Effects of age, sex and breed on antipyrine disposition in calves

In domestic animals relatively little is known about the functions of hepatic microsomal enzymes and their role in biotransformation. In this study, antipyrine was used to assess microsomal oxidative function and particularly to determine the effect of age, sex and breed on drug metabolising enzymes. At birth, the elimination rate of antipyrine was very low as reflected by a half-life of 24 hours. The first two months of life were characterised by a steady decrease of antipyrine half-life values of three to four hours being reached at six months. The decrease observed during early life was not identical in the two breeds used in this experiment. By six months the Friesian calves eliminated antipyrine twice as fast as the Blue White Belgian (BWB) breed: 2.1 +/- 0.3 hours and 4.9 +/- 0.3 hours, respectively. The BWB breed is characterised by muscular hypertrophy and by a relative imbalance in muscle:body ratio. The apparent volume of distribution of antipyrine did not vary with age, sex and breed. No differences in antipyrine clearance were found between male and female calves.     

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.     

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).     

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.     

The effect of experimental fascioliasis on the pharmacokinetics of antipyrine and sulphadimidine in desert sheep

Healthy adult male desert sheep were experimentally infected with Fasciola gigantica , to investigate the influence of experimental fasciolasis on the pharmacokinetics of antipyrine and sulphadimidine. Each animal received 500 metacercariae orally. The experimental infection was confirmed histologically, by detection of Fasciola eggs in faeces and by measuring the activities of the enzymes sorbitol dehydrogenase (SD), glutamate dehydrogenase (GD) and aspartate aminotransferase (AST) in plasma during the course of the disease. Changes in the pharmacokinetics of antipyrine and sulphadimidine were reported in the experimentally infected animals. Significant prolongation of antipyrine half life was observed 16 weeks after infection. The half-life of sulphadimidine was also significantly prolonged 5, 9 and 16 weeks after infection. Clearance of the sulphonamide was decreased significantly 5 and 9 weeks after infection and it regained its pre-infection value 16 weeks after infection.     

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.     

Effect of tiamulin on antipyrine kinetics in chickens

Tiamulin {14-deoxy-14[(2-diethylaminoethyl)-mercaptoacetoxy]-mutilin} hydrogen fuma-rate is a semisynthetic antibiotic. It is clinically effective against pathogenic mycoplasma organisms, e.g. Treponema hyodysenteriae , a large number of Gram-positive and some Gram-negative organisms (Drews et al. , 1975). Tiamulin has been shown, under controlled laboratory conditions (Laber & Schutze, 1975; Baughn et al. , 1978) and against natural infection under field conditions (Stipkovits et al. , 1977), to control respiratory tract infections effectively involving Mycoplasma galliseptkum in chickens and turkeys. It has also been demonstrated that tiamulin could be used as an aid in the control of avian coccidiosis produced by Eimeria acervulina and E. tenella in broilers chickens (Cruthers et al. , 1980).     

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.     

Effect of age and training status on pharmacokinetics of flunixin meglumine in thoroughbreds

The effect of age and training status on the pharmacokinetics of flunixin meglumine was evaluated in 16 Thoroughbreds. Horses were assigned to 1 of 3 groups on the basis of age and training status: group A (n = 6), horses in active training and less than or equal to 5 years old; group B (n = 5), horses out of training for a minimum of 6 weeks and less than or equal to 5 years old; and group C (n = 5), horses out of training for at least 2 years and greater than or equal to 9 years old. After administration of 500 mg of flunixin meglumine IV, multiple serum and urine samples were obtained over 24 hours and assayed for flunixin by high-performance liquid chromatography. Although the mean distribution rate constant and volume of distribution were similar for the 3 groups, mean total body clearance and elimination rate constant were significantly (P less than 0.05) greater and half-life significantly (P less than 0.01) less in groups A and B, compared with group C. Differences in pharmacokinetic values were not observed between the horses in group A and B. In addition, the changes in clearance, elimination rate constant, and half-life of flunixin were found to significantly (P less than 0.05) correlate with age. The results of this investigation indicated that age, but not training status, influences disposition of flunixin meglumine in Thoroughbreds.     

Influence of oxytetracycline on carprofen pharmacodynamics and pharmacokinetics in calves

A tissue cage model of inflammation in calves was used to determine the pharmacokinetic and pharmacodynamic properties of individual carprofen enantiomers, following the administration of the racemate. RS(±) carprofen was administered subcutaneously both alone and in combination with intramuscularly administered oxytetracycline in a four‐period crossover study. Oxytetracycline did not influence the pharmacokinetics of R(?) and S(+) carprofen enantiomers, except for a lower maximum concentration (C_max) of S(+) carprofen in serum after co‐administration with oxytetracycline. S(+) enantiomer means for area under the serum concentration–time curve (AUC_0–96h were 136.9 and 128.3 μg·h/mL and means for the terminal half‐life (T_½k₁₀) were = 12.9 and 17.3 h for carprofen alone and in combination with oxytetracycline, respectively. S(+) carprofen AUC_0–96h in both carprofen treatments and T_½k₁₀ for carprofen alone were lower (P < 0.05) than R(?) carprofen values, indicating a small degree of enantioselectivity in the disposition of the enantiomers. Carprofen inhibition of serum thromboxane B₂ ex vivo was small and significant only at a few sampling times, whereas in vivo exudate prostaglandin (PG)E₂ synthesis inhibition was greater and achieved overall significance between 36 and 72 h (P < 0.05). Inhibition of PGE₂ correlated with mean time to achieve maximum concentrations in exudate of 54 and 42 h for both carprofen treatments for R(?) and S(+) enantiomers, respectively. Carprofen reduction of zymosan‐induced intradermal swelling was not statistically significant. These data provide a basis for the rational use of carprofen with oxytetracycline in calves and indicate that no alteration to carprofen dosage is required when the drugs are co‐administered.     

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.     

Influence of marbofloxacin on the pharmacokinetics and pharmacodynamics of tolfenamic acid in calves

Pharmacokinetic and pharmacodynamic properties of tolfenamic acid (TA) in calves were determined in serum and fluids of inflamed (carrageenan administered) and non-inflamed subcutaneously implanted tissue cages after intramuscular administration both alone and in combination with marbofloxacin (MB). MB significantly altered the pharmacokinetics of TA: mean values were Cmax = 2.14 and 1.64 microg/mL, AUC = 27.38 and 16.80 microg.h/mL, Vd(area)/F = 0.87 and 1.17 L/kg, and ClB/F = 0.074 and 0.128 L/kg/h, respectively, after administration of TA alone and TA + MB. T(1/2)K10 and MRT were not significantly different for the two treatments. The pharmacodynamic properties of TA were not influenced by MB co-administration, in spite of the alterations in some TA pharmacokinetic parameters. TA inhibited prostaglandin E2 (PGE2) synthesis in vivo in inflammatory exudate by 50-88% for up to 48 h after both TA treatments. Inhibition of synthesis of serum thromboxane B2 (TxB2) ex vivo ranged from 40 to 85% up to 24 h after both TA and TA + MB. From the derived pharmacokinetic and eicosanoid inhibition data for TA, pharmacodynamic parameters for serum TxB2 and exudate PGE2 inhibition expressing efficacy (Emax = 78.1 and 97.5%), potency (IC50 = 0.256 and 0.265 microg/mL), sensitivity (N = 1.96 and 2.29) and the pharmacokinetic parameter equilibration time (t(1/2)K(e0) = 0.695 and 24.0 h), respectively, were determined. In this model TA was a nonselective inhibitor of cyclo-oxygenase (COX) (COX-1:COX-2 IC50 ratio = 1.37). TA, both alone and co-administered with MB, did not affect leucocyte numbers in exudate, transudate or blood. Partial attenuation of skin temperature rise over inflamed tissue cages and reduction of zymosan-induced skin swelling were recorded after administration of TA and TA + MB with no significant differences between the two treatments. These data provide a basis for the rational use of TA in combination with MB in calf medicine.     

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.     

Effect of age at the time of vaccination on antibody titers and feedlot performance in beef calves

OBJECTIVE: To compare antibody responses, feedlot morbidity and mortality rates, feedlot performance, and carcass value for calves vaccinated with 1 of 2 vaccination strategies and for unvaccinated control calves. DESIGN: Randomized controlled clinical trial. ANIMALS: 451 beef steers and heifers. PROCEDURES: Calves were vaccinated with a modified-live infectious bovine rhinotracheitis virus (IBRV), bovine viral diarrhea virus types 1 (BVDV1) and 2 (BVDV2), parainfluenza type 3 virus, and bovine respiratory syncytial virus vaccine and Mannheimia haemolytica and Pasteurella multocida bacterin-toxoid at approximately 67 and 190 days of age (group 1; n = 151) or at approximately 167 and 190 days of age (group 2; 150) or were not vaccinated (control; 150). Serum antibody titers were measured at approximately 2, 67, 167, 190, and 232 days of age. Morbidity and mortality rates, feedlot performance, and carcass value were recorded for 361 calves shipped to feedlots. RESULTS: Percentages of calves seroconverting to IBRV, BVDV1, and BVDV2 were significantly higher for groups 1 and 2 than for the control group. Mean treatment costs were significantly lower for vaccinated than for control calves, and mean mortality rate was significantly higher for control calves than for group 1 calves. Feedlot performance and carcass value did not vary significantly among groups. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that vaccination of beef calves with a 5-antigen modified-live virus vaccine at 67 and 190 days of age was as effective in terms of immunologic responses as was vaccination at 167 and 190 days of age.     

Preliminary observations on the pharmacokinetics of CDRI compound 81/470 in calves

Veterinary Research Communications -     

The pharmacokinetics of transdermal flunixin meglumine in Holstein calves

This study describes the pharmacokinetics of topical and intravenous (IV) flunixin meglumine in Holstein calves. Eight male Holsteins calves, aged 6 to 8 weeks, were administered flunixin at a dose of 2.2 mg/kg intravenously. Following a 10‐day washout period, calves were dosed with flunixin at 3.33 mg/kg topically (transdermal). Blood samples were collected at predetermined times from 0 to 48 h for the intravenous portions and 0 to 72 h following topical dosing. Plasma drug concentrations were determined using liquid chromatography with mass spectroscopy. Pharmacokinetic analysis was completed using noncompartmental methods. The mean bioavailability of topical flunixin was calculated to be 48%. The mean AUC for flunixin was determined to be 13.9 h × ug/mL for IV administration and 10.1 h × ug/mL for topical administration. The mean half‐life for topical flunixin was 6.42 h and 4.99 h for the intravenous route. The C_max following topical application of flunixin was 1.17 μg/mL. The time to maximum concentration was 2.14 h. Mean residence time (MRT) following IV injection was 4.38 h and 8.36 h after topical administration. In conclusion, flunixin when administered as a topical preparation is rapidly absorbed and has longer half‐life compared to IV administration.     

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.