Elevation and prolongation of serum ampicillin and amoxycillin concentrations in calves by the concomitant administration of probenecid

The effects of probenecid on serum ampicillin and amoxycillin concentrations were investigated in 1–5 week old calves after oral and parenteral drug administration. Ampicillin trihydrate was administered orally at 250mg/calf, after an overnight fast, alone and with 1.5g probenecid. Peak serum ampicillin concentrations were elevated from 0.60 to 1.22 μg/ml by the co-administration of probenecid. In calves given 0.5 g amoxycillin trihydrate with the milk replacer, peak serum drug concentration increased from 1.74 to 3.16 μg/ml when 1.5 g probenecid was given too. Maximal effect of probenecid administered orally was with the 1.5 g/calf dose with considerably lesser increase in peak serum amoxycillin being observed with doses of 0.5 g, 1 g and 2 g/calf. After parenteral injection of probenecid solution at 1 g and 2 g/calf serum ampicillin concentrations peaked at more than twice the concentrations measured after equal doses of the two antibiotics were injected alone. The co-administration of 2 g probenecid and 1 g sodium ampicillin or 0.5 g sodium amoxycillin parenterally resulted in peak antibiotic concentrations considered to be effective against some of the more resistant pathogenic Gram-negative bacteria associated with diseases in calves and serum antibiotic concentrations 5 μg/ml were maintained during 5–6 h as opposed to 2–3 h after the antibiotics were injected alone. Oral administration of 1.5 g probenecid at three consecutive milk feeding times did not alter serum urea or serum creatinine concentrations.     

Pharmacokinetics of a single bolus intravenous, intramuscular and subcutaneous dose of disodium fosfomycin in horses

Pharmacokinetic parameters of fosfomycin were determined in horses after the administration of disodium fosfomycin at 10 mg/kg and 20 mg/kg intravenously (IV), intramuscularly (IM) and subcutaneously (SC) each. Serum concentration at time zero (C_S0) was 112.21 ± 1.27 μg/mL and 201.43 ± 1.56 μg/mL for each dose level. Bioavailability after the SC administration was 84 and 86% for the 10 mg/kg and the 20 mg/kg dose respectively. Considering the documented minimum inhibitory concentration (MIC₉₀) range of sensitive bacteria to fosfomycin, the maximum serum concentration (Cmax) obtained (56.14 ± 2.26 μg/mL with 10 mg/kg SC and 72.14 ± 3.04 μg/mL with 20 mg/kg SC) and that fosfomycin is considered a time-dependant antimicrobial, it can be concluded that clinically effective plasma concentrations might be obtained for up to 10 h administering 20 mg/kg SC. An additional predictor of efficacy for this latter dose and route, and considering a 12 h dosing interval, could be area under the curve AUC_0-12/MIC₉₀ ratio which in this case was calculated as 996 for the 10 mg/kg dose and 1260 for the 20 mg/kg dose if dealing with sensitive bacteria. If a more resistant strain is considered, the AUC_0-12/MIC₉₀ ratio was calculated as 15 for the 10 mg/kg dose and 19 for the 20 mg/kg dose.     

Serum chloramphenicol concentrations in preruminant calves: a comparison of two formulations dosed orally

Serum concentrations of chloramphenicol were determined after oral doses (55 mg/kg body weight) were administered to 7–9 day old Holstein-Friesian calves. Chloramphenicol in an oral solution produced greater serum concentrations than did an equivalent dose of chloramphenicol in capsules ( P <0.005). A second dose of each formulation administered 12 h after the first dose elevated serum chloramphenicol concentrations significantly ( P <0.001). The average serum chloramphenicol concentration exceeded 5 μg/ml of serum 1 h after administration of the solution compared with 4 h for the capsules. Average serum chloramphenicol concentration was greater than 5 μg/ml for at least 12 h after the dose was administered for both formulations. Of the eight calves receiving repeat doses of chloramphenicol, seven (87.5%) developed diarrhea in 76 ± 8.6 h. Six of the eight calves (75%) died during or shortly after the period of chloramphenicol administration.     

