and the elimination half-life was short (2.7 h). At most time points, the mean concentration of meloxicam in plasma exceeded the concentrations in exudate indicating a limited accumulation of the drug at the site of the inflammation. There were significant differences between the groups in the exudate prostaglandin E2 (PGE2) concentration, but the inhibition of PGE2 in the meloxicam group was limited. The inhibition of thromboxane B2 (TXB2) production in serum in the meloxicam group was extensive, but of shorter duration than the PGE2 inhibition in exudate.  相似文献   

8.
Cimetidine was administered intravenously and by the intragastric route to six mares at a dose of 4.0 mg/kg of body weight (bw). Specific and sensitive high performance liquid chromatographic methods for the determination of cimetidine in horse plasma and urine and cimetidine sulfoxide in urine are described. Plasma cimetidine concentration vs. time data were analysed by non-linear least squares regression analysis to determine pharmacokinetic parameter estimates. The median (range) plasma clearance (Cl) was 8.20 (4.96–10.2) mL/min.kg of body weight, that of the steady-state volume of distribution (Vdss) was 0.771 (0.521–1.15) L/kg bw, and that of the terminal elimination half-life ( t ½β) was 92.4 (70.6–125) minutes. The median (range) renal clearance of cimetidine was 4.08 (2.19–6.23) mL/min.kg bw or 55.4 (36.3–81.8)% of the corresponding plasma clearance. Cimetidine sulfoxide was excreted in urine and its urinary excretion through 8 h accounted for 12.0 (9.8–16.6)% of the plasma clearance of cimetidine. The median (range) extent of intragastric bioavailability was 14.4 (6.82–21.8)% and the maximum plasma concentration after intragastric administration was 0.31 (0.24–0.50) μg/mL.
Intravenous cimetidine had no effect on the disposition of intravenous phenylbutazone or its metabolites except that the maximum plasma concentration of γ-hydroxyphenylbutazone was less after cimetidine treatment.  相似文献   

9.
The pharmacokinetics of flunixin meglumine in the sheep   总被引：4，自引：0，他引：4  
Flunixin meglumine was administered intravenously and intramuscularly in sheep and the pharmacokinetics of the drug studied. Plasma concentrations of flunixin were measured by high performance liquid chromatography. The decline in plasma- flunixin concentration with time was best fitted by a triexponential equation. The pharmacokinetics following intravenous administration of 1.0 mg/kg indicate that flunixin has a rapid distribution half-life (t½π= 2.3 min), a slow body clearance rate (Clb= 0.6 ml/kg/min) and an elimination half-life of 229 min. Similarly, at 2.0 mg/kg, flunixin is rapidly distributed from the plasma, t½π= 2.7 min, has a slow body clearance rate (C/b = 0.7 mk/lg/min) and an elimination half-life of 205 min.
Following intramuscular injection flunixin is rapidly and well absorbed from the injection site. It had a mean maximum concentration ( C max) of ≫5.9 μg/ml when administered at a dose rate of 1.1 mg/kg, and a relative bioavailability of 70%. Plasma concentrations increase proportionally to dose over the range 1.1 mg/kg-2.2 mg/kg when administered by the intramuscular route.  相似文献   

10.
In this investigation the pharmacokinetics of three commonly used antibiotics, ampicillin trihydrate (10 mg/kg), gentamicin sulphate (3 mg/kg) and oxytetracycline hydrochloride (5 mg/kg), given intravenously, were each studied in five Nubian goats and five desert sheep. The pharmacokinetic parameters were described by a two-compartment open model. The results indicated that there were significant differences between the two species in some kinetic parameters of ampicillin and oxytetracycline but not gentamicin. Ampicillin elimination half life ( t 1/2β) in goats (1.20 h) was shorter than that in sheep (2.48 h), and its clearance ( Cl ) significantly higher in goats (2921mL/h·kg) compared to sheep (262 mL/h·kg) ( P < 0.01). Ampicillin volume of distribution ( V darea) was found to be significantly larger in goats (5673 mL/kg) than in sheep (992 mL/kg) ( P < 0.01). For oxytetracycline, the t 1/2β in goats (3.89 h) was significantly shorter than that in sheep (6.30 h) and the Cl value in goats (437 mL/h·kg) was significantly higher than in sheep (281 mL/h·kg). The results suggest that when treating sheep and goats, the pharmacokinetic differences between the two species must be considered in order to optimize the therapeutic doses of ampicillin and oxytetracycline.  相似文献   

11.
Strøm, H. & Krogsgaard Thomsen, M. Effects of non-steroidal anti-inflammatory drugs on canine neutrophil chemotaxis. J. vet. Pharmacol. Therap. 13, 186–191.
Non-steroidal anti-inflammatory drugs exhibit differences in their ability to suppress polymorphonuclear leucocyte (PMN) functions in different species. The present study investigated the in-vitro and ex-vivo effects of phenylbutazone and flunixin on leukotriene-B4-directed migration of canine PMN. Furthermore, in-vitro comparison was made to indomethacin and the 5-lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA). In vitro , flunixin and NDGA were the most potent inhibitors, with IC 50s of 13 and 7 μmol/l, respectively. Phenylbutazone had an IC 50 of 42 μmol/l whereas indomethacin did not achieve 50% inhibition at concentrations less than 100 μmol/l. Ex vivo , flunixin almost completely abolished the LTB4 response at 1h, and still possessed significant inhibitory activity 24 h after a dosage of 1mg/kg i.v. Phenylbutazone was less active ex vivo but did suppress chemotaxis by 23% (P<0.05) at 1h following an i.v. dose of 20mg/kg. It is suggested that part of the anti-inflammatory action of flunixin in dogs may be attributed to inhibition of PMN recruitment.
M. Krogsgaard Thomsen, Department of Pharmacology, Leo Pharmaceutical Products, DK-2750, Ballerup, Denmark.  相似文献   

12.
The pharmacokinetics of oral and intravenous allopurinol was studied in five horses and compared with intravenous oxypurinol. The plasma concentration vs. time curves, following intravenous administration of 5 mg/kg, were best described by the biexponential equations Cp = 106.58e-25.141+ 159.93e-10.96tfor allopurinol and Cp = 321.09e-972t+ 82.39e-0.44tfor oxypurinol. Allopurinol was rapidly removed from the plasma, compared to oxypurinol, with an elimination half-life ( t 1/2β) of 0.09 h and an area under the curve ( AUC ) of 19.8 μmol·h/L after intravenous administration, while the t 1/2β and AUC of oxypurinol were 1.09 h and 231 μmol·h/L, respectively. The bioavailability of allopurinol was low (14.3%), although no allopurinol was detected in the plasma of two horses after oral administration. However, the AUC of drug and metabolite after intravenous administration of allopurinol was equivalent to that of intravenously injected oxypurinol. The results suggest that allopurinol is rapidly metabolised in vivo and that the majority of the pharmacological activity of allopurinol in the horse may result from the action of the active metabolite, oxypurinol.  相似文献   

13.
The objectives of this study were to determine if phenylbutazone decreased serum thyroxine (TT4) and free thyroxine (FT4) concentrations using radioimmunoassay and equilibrium dialysis techniques in horses, and, if so, an additional objective was to determine the duration of this decreased concentration once phenylbutazone administration was discontinued. Serum TT4 and FT4 concentrations were determined before and after administration of 4.4 mg/kg of phenylbutazone IV bid for 5 days. Treatment with phenylbutazone caused a significant decrease in TT4 and FT4 concentrations ( P < .05). Serum TT4 concentration significantly decreased after day 4 of treatment and remained significantly below baseline value for 10 days after discontinuing phenylbutazone administration; it returned to a value not different from the baseline value by the 11th day. Serum FT4 concentration significantly decreased after day 4 of treatment and remained significantly below the baseline value for only 1 day after phenylbutazone administration was discontinued; it returned to a value not different from the baseline value by the 3rd day after discontinuation of phenylbutazone. These results indicate that serum TT4 and FT4 should not be used to evaluate thyroid function in horses receiving phenylbutazone. In addition, results should be interpreted cautiously when phenylbutazone has been administered within 2 days (for FT4) or within 10 days (for TT4) of sample collection.  相似文献   

14.
The pharmacokinetics of sulphadiazine (SDZ) (100 mg/kg, body weight) were investigated in six camels ( Camelus dromedarius ) after intravenous (i.v.) and oral (p.o.) administration. Following i.v. administration, the overall elimination rate constant (β) was 0.029±0.001/h and the half-life ( t ½β) was 23.14±1.06 h. The apparent volume of distribution ( V d(area)) was 0.790±0.075 L/kg and the total body clearance ( Cl B) was 23.29±2.50 mL/h/kg. After p.o. administration, SDZ reached a peak plasma concentration ( C max(cal.)) of 62.93±2.79 μg/mL at a post injection time of ( T max(cal.)) 22.98±0.83 h. The elimination half-life was 19.79±1.22 h, not significantly different from that obtained by the i.v. route. The mean absorption rate constant (Ka) was 0.056±0.002 h−1 and the mean absorption half-life ( t ½Ka) was 12.33±0.37 h. The mean availability ( F ) of sulphadiazine was 88.2±6.2%.
  To achieve and maintain therapeutically satisfactory plasma SDZ levels of 50 μg/mL, the priming and maintenance doses would be 80 mg/kg and 40 mg/kg intravenously and 90 mg/kg and 45 mg/kg orally, respectively, to be repeated at 24 h intervals.  相似文献   

15.
A method for the analytical determination of metronidazole concentrations in biological tissues was developed using high performance liquid chromatography. The procedure was employed to investigate the pharmacokinetics of metronidazole in dogs following intravenous and oral administration (44 mg/kg). The overall elimination rate constant β was 0.0027 ± 0.0005 min-1, the apparent specific volume of distribution (V'd) was 0.948 ± 0.096 L/kg overall clearance (ClB) was 2.49 ± 0.54 ml/kg/min and the rate constant for absorption Kab was 0.0456 ± 0.0353 min-1. Oral bioavailability was high but variable (59%–100%). Implications of these data for chemotherapy of infections caused by anaerobic bacteria, trichomonads, and Giardia and for the sensitization of hypoxic neoplastic cells to radiotherapy are discussed.  相似文献   

16.
The pharmacodynamics and enantioselective pharmacokinetics of vedaprofen were studied in six ponies in a two period cross-over study, in which a mild acute inflammatory reaction was induced by carrageenan soaked sponges implanted subcutaneously in the neck. Vedaprofen, administered intravenously at a dosage of 1 mg/kg, produced significant and prolonged inhibition of ex vivo serum thromboxane B2 (TXB2) synthesis and short-lived inhibition of exudate prostaglandin E2 (PGE2) and TXB2 synthesis. Vedaprofen also partially inhibited oedematous swelling and leucocyte infiltration into exudate. Vedaprofen dis-played enantioselective pharmacokinetics, plasma concentrations of the R(–) enantiomer exceeding those of S(+) vedaprofen. The plasma concentration ratio, R:S, increased from 69: 31 at 5 min to 96: 4 at 3 h and plasma mean AUC values were 7524 and 1639 ng.h/mL, respectively. Volume of distribution was greater for S(+) vedaprofen, whilst elimination half-life (t½β) and mean residence time were greater for R(–) vedaprofen. The penetration of vedaprofen into inflammatory exudate was also enantioselective. For R(–) and S(+) veda-profen maximum concentration (Cmax) values were 2950 and 1534 ng/mL, respectively, and corresponding AUC values were 9755 and 4400 ng.h/mL. Vedaprofen was highly protein bound (greater than 99%) in both plasma and exudate. The significance of these data for the therapeutic use of vedaprofen is discussed.  相似文献   

17.
The bioavailability of amprolium (APL) was measured after intravenous (i.v.) and oral (p.o.) administration to chickens. Twelve healthy chickens weighing 1.28–1.41 kg received a dose of 13 mg APL/kg intravenously, and 13 or 26 mg APL/kg orally in both a fasted and a nonfasted condition in a Latin square design. Plasma samples were taken from the subwing vein for determination of APL concentration by HPLC method. The data following intravenous and oral administration were best fitted by 2-compartment and 1-compartment models, respectively, using weighted nonlinear least squares regression. The half-life beta t ½β, volume of distribution ( V d) and total body clearance ( Cl ) after intravenous administration were 0.21 h, 0.12 L/kg and 1.32 L/h.kg, respectively. The elimination half-life ( t ½ Kel) after oral administration was 0.292–0.654 h which is 1.5–3.2 times longer than after intravenous administration, suggesting the presence of a 'flip-flop' phenomenon in chickens. The maximum plasma concentration ( C max) of 13 mg/kg APL administered orally to chickens during fasting was significantly (about four times) higher than that during nonfasting ( P < 0.05). Bioavailability during nonfasting was from 2.3 to 2.6%, and 6.4% during fasting.  相似文献   

18.
Phenylbutazone was administered intravenously to a group of 11 beef steers at a dosage of 6 mg/kg of body weight. Whole plasma and protein-free plasma were analyzed for phenylbutazone residues. Pharmacokinetic parameters of total and free phenylbutazone in plasma were calculated using a noncompartmental method. In regards to whole plasma data, the mean volume of distribution at steady state (Vss), was 140 mL/kg body weight, with a mean (+/-SEM) terminal elimination half-life (t1/2) of 34 +/- 9 h. The mean clearance was 3.2 mL/h/kg body weight. The Vss, as determined from the protein-free plasma fraction, was 54093 mL/kg body weight. This larger Vss of free phenylbutazone compared with total plasma phenylbutazone was attributed to a high degree of plasma protein binding, as well as the greater penetration of free phenylbutazone into tissues. The mean t1/2 of free phenylbutazone was 35 +/- 12 h. This similarity to the t1/2 estimated from total plasma phenylbutazone data is attributed to an equilibrium between free and plasma phenylbutazone during the terminal elimination phase. The pharmacokinetic parameters of free and total plasma phenylbutazone in beef steers are statistically similar to those previously reported for lactating dairy cows.  相似文献   

19.
A high performance liquid chromatographic method is described to determine the anti-inflammatory drug suxibuzone (SXB) and its major metabolites phenylbutazone (PBZ) and oxyphenbutazone (OPBZ) in equine plasma and urine. When suxibuzone (6 mg/kg) was administered intravenously (i.v.) or orally (p.o.) no parent drug was detected in plasma or in urine. The disposition of the metabolite PBZ (i.v.) could be described by a 2 compartment model with a P half-life varying from 7.40 to 8.35 h. Due to severe side effects the use of i.v. suxibuzone should not be encouraged in the horse. PBZ and OPBZ were detected in plasma and urine after p.o. SXB administration. Peak plasma PBZ concentrations (8.8 ± 3.0 μg/ml) occurred 6 h after oral dosing and the terminal exponential constant was 0.11 ± 0.01 h-1. Phenylbutazone and oxyphenbutazone were detectable in urine (> 1 μg/ml) for at least 36 h, after p.o. administration.
SXB was not hydrolyzed in vitro by horse plasma. Equine liver homogenates however appeared to have a very high capacity for hydrolysing SXB, indicating that first-pass effect could be responsible for the rapid disappearance of this NSAID in the horse.  相似文献   

20.
Phenylbutazone given during the perisurgical period has been reported to increase the intensity and duration of thiamylal anaesthesia in horses. A possible mechanism of competitive plasma protein binding has been suggested. The purpose of the present study was to experimentally reproduce the phenomenon of increased intensity and/or duration of thiamylal anaesthesia and to determine if there is competitive displacement of plasma protein bound thiamylal by phenylbutazone. Six ponies each received one of three treatments, 11 mg/kg intravenous (i.v.) thiamylal; 8.8 mg/kg i.v. phenylbutazone; and 11 mg/kg i.v. thiamylal with 8.8 mg/kg i.v. phenylbutazone given 9 min later. Thirteen blood samples were collected from 0 time through 600 min following drug administration and plasma drug concentrations quantified by high performance liquid chromatography. The pharmacokinetics of thiamylal and phenylbutazone were best described by three- and two-compartment models, respectively. There were no significant differences in pharmacokinetic parameters for thiamylal in the presence of phenylbutazone. However, there were differences in phenylbutazone pharmacokinetics when preceded by thiamylal administration. Unbound phenylbutazone concentrations were increased at 171, 231 and 351 min when given with thiamylal, accompanied by decreases in per cent bound phenylbutazone (P < 0.05). There were also significant (P < 0.05) changes in per cent plasma protein binding of thiamylal and phenylbutazone between 120 and 360 min, when in combination. No changes in intensity or duration of anaesthesia were observed.  相似文献   

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