Age-dependent pharmacokinetics of phenylbutazone in calves

The pharmacokinetics of phenylbutazone (PBZ) in relation to age was studied in calves. The drug was applied intravenously to calves (dose 22 mg/kg), which were divided, depending on age, into three groups. Heparinised blood samples were taken in defined intervals. The concentrations of phenylbutazone and two of its metabolites were determined in plasma by high performance liquid chromatography. The pharmacokinetic data derived from 1-month-old calves revealed a longer persistence (elimination half-lives twice as long, total body clearance 40-50% lower) of PBZ in the body than in the other two groups of calves aged 3-6 months. With respect to the long elimination half-lives (mean values 39-94 h), caution is needed in case of repeated doses (accumulation).     

Pharmacodynamics and pharmacokinetics of tolfenamicacid in ruminating calves: Evaluation in models of acute inflammation

Injections of mild irritants intradermally (carrageenan, zymosan and dextran) and intracaveally (carrageenan)in a tissue cage model of inflammation were used in studies of the pharmacodynamics and pharmacokinetics of tolfenamic acid administered intramuscularly in calves. Inhibition of serum thromboxane (TX) B₂ and inflammatory exudate prostaglandin (PG) E₂ were used as indicators of the magnitude and time course of blockade of cyclo-oxygenase isoforms COX-1 and COX-2, respectively. Single doses of 2, 4 and 8mgkg⁻¹ tolfenamic acid partially inhibited irritant-induced rises in skin temperature (non-dose dependently) and skin oedema (dose-dependently). These doses also markedly inhibited serum TXB₂ synthesis and the duration of inhibition was dose-related. A dose of 2mgkg⁻¹ tolfenamic acid also attenuated skin temperature rise over carrageenan-injected tissue cages, and markedly inhibited exudate PGE₂ synthesis, even though drug penetration into both exudate and tissue cage transudate was limited. Tolfenamic acid pharmacokinetics were characterized by a relatively short t_max (0.94–2.0411), a high estimated Vdarea (1.79–3.20Lkg⁻¹), an estimated ticase 1/2β of 8.01–13.5011 and Cl_β of 0.142–0.175Lkg⁻¹h⁻¹. The actions of tolfenamic acid in inhibiting PGE₂ synthesis and in attenuating two of the cardinal signs of inflammation (heat and swelling) suggest that a dosage of 2mgkg⁻¹ administered intramuscularly should be effective clinically as an anti-inflammatory agent.     

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.     

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.     

Ketoprofen and phenylbutazone attenuation of PAF-induced lung inflammation in calves

The purposes of this study were: (1) to investigate which arachidonic acid metabolites contributed to platelet-activating factor (PAF) induced pulmonary dysfunction; and (2) to compare the effect of two non-steroidal anti-inflammatory drugs, phenylbutazone and ketoprofen in a model of PAF-induced reversible lung inflammation in six calves. In placebo and phenylbutazone groups, PAF infusion induced significant dysfunctions in the pattern of breathing, mechanics of breathing and gas exchange. These dysfunctions were prevented by ketoprofen pretreatment, except for the mechanics of breathing which was moderately but significantly altered by the PAF challenge. In all calves, leukotriene (LT) B4 plasma concentrations did not significantly increase above baseline values at any time. Prostaglandin (PG) E2 plasma concentrations showed a minor significant increase in phenylbutazone pretreated calves (55.8 +/- 25.8 pg/mL from 36.7 +/- 16.13 pg/mL). Thromboxane (TX) B2 plasma concentration was significantly increased during PAF challenge in placebo- and phenylbutazone-pretreated groups, but not in ketoprofen-pretreated calves (1580.0 +/- 1370 from 42.7 +/- 10.7 pg/mL; 2340 +/- 477 from 63 +/- 32 pg/mL; and 36.5 +/- 4.12 from 39.3 +/- 12.0 pg/mL, respectively). These data suggest that TXA2 is an important cyclooxygenase metabolite of arachidonic acid produced in response to PAF and that ketoprofen (intramuscular injection, 3 mg/kg) is more effective than phenylbutazone (intramuscular injection, 10 mg/kg) in preventing respiratory dysfunctions induced by the PAF challenge 30 min after drug administration. Ketoprofen did not suppress totally the PAF-induced changes in mechanics of breathing, which suggests that PAF or a secondary release of mediators could have a direct action on airway smooth muscle.     