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.     

Pharmacokinetics of enrofloxacin in the red pacu (Colossoma brachypomum) after intramuscular, oral and bath administration

The intramuscular (i.m.), oral (p.o.), and bath immersion disposition of enrofloxacin were evaluated following administration to a cultured population of red pacu. The half-life for enrofloxacin following i.m. administration was 28.9 h, considerably longer than values calculated for other animals such as dogs, birds, rabbits, and tortoises. The 4 h maximum concentration ( C _max) of 1.64 μg/mL following a single 5.0 mg/kg dosing easily exceeds the in vitro minimum inhibitory concentration (MIC) for 20 bacterial organisms known to infect fish. At 48 h post i.m. administration, the mean plasma enrofloxacin concentration was well above the MIC for most gram-negative fish pathogens. The gavage method of oral enrofloxacin administration produced a C _max of 0.94 μg/mL at 6–8 h. This C _max was well above the reported in vitro MIC. A bath immersion concentration of 2.5 mg/L for 5 h was used in this study. The C _max of 0.17 μg/mL was noted on the 2 hour post-treatment plasma sample. Plasma concentrations of enrofloxacin exceeded published in vitro MIC's for most fish bacterial pathogens 72 h after treatment was concluded. Ciprofloxacin, an active metabolite of enrofloxacin, was detected and measured after all methods of drug administration. It is possible and practical to obtain therapeutic blood concentrations of enrofloxacin in the red pacu using p.o., i.m., and bath immersion administration. The i.m. route is the most predictable and results in the highest plasma concentrations of the drug.     

Florfenicol pharmacokinetics in lactating cows after intravenous, intramuscular and intramammary administration

Pharmacokinetics of florfenicol 30% injectable solution was determined in lactating cows after intravenous, intramammary and intramuscular administration. Serum concentration-time data generated in the present study were analysed by non-compartmental methods based on statistical moment theory. Florfenicol half-life was 176 min, mean residence time 129 min, volume of distribution at steady-state 0.35 L/kg, and total body clearance 2.7 mL/min·kg after intravenous administration at 20 mg/kg. The absorption after intramuscular administration appeared slow and the kinetic parameters and the serum concentration vs. time curve were characteristic of absorption rate-dependent elimination. The absorption after intramammary administration of florfenicol at 20 mg/kg was good (53.9%) and resulted in serum concentrations with apparent clinical significance. The intramammary administration resulted in serum florfenicol concentrations that were significantly higher than the respective serum concentrations following Intravenous administration 4 h after administration and thereafter. Florfenicol absorption was faster from the mammary gland than from the muscle. The maximum serum concentrations ( C _max) were 6.9 μg/mL at 360 min after intramammary administration and 2.3 μg/mL at 180 min after intramuscular administration. The bioavailability of florfenicol was 54% and 38% after intramammary and intramuscular administration, respectively. The C _max in milk was 5.4 μg/mL at 180 min after intravenous and 1.6 μg/mL at 600 min after intramuscular administration.     

Pharmacokinetics of erythromycin in foals and in adult horses

The pharmacokinetic parameters of erythromycin in foals were determined following intravenous administration of 5.0 mg/kg to animals aged 1, 3, 5 and 7 weeks. The distribution of the drug was described by a two-compartment open model, and no significant differences were observed between coefficients on which the parameters were based. Pharmacokinetic values were also determined for four mares given 5.0 mg/kg intravenously and for six 10–12 week-old foals given 20.0 mg/kg intravenously. The half-life of erythromycin for all groups of animals (foals less than 7 weeks, mares, foals 10–12 weeks) was 1.0–1.1 h; the apparent volume of distribution was between 2.3 and 7.2 l/kg, and the clearance of the drug from the body was between 1.9 and 5.0 mg/kg/h. No drug could be detected in the serum following oral administration of 5.0 mg/kg erythromycin estolate; detectable levels were found for 5 h in mares given 12.5 mg/kg, and for 8 h in foals given 20.0 mg/kg orally. Peak levels in foals given the drug orally were 0.42 μg/ml at 120 min after administration. Foals given 10.0 mg/kg of erythromycin base intramuscularly had serum concentrations detectable 12 h later, the peak level achieved was 1.44 μg/ml serum 90 min after administration and concentrations exceeded 0.25 μg/ml for 6 h. In the mares the milk concentrations were approximately twice those in serum. Recommendations were made for drug dosage to be used in the treatment of Corynebacterium equi pneumonia of foals.     

High performance liquid chromatography and pharmacokinetics of the non-steroidal anti-inflammatory drug oxindanac in calves

A high-performance liquid chromatographic method for the determination of the non-steroidal anti-inflammatory drug, oxindanac, in calf plasma is described. Recoveries over the concentration range 0.3 75 to 62.5 μg/ml were 90.2–107.8% with interassay coefficients of variation of 2.1–22.3%. The limit of detection was estimated as 0.10 μg/ml and the limit of quantification calculated to be 0.24 pg/ml in a 1 ml plasma sample. This method was used to establish the pharmacokinetics following intravenous (i.v.), intramuscular (i.m.) and oral (p.o.) administration to calves of oxindanac at a dose rate of 2 mg/kg. The elimination t ¹/₂, was long ( t 1/2 21.2 h after i.v. injection) and absorption was rapid (t¹/_2B 0.072 h) and complete ( F > 100%) following i.m. administration. Bioavailability was incomplete ( F = 66.6%) following p.o. administration to calves that had been fed on milk, and Wagner-Nelson analysis revealed twoabsorption phases ( t ¹/₂'s 0.20 and 1.9 h). Oxindanac produced long-lasting inhibition of serum TxB₂ production, with mean k_max values (% inhibition) of 96.8, 94.1 and 81.3 following i.v., i.m. and p.0. administration, respectively. A single i.v. or i.m. injection of 2 mg/kg oxindanac will probably be active in calves for at least 36–48 h.     

Bioavailability of spiramycin and lincomycin after oral administration to fed and fasted pigs

The disposition of spiramycin and lincomycin was measured after intravenous (i.v.) and oral (p.o.) administration to pigs. Twelve healthy pigs (six for each compound) weighing 16–43 kg received a dose of 10 mg/kg intravenously, and 55 mg/kg (spiramycin) or 33 mg/kg (lincomycin) orally in both a fasted and a fed condition in a three-way cross-over design. Spiramycin was detectable in plasma up to 30 h after intravenous and oral administration to both fasted and fed pigs, whereas lincomycin was detected for only 12 h after intravenous administration and up to 15 h after oral administration. The volume of distribution was 5.6 ± 1.5 and 1.1 ± 0.2 L/kg body weight for spiramycin and lincomycin, respectively. For both compounds the bioavailability was strongly dependent on the presence of food in the gastrointestinal tract. For spiramycin the bioavailability was determined to be 60% and 24% in fasted and fed pigs, respectively, whereas the corresponding figures for lincomycin were 73% and 41%. The maximum plasma concentration of spiramycin (C_max) was estimated to be 5 μg/mL in fasted pigs and 1 μg/mL only in fed pigs. It is concluded that an oral dose of 55 mg/kg body weight is not enough to give a therapeutically effective plasma concentration of spiramycin against species of Mycoplasma, Streptoccocus, Staphylococcus and Pasteurella multocida. The maximum plasma concentration of lincomycin was estimated to be 8 μg/mL in fasted pigs and 5 μg/mL in fed pigs, but as the minimum inhibitory concentration for lincomycin against Actinobacillus pleuropneumoniae and P. multocida is higher than 32 μg/mL a therapeutically effective plasma concentration could not be obtained following oral administration of the drug. For Mycoplasma the MIC₉₀ is below 1 μg/mL and a therapeutically effective plasma concentration of lincomycin was thus obtained after oral administration to both fed and fasted pigs.     

Cephalothin and Cefazolin In Vitro Antibacterial Activity and Pharmacokinetