Pharmacokinetics Of Phenylbutazone Research Articles

The pharmacokinetics of phenylbutazone and its interaction with dexamethasone in chicks

The present study aims to investigate the influence of dexamethasone administration on the pharmacokinetics of phenylbutazone and its plasma concentration as well as its pharmacological interaction in a chick model. The analgesic median effective doses (ED50s) of phenylbutazone and dexamethasone are separately evaluated as 5.60 and 0.63 mg/kg, IP, and their ED50s are estimated and reduced to 1.76 and 0.19 mg/kg, IP, respectively. The type of pharmacological interaction between phenylbutazone and dexamethasone is synergistic as determined by the isobolographic analysis. The phenylbutazone administration at 11.20 mg/kg, IP has plasma concentrations of 39.83, 66.17, 48.00, 35.30, 26.50 and 13.33 µg/ml in the estimated times of 0.25, 0.5, 1, 2, 4, and 24 hours, respectively. These concentrations are increased to 57.00, 384.17, 210.67, 138.67, 65.50 and 50.10 µg/ml as dexamethasone 1.26 mg/kg, IP is given by 43, 426, 339, 293, 147 and 276%. Phenylbutazone pharmacokinetics are increased and result in an elevation in an area under the curve (AUC0-∞) 196%, area under the moment curve (AUMC0-∞) 140%, elimination rate constant (Kel) 50%, and maximum concentration (Cmax) 426%. However, other parameters are reduced to include half-life (t1/2β) 33%, mean residence time (MRT) 18%, steady state of the volume of distribution (Vss) 78%, and clearance (Cl) 60%. The overall findings reveal a synergism as a type of pharmacological interaction between phenylbutazone and dexamethasone. In addition, a change in phenylbutazone pharmacokinetics and its plasma concentration which improves phenylbutazone therapeutic efficiency in the chick model is noticed.

Phenylbutazone blood and urine concentrations, pharmacokinetics, and effects on biomarkers of inflammation in horses following intravenous and oral administration of clinical doses.

Phenylbutazone (PBZ) is a potent mon-steroidal anti-inflammatory drug used commonly in performance horses. The objectives of the current study were to describe blood and urine concentrations and the pharmacokinetics of PBZ and its metabolites following intravenous (IV) and oral administration and to describe the duration of pharmacodynamic effect. To that end, 17 horses received an IV administration and 18 horses an oral administration of 2 g of PBZ. Blood and urine samples were collected prior to and for up to 96hours post drug administration. Whole blood samples were collected at various time points and challenged with lipopolysaccharide or calcium ionophore to induce ex vivo synthesis of eicosanoids. Concentrations of PBZ and eicosanoids were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and non-compartmental pharmacokinetic analysis performed on concentration data from IV and oral administration. Serum concentrations of PBZ and its metabolites were below the limit of quantitation at 96hours post administration. The volume of distribution at steady state, systemic clearance, and terminal half-life was 0.194±0.019L/kg, 23.9±4.48mL/h/kg, and 10.9±5.32hours, respectively. The terminal half-life following oral administration was 13.4±3.01 (paste) and 15.1±3.96hours (tablets). Stimulation of PBZ treated whole blood with lipopolysaccharide and calcium ionophore resulted in an inhibition of TXB2 , PGE2 , LTB4 and 15-HETE production for a prolonged period of time post drug administration. The results of this study suggest that PBZ has a prolonged anti-inflammatory following IV or oral administration of 2 g to horses.

Pharmacodynamics and pharmacokinetics of phenylbutazone in calves.

Phenylbutazone (PBZ) was administered to six calves intravenously (i.v.) and orally at a dose rate of 4.4 mg/kg in a three-period cross-over study incorporating a placebo treatment to establish its pharmacokinetic and pharmacodynamic properties. Extravascular distribution was determined by measuring penetration into tissue chamber fluid in the absence of stimulation (transudate) and after stimulation of chamber tissue with the mild irritant carrageenan (exudate). PBZ pharmacokinetics after i.v. dosage was characterized by slow clearance (1.29 mL/kg/h), long-terminal half-life (53.4 h), low distribution volume (0.09 L/kg) and low concentrations in plasma of the metabolite oxyphenbutazone (OPBZ), confirming previously published data for adult cattle. After oral dosage bioavailability (F) was 66%. Passage into exudate was slow and limited, and penetration into transudate was even slower and more limited; area under curve values for plasma, exudate and transudate after i.v. dosage were 3604, 1117 and 766 microg h/mL and corresponding values after oral dosage were 2435, 647 and 486 microg h/mL. These concentrations were approximately 15-20 (plasma) and nine (exudate) times greater than those previously reported in horses (receiving the same dose rate of PBZ). In the horse, the lower concentrations had produced marked inhibition of eicosanoid synthesis and suppressed the inflammatory response. The higher concentrations in calves were insufficient to inhibit significantly exudate prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and beta-glucuronidase concentrations and exudate leucocyte numbers, serum thromboxane B2 (TxB2), and bradykinin-induced skin swelling. These differences from the horse might be the result of: (a) the presence in equine biological fluids of higher concentrations than in calves of the active PBZ metabolite, OPBZ; (b) a greater degree of binding of PBZ to plasma protein in calves; (c) species differences in the sensitivity to PBZ of the cyclo-oxygenase (COX) isoenzymes, COX-1 and COX-2 or; (d) a combination of these factors. To achieve clinical efficacy with single doses of PBZ in calves, higher dosages than 4.4 mg/kg will be probably required.

Pharmacokinetics of phenylbutazone in beef steers.

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.

Pharmacokinetics of phenylbutazone in llamas following single intravenous and oral doses.

Pharmacokinetics of phenylbutazone in llamas following single intravenous and oral doses.

Pharmacokinetics of phenylbutazone and its metabolite oxyphenbutazone in miniature donkeys.

To describe the pharmacokinetics of phenylbutazone and oxyphenbutazone after IV administration in miniature donkeys. 6 clinically normal miniature donkeys. Blood samples were collected before and 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300, 360, and 480 minutes after IV administration of phenylbutazone (4.4 mg/kg of body weight). Serum was analyzed in triplicate by use of high-performance liquid chromatography for determination of phenylbutazone and oxyphenbutazone concentrations. The serum concentration-time curve for each donkey was analyzed separately to estimate model-independent pharmacokinetic variables. Serum concentrations decreased rapidly after IV administration of phenylbutazone, and they reached undetectable concentrations within 4 hours. Values for mean residence time ranged from 0.5 to 3.0 hours (median, 1.1 hour), whereas total body clearance ranged from 4.2 to 7.5 ml/kg/min (mean, 5.8 ml/kg/min). Oxyphenbutazone appeared rapidly in the serum; time to peak concentration ranged from 13 to 41 minutes (mean, 26.4 minutes), and peak concentration in serum ranged from 2.8 to 4.0 mg/ml (mean, 3.5 microg/ml). Clearance of phenylbutazone in miniature donkeys after injection of a single dose (4.4 mg/kg, IV) is rapid. Compared with horses, miniature donkeys may require more frequent administration of phenylbutazone to achieve therapeutic efficacy.

Pharmacokinetics of phenylbutazone in plasma and milk of lactating dairy cows.

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 (Vss), was 147 mL/kg body weight, with a mean (+/-SEM) terminal elimination half-life (t1/2) of 40+/-6 h. The mean clearance (Cl) was 3 mL/h/kg body weight. The Vss as determined from the protein-free plasma fraction was 50021 mL/kg body weight. This larger Vss 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 t1/2 of free phenylbutazone was 39+/-5 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. Mean t1/2 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.

Pharmacokinetics of phenylbutazone in camels

Abstract Objective To document disposition variables of phenylbutazone and its metabolite, oxyphenbutazone, in camels (Camelus dromedarius) after single IV bolus administration of phenylbutazone, with a view to making recommendation on avoiding violative residues in racing camels. Animals 6 healthy camels (4 males, 2 females), 5 to 7 years old, and weighing from 350 to 450 kg. Procedure Blood samples were collected at 0, 5, 10, 15, 45, and 60 minutes and at 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 26, 28, 30, 40, 48, 50, 53, and 60 hours after IV administration of 4.5 mg of phenylbutazone per kg of body weight. Urine was obtained in fractions during the entire blood sample collection period. Serum and urine phenylbutazone concentrations were measured by high-performance liquid chromatography; assay sensitivity was 100 ng/ml. Serum oxyphenbutazone concentration was measured by gas chromatography/mass spectrometry; assay sensitivity was 10 ng/ml. Results Disposition of phenylbutazone was best described by a two-compartment open model. Mean ± SEM elimination half-life was 13.44 ± 0.44 hours. Total body clearance was 12.63 ± 1.64 mg/kg/h. Renal clearance was between 0.3 and 0.4% of total body clearance. The elimination half-life of oxyphenbutazone was 23.9 ± 2.09 hours. Conclusions The elimination half-life and total body clearance of phenylbutazone in camels are intermediate between reported values in horses and cattle. Extrapolation of a dosage regimen from either species to camels is, therefore, not appropriate. Elimination of phenylbutazone in camels is mainly via metabolism. Owing to the long half-life of phenylbutazone and of oxyphenbutazone, and to the zero drug concentration regulation adopted by the racing commissioner in the United Arab Emirates, practicing veterinarians would be advised not to use phenylbutazone in camels for at least 7 days prior to racing. (Am J Vet Res 1997;58:636–640)

Pharmacokinetics of phenylbutazone given intravenously or orally in mature Holstein bulls

SUMMARY Six mature Holstein bulls were each given 10 mg of phenylbutazone (pbz)/kg of body weight, po. Of the 6 bulls, 3 were given 10 mg of pbz/kg by rapid iv administration 4 weeks later. Plasma concentration-vs-time data were analyzed, using nonlinear regression modeling (sum of exponential functions). The harmonic mean of the biologic half-life of pbz was 62.6 ± 12.9 hours after oral administration and 61.6 ± 7.2 hours after iv administration. The mean residence time was 94.61 ± 8.44 hours and 90.49 ± 8.93 hours for oral and iv administration, respectively. The mean total body clearance was 0.0015 ± 0.0003 L/h/kg, with the mean apparent volume of distribution 0.134 ± 0.021 L/kg. Mean bioavailability was 73 ± 2% after oral administration. Phenylbutazone was adequately absorbed from the gastrointestinal tract in bulls. The apparent volume of distribution was small, indicating that pbz distributed mainly into plasma and extracellular fluid. The total body clearance was also small, which accounted for the long half-life of pbz in bulls.

Absorption and pharmacokinetics of phenylbutazone in Welsh Mountain ponies.

The disposition of phenylbutazone (4.4 mg/kg), administered intravenously to six Welsh Mountain ponies, was described by a two-compartment open model. Pharmacokinetic parameters were not significantly different after morning dosing in comparison with afternoon dosing. When phenylbutazone (4.4 mg/kg) was administered orally to the same ponies, marked variations in time to peak concentrations were produced with different feeding schedules. When access to hay was permitted before and after dosing, the mean time to peak concentration was 13.2 +/- 1.2 h and double peaks in the plasma concentration-time curve were common. Double peaks were also encountered when phenylbutazone was given to ponies deprived of food prior to, and allowed access to hay after, dosing. In this circumstance, mean times to peak concentration were much shorter (3.8 +/- 1.3 h after morning dosing and 5.3 +/- 1.5 h followed afternoon dosing). Absorption was more regular and double peaks were less apparent when food was withheld both before and after dosing. In order to explain these findings, it is tentatively postulated that, whereas some of the administered dose of phenylbutazone may be absorbed quickly, some may become adsorbed on to the feed and subsequently released by fermentative digestion in the large intestine and/or caecum. The consequences of delayed absorption in fed animals for toxicity and clinical efficacy, and for the use of phenylbutazone in equestrian sports, are considered. Delayed absorption in ponies given access to hay was not accompanied by a significant reduction in total absorption. Bioavailability was estimated to be approximately 69% in fed and 78% in unfed ponies. Estimates of bioavailability gave similar values for morning (72%) and afternoon (71%) dosing.

Modelling and simulation of the nonlinear dose-plasma concentration response of phenylbutazone on periodic multiple oral dosing: A mechanistic approach

The dose-ranging pharmacokinetics of phenylbutazone on periodic multiple oral dosing have previously been shown to be nonlinear, inasmuch as there is a plateauing of steady-state plasma concentrations with increasing dose. The mechanistic hypothesis of saturable protein binding, postulated to explain this behaviour was tested, in the context of whole-body pharmacokinetic modelling of the observed dose dependancy, using the circuit simulation program SPICE2. The alternate hypothesis, operating singly or in tandem, of loss of unabsorbed drug due to gastrointestinal emptying, saturable absorption, change in the volume of distribution of the drug, were also examined. Within the constraints of the proposed whole-body pharmacokinetic model, the absorption kinetics of increasing oral daily doses of phenylbutazone were shown to be saturable in their mechanism.

Pharmacokinetics of phenylbutazone and its metabolites in the horse.

Phenylbutazone was given orally to 2 groups of horses and the plasma levels of the drug and its 2 principal metabolites oxyphenbutazone and gamma-hydroxyphenylbutazone measured by high performance liquid chromatography. Animals in Group 1 received single oral doses in a range from 1.1 to 13.2 mg/kg and were sampled over the succeeding 24 h. Considerable individual variation was observed both in timing and magnitude of the plasma drug responses between horses, but 24 h after dosing a clear dose response relation was recorded. Group 2 horses were given the recommended therapeutic dosage regimen and sampled over 24 h periods twice weekly. After 4 days at 8.8 mg/kg in 2 divided doses mean peak plasma levels of phenylbutazone reached 24 micrograms/ml and showed evidence of cumulation. After 4 days at 4.4 micrograms/kg, peak plasma concentrations had fallen to 10 micrograms/ml and mean peak levels just failed to reach 4 micrograms/ml 3 days after reducing dosage to 2.2 mg/kg once daily. Plasma concentrations of oxyphenbutazone did not exceed 25 per cent of the parent drug and the gamma-hydroxy metabolite was only just detectable and never exceeded 1 microgram/ml.

The effect of malnutrition on the pharmacokinetics of phenylbutazone.

The pharmacokinetics of phenylbutazone were studied after a single oral dose of 6 mg/kg bodyweight in 35 adult male subjects with differing nutritional status. The elimination half-life was significantly shorter and plasma clearance accelerated in undernourished patients who had significant weight deficit and low serum albumin concentration. Plasma protein binding was only 86% compared with 95 to 96% in normal subjects (smokers and non-smokers). The apparent volume of distribution was also higher in undernourished patients. Significant correlations were observed between serum albumin, protein binding and bodyweight. Multiple regression analysis of the data indicated that altered drug protein binding partially contributed towards variation in half-life and clearance; and the plasma albumin concentration significantly influenced the amount of drug bound in plasma. The results indicate that nutritional status is one of the important environmental variables that can alter drug kinetics and disposition in man. Further studies, including measurement of steady-state plasma concentrations of various other drugs, are necessary to elucidate drug kinetics in malnourished subjects.

Bioavailability and pharmacokinetics of phenylbutazone in the cow

Phenylbutazone was administered orally and intravenously at a dose of 5 mg/kg to healthy cows and to cows positive for bovine leukaemia virus (BLV). Pharmacokinetic parameters and bioavailability were investigated. No differences were seen in the parameters between the healthy and BLV positive animals. The biological half‐lives ranged from 31.4 to 82.1 h after intravenous administration and from 38.6 to 78.2 h after oral administration. The mean value of the apparent volume of distribution was 0.09 litres/kg. Total body clearance ranged from 0.78 to 1.94 ml/kg/h. The average systemic availability was 67.5% with a wide variation among the animals (range 41.9–95.5%). Based on the disposition kinetics and on the therapeutic concentration range suggested in man, an oral loading dose ranging from 10 to 20 mg/kg and a daily maintenance dose ranging from 2.5 to 5 mg/kg can be proposed.