Pharmacodynamics and pharmacokinetics of flunixin in the cat

The non-steroidal anti-inflammatory agent (NSAID) flunixin was administered as single doses both orally and intravenously to six cats at a dose rate of 1.0 mg/kg in a two-part cross-over study. After oral dosing rapid absorption to a mean peak concentration of 2.586 micrograms/ml occurred at a mean time of 1.33 h. Similar mean plasma concentration-time AUC values for oral and intravenous dosing indicated that absorption by the former route was virtually complete. The decline in plasma concentration occurred fairly rapidly with both routes, and elimination half-life was approximately 1.0-1.5 h. The time course of inhibition of serum TXB2 concentration was similar for the two routes of administration, suggesting that similar dosing schedules are likely to be appropriate for evaluation of flunixin in clinical trials.     

Pharmacodynamics and pharmacokinetics of miloxicam in the horse

The novel non-steroidal anti-inflammatory drug (NSAID) miloxicam was administered intravenously to six New Forest ponies at a dosage rate of 0.6 mg/kg in a two-part cross-over study. In each part, three horses received miloxicam and three were given a placebo preparation. The actions of miloxicam, compared to placebo, were assessed in a carrageenan-sponge model of acute inflammation. The rise in skin temperature over the site of the acute inflammatory reaction was less in treated ponies, but differences were not statistically significant. Concentrations of the enzymes acid phosphatase (AP) and lysozyme in inflammatory exudates harvested at 4, 8, 12 and 24 h were not significantly different in drug-treated animals compared with those receiving placebo. Concentrations of protein and lactate dehydrogenase (LDH) in exudate and exudate leucocyte numbers were significantly reduced in drug-treated horses when data for all sampling times were pooled. The differences were not significant, however, at each sampling time. Exudate concentrations of the eicosanoids, bicyclic-PGE2, 6-keto-PGF1 alpha and TXB2, were reduced significantly by miloxicam at most sampling times, and serum TXB2 was also significantly reduced at 4 and 8 h but not at 12 and 24 h after drug administration. These pharmacodynamic findings correlated with the pharmacokinetic properties of miloxicam. The plasma concentration-time curve was defined by a three-compartment open model in one pony and by a two-compartment model in five ponies. Mean values for pharmacokinetic parameters for the five ponies were: t1/2 alpha 0.40 h; t1/2 beta 2.70 h; Vd area 0.158 l/kg; ClB 41.87 ml/kg/h. Exudate concentrations of miloxicam were initially similar to and eventually greater than concentrations in plasma, and this may explain the more prolonged inhibition of eicosanoid synthesis in exudate than in serum. These findings demonstrate the value of relating, in a single experimental study, drug action on a range of variables to drug fate in the body.     

Pharmacodynamics and pharmacokinetics of ketoprofen enantiomers in sheep

OBJECTIVE: To establish pharmacokinetic and pharmacodynamic properties of a racemic mixture and individual R(-) and S(+) enantiomeric forms of ketoprofen (KTP) in sheep and determine pharmacodynamic variables of KTP by pharmacokinetic-pharmacodynamic modeling. ANIMALS: 8 female Dorset crossbred sheep. PROCEDURE: A tissue cage model of inflammation was used. Carrageenan was administered into tissue cages. Time course of cyclooxygenase (COX)-2 inhibition was determined in vivo by measurement of exudate prostaglandin E2 (PGE2) concentrations. Time course of COX-1 inhibition was determined ex vivo by measurement of serum thromboxane B2 (TXB2) concentrations. In addition, plasma concentration-time course and penetration of KTP enantiomers into inflammatory exudate and transudate (noninflamed tissue cage fluid) were investigated. Four treatments were compared: placebo, racemic mixture (rac-KTP [3 mg/kg of body weight, IV]), S(+) KTP (1.5 mg/kg, IV),and R(-) KTP (1.5 mg/kg, IV). RESULTS: Both KTP enantiomers had elimination half-life and mean residence time measurements that were short and volume of the central compartment and steady state volume of distribution that were low. Clearance was rapid, particularly for R(-) KTP Elimination of both enantiomers from exudate was > 10 times slower than from plasma. Both rac-KTP and the individual enantiomers significantly inhibited serum TXB2 concentrations for 12 hours. Rac-KTP and S(+) KTP, but not R(-) KTP, also significantly inhibited PGE2 synthesis in exudate for 12 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Inhibition of serum TXB2 concentration and exudate PGE2 synthesis for similar time courses after S(+) KTP administration indicates that it is a nonselective inhibitor of COX in sheep.     

Pharmacodynamics and enantioselective pharmacokinetics of carprofen in the cat

The pharmacodynamics and enantioselective pharmacokinetics of the arylpropionic acid non-steroidal anti-inflammatory drug, carprofen, were investigated in cats after administration of the racemic mixture (rac-carprofen) at dose rates ranging from 0·7 to 4·0 mg kg⁻¹ intravenously and subcutaneously. A low dose of rac-carprofen (0·7 mg kg⁻¹) partially inhibited the rise in skin temperature at a site of acute inflammation but had no effect on the ex vivo synthesis of serum thromboxane (Tx) B₂. A higher dose (4·0 mg kg⁻¹) inhibited oedematous swelling, although the response was statistically significant at only one time, and also reduced the ex vivo synthesis of serum TxB₂ for 12 hours after intravenous injection or 24 hours after subcutaneous injection. The main features of carprofen pharmacokinetics were a low distribution volume, a relatively long elimination half-life, the predominance of the R(−) enantiomer and a bioavailability (after subcutaneous dosing) of 100 per cent and 92 per cent, respectively, after doses of 0·7 and 4·0 mg kg⁻¹. On the basis of these data, it is suggested that a dose of 4·0 mg kg⁻¹ by both intravenous and subcutaneous routes should be evaluated in clinical subjects.     

Clinical pharmacokinetics of flumequine in calves

The minimal inhibitory concentration (MIC) of flumequine for 249 Salmonella, 126 Escherichia coli, and 22 Pasteurella multocida isolates recovered from clinical cases of neonatal calf diarrhoea, pneumonia and sudden death was less than or equal to 0.78 microgram/ml. The pharmacokinetics of flumequine in calves was investigated after intravenous (i.v.), intramuscular (i.m.) and oral administration. The two-compartment open model was used for the analysis of serum drug concentrations measured after rapid i.v. ('bolus') injection. The distribution half-life (t1/2 alpha) was 13 min, elimination half-life (t1/2 beta) was 2.25 h, the apparent area volume of distribution (Vd(area)), and the volume of distribution at steady state (Vd(ss)) were 1.48 and 1.43 l/kg, respectively. Flumequine was quickly and completely absorbed into the systemic circulation after i.m. administration of a soluble drug formulation; a mean peak serum drug concentration (Cmax) of 6.2 micrograms/ml was attained 30 min after treatment at 10 mg/kg and was similar to the concentration measured 30 min after an equal dose of the drug was injected i.v. On the other hand, the i.m. bioavailability of two injectable oily suspensions of the drug was 44%; both formulations failed to produce serum drug concentrations of potential clinical significance after administration at 20 mg/kg. The drug was rapidly absorbed after oral administration; the oral bioavailability ranged between 55.7% for the 5 mg/kg dose and 92.5% for the 20 mg/kg dose. Concomitant i.m. or oral administration of probenecid at 40 mg/kg did not change the Cmax of the flumequine but slightly decreased its elimination rate. Flumequine was 74.5% bound in serum. Kinetic data generated from single dose i.v., i.m. and oral drug administration were used to calculate practical dosage recommendations. Calculations showed that the soluble drug formulation should be administered i.m. at 25 mg/kg every 12 h, or alternatively at 50 mg/kg every 24 h. The drug should be administered orally at 30 and 60 mg/kg every 12 and 24 h, respectively. Very large, and in our opinion impractical, doses of flumequine formulated as oily suspension are required to produce serum drug concentrations of potential clinical value.     

Pharmacodynamics and pharmacokinetics of orally administered bishydroxycoumarin in the goat

Eight goats, 2 nontreated controls and 6 treated, were used to study the pharmacodynamics and pharmacokinetics of bishydroxycoumarin. In 5 of the 6 treated goats, there was a significant relationship between prothrombin times and drug concentrations. Activated clotting times did not change with time in either the controls or the treated goats. Five of 6 treated goats reached a plateau of drug concentration after 24 to 36 hours. Lag times for onset of pharmacologic effect ranged from 12 to 24 hours. The one goat (No. 3) that did not respond in concert with the other 5 was extremely nervous and became anorectic during the period of indoor confinement.     

Pharmacodynamics and enantioselective pharmacokinetics of racemic carprofen in the horse

Carprofen is a nonsteroidal anti-inflammatory drug of the 2-arylpropionate subclass. It contains a single chiral centre and exists in two enantiomeric forms. In this study rac-carprofen, at two dosages, 0.7 and 4.0 mg/kg, and placebo were administered i.v. to six New Forest horses in a three period cross-over study. The concentration-time profiles were established for R(-) and S(+)-carprofen for plasma and both inflamed (exudate) and noninflamed (transudate) tissue cage fluids. R(-)-carprofen was the predominant enantiomer in all three fluids, as indicated by plasma area under the curve (AUC) values for R(-) and S(+)-carprofen of 117.4 and 22.6 microg h/mL (low dose carprofen) and 557.5 and 138.1 microg h/mL (high dose carprofen) respectively. Penetration of both enantiomers into exudate was slow and limited and passage into transudate was even lower. The pharmacodynamics of rac-carprofen was investigated at both the molecular level and in terms of the ability to suppress components of the tissue cage inflammatory response. Low dose carprofen produced only moderate and transient inhibition of serum thromboxane (Tx)B2 but failed to affect exudate prostaglandin (PG)E2 concentrations, whilst suppression of exudate leukotriene (LT)B4 and beta-glucuronidase was not significant. High dose carprofen produced greater and more persistent inhibition of serum TxB2 and virtually abolished exudate PGE2 synthesis. Some inhibition of LTB4 and beta-glucuronidase in exudate was also obtained. At both dosages rac-carprofen reduced the swelling produced by intradermal bradykinin injection but only high dose carprofen was anti-inflammatory as indicated by suppression of temperature rise over exudate tissue cages and neither dose affected leucocyte numbers in exudate. When considered in conjunction with previous data on carprofen, the present findings indicate that carprofen is not a selective inhibitor of cyclooxygenase (COX) isoenzymes, COX-1 and COX-2 in the horse, although it may show some preference for COX-2 inhibition. Because low dose carprofen, which is the clinically recommended dosage, produces minimal inhibition of COX, it is likely to achieve its therapeutic effects at least partially through other pathways, possibly including weak to moderate inhibition of 5-lipoxygenase and of enzyme release. The good safety margin of carprofen in clinical use might also be explained by weak COX inhibition and by other actions at the molecular level.     

Pharmacodynamics of oxytetracycline administered alone and in combination with carprofen in calves

The pharmacodynamics (PD) of oxytetracycline was investigated against a strain of Mannheimia haemolytica. In vitro measurements, comprising minimum inhibitory concentration (MIC), minimum bactericidal concentration and time-kill curves, were conducted in five matrices; Mueller Hinton Broth (MHB), cation-adjusted MHB (CAMHB) and calf serum, exudate and transudate. MICs were much higher in the biological fluids than in MHB and CAMHB. Ratios of MIC were, serum: CAMHB 19 : 1; exudate:CAMHB 16.1; transudate:CAMHB 14 : 1. Ex vivo data, generated in the tissue cage model of inflammation, demonstrated that oxytetracycline, administered to calves intramuscularly at a dose rate of 20 mg/kg, did not inhibit the growth of M haemolytica in serum, exudate and transudate, even at peak concentration. However, using in vitro susceptibility in CAMHB and in vivo-determined pharmacokinetic (PK) variables, average and minimum oxytetracycline concentrations relative to MIC (C(av)/MIC and C(min)/MIC) predicted achievement of efficacy for approximately 48 hours after dosing. Similar C(av)/MIC and C(min)/MIC data were obtained when oxytetracycline was administered in the presence of carprofen. PK-PD integration of data for oxytetracycline, based on MICs determined in the three biological fluids, suggests that it possesses, at most, limited direct killing activity against M haemolytica. These data raise questions concerning the mechanism(s) of action of oxytetracycline, when administered at clinically recommended dose rates.     

Norfloxacin nicotinate pharmacokinetics in unwearied and weaned calves

The pharmacokinetics of norfloxacin nicotinate were investigated in unweaned and weaned calves. Following intravenous administration of 7.5 and 15 mg/kg (calculated as norfloxacin base) the clearance values were 8.5/pm 2.0 or 7.7/pm 1.2mL/min·kg (unweaned calves) and 11.7/pm 3.2 or 16.1/pm 3.3mL/min·kg (weaned calves). Norfloxacin mean residence time and volume of distribution values were 211/pm 33 or 227/pm 41 min (unweaned calves) and 185/pm 79 or 128/pm18 minutes (weaned calves), and 1.8/pm0.3 or 1.7/pm0.1L/kg (unweaned calves) and 2.0/pm0.7 or 2.1/pm0.7L/kg (weaned calves) following administration of the lower and higher dose, respectively. These results indicated that norfloxacin pharmacokinetics were similar at a dose range of 7.5-15 mg/kg. However, a significant difference was observed in clearance, mean residence time and the half-life values between the unweaned and weaned calves. The only major pharmacokinetic parameter which did not show a significant difference between the investigated groups was the volume of distribution. The pharmacokinetic differences between the non-ruminating (unweaned) and ruminating (weaned) animals seemed to result from changes in drug clearance. The absorption rate after intramuscular administration appeared to change as a result of dose increase. Norfloxacin bioavailability following intramuscular administration ranged from 73 to 106%. The results suggested that larger injection volumes may reduce the extent of absorption.     

Comparative pharmacokinetics of amikacin sulphate in calves and sheep

The pharmacokinetics of amikacin sulphate were investigated in calves and sheep. Five animals of each species were given 7.5 mg kg-1 intravenously and intramuscularly. After intravenous administration the pharmacokinetic parameters significantly different (P less than 0.01) between calves (first value) and sheep (second value), were: the initial concentration (87.05, 146.6 micrograms ml-1), the apparent distribution volume (350, 200 ml kg-1), the area under curve (5512, 11,018 min micrograms ml-1) and the clearance (1.5, 0.7 ml min-1 kg-1). After dosing intramuscularly the peak concentration (23.5, 34.36 micrograms ml-1), the peak time (45, 75 min) and the area under curve (5458, 9191 min micrograms ml-1) were significantly different (P less than 0.01). No significant differences were observed in the terminal halflife values, suggesting that elimination rate was independent of both route of administration and animal species. The drug in aqueous solution showed a good bioavailability in both animal species (about 0.87 in sheep and greater than 0.99 in calves) despite the greater serum concentrations always attained in sheep.     

Comparative pharmacokinetics of ampicillin-sulbactam combination in calves and sheep

The pharmacokinetics of ampicillin and sulbactam administered in combination were studied in calves and sheep. The animals were administered an aqueous solution of ampicillin/sulbactam (2: 1, w/w) intravenously and intramuscularly at doses of 13.2 and 6.6 mg.kg^-1, respectively. A microbiological method was used to detect ampicillin, and HPLC was used to detect sulbactam in serum. Following intravenous (i, v.) administration, the distribution phases were rapid and similar (about 15 min) for both drugs in both species, whereas sulbactam in calves and ampicillin in sheep showed a faster elimination rate. After intramuscular (i.m.) administration both drugs showed peak concentrations higher in calves than in sheep: the peak time of sulbactam was shorter in calves than in sheep. No other significant differences in the pharmacokinetics of the combination were observed between the species after i.m. injection. The mean residence and absorption times, calculated by non-compartmental analysis, for both calves and sheep suggested that the differences in ampicillin and sulbactam phgrmacokinetics could be attributable to the different molecular structures.     

Probenecid effect on cefuroxime pharmacokinetics in calves

Cefuroxime pharmacokinetics were studied in unweaned calves. The antibiotic was administered at 10 mg/kg to six calves i.v., to 12 calves i.m. and to ten of the previous 12 calves i.m. at 10 mg/kg together with probenecid at 40 mg/kg. Intramuscular doses of cefuroxime alone at 20 mg/kg were given to seven calves; to five of these calves cefuroxime was also given together with probenecid at 40 mg/kg and at 80 mg/kg. The serum concentration-time data were analyzed using statistical moment theory (SMT). The elimination half-life (t1/2) was 69.2 min (harmonic mean) after i.v. and 64.8 min and 64.9 min following i.m. administration of the lower and higher dose, respectively. Co-administration of probenecid did not affect the t1/2. The mean residence time (MRT) was 80.9 +/- 23.5 min (mean +/- SD) after i.v. and 117.8 +/- 9.3 min and 117.7 +/- 5.4 min after i.m. administration of cefuroxime at 10 and 20 mg/kg, respectively. The MRTi.m. following administration of cefuroxime at 10 mg/kg together with probenecid at 40 mg/kg was 140.0 +/- 8.8 min. The MRTi.m. values were 132.8 +/- 2.3 min and 150.8 +/- 5.1 min after cefuroxime was given at 20 mg/kg together with probenecid at 40 mg/kg or 80 mg/kg, respectively. The total body clearance (ClT) was 3.56 +/- 1.11 ml/min/kg and the volume of distribution at steady state (Vd(ss] 0.270 +/- 0.051 l/kg. The MIC90 values of cefuroxime were 16 micrograms/ml for E. coli and Salmonella isolates, 0.5 microgram/ml for Pasteurella multocida and 2.0 micrograms/ml for P. haemolytica.     

Metabolism, excretion, pharmacokinetics and tissue residues of phenylbutazone in the horse

The pharmacokinetics, metabolism, excretion and tissue residues of phenylbutazone (PBZ) in the horse were studied following both intravenous and oral administration of the drug at a dose rate of 4.4 mg/kg. A 72-hour blood sampling schedule failed to demonstrate a third exponential phase; the plasma disposition following intravenous injection being described by a two compartment open model, with the following elimination phase parameters: beta = 0.13h-1, t1/2 beta = 5.46h, Vdarea = 0.141 1/kg and C1B = 17.9 ml/kg/h. The hydroxylated metabolites oxyphenbutazone (OPBZ) and gamma-hydroxyphenylbutazone (OHPBZ) were present in detectable concentrations in plasma for 72 and 24 h, respectively. After 36 h OPBZ concentrations exceeded plasma PBZ concentrations. In urine the principal metabolites were OPBZ and OHPBZ but smaller concentrations of another compound, probably gamma-hydroxyoxyphenbutazone (OHOPBZ), were also detected. The percentages of the administered dose recovered from urine were 30.7, 39.0 and 40.3 after 24, 48 and 72 h from the time of injection. Recovery of PBZ and its metabolites from urine was significantly reduced in the first 24 h after oral dosing when the horses had free access to hay, probably as a result of markedly delayed absorption, but this did not occur in animals deprived of food for a few hours before and after dosing. Determination of approximate values of urine/plasma (U/P) concentration ratios for PBZ and its metabolites relative to endogenous creatinine U/P concentration ratio suggested that PBZ was filtered in small amounts only because of the high degree of plasma protein binding and then excreted by diffusion trapping in the alkaline urine. Much higher U/P ratios were obtained for the hydroxylated derivatives, and one at least (OHPBZ) was secreted into urine.     

Clinical pharmacokinetics of five oral cephalosporins in calves

The minimal inhibitory concentrations (MIC) of cephalexin, cephradine, cefaclor, cefatrizine and cefadroxil for Salmonella species, Escherichia coli and Pasteurella multocida isolated previously from young calves were determined. The MIC90 values for cephalexin, cephradine and cefadroxil ranged between 3.12 micrograms ml-1 and 12.5 micrograms ml-1, whereas those of cefatrizine and cefaclor were 3.12 micrograms ml-1 and 0.78 microgram ml-1, respectively. Each drug was administered intravenously and orally to groups of pre-ruminating calves and orally to early ruminating calves. Although the pharmacokinetic characteristics of the drugs after intravenous injection were similar to other beta-lactam antibiotics, significant differences between the cephalosporins examined were found in respect of certain kinetic parameters. The drugs showed rapid absorption into the systemic circulation after oral administration to pre-ruminating calves but the elimination half-life values (t1/2 beta) varied between three hours (cefaclor and cefadroxil) and nine hours (cefatrizine). The bioavailability of the drugs was about 35 per cent of the administered dose. Co-administration of probenecid with each antibiotic caused a twofold or greater increase in peak serum drug concentrations (Cmax) but the effect on t1/2 beta was variable. Cephalexin, cephradine and cefaclor given to the ruminating calves resulted in very low serum or plasma concentrations and their use should be restricted to younger calves. Cefadroxil was found to give the highest serum concentrations in this age group but had significantly lower bioavailability when compared with the unweaned calves. Provisional oral dosage regimens were computed for each cephalosporin on the basis of the MIC data and the kinetic parameters derived from intravenous and oral drug administration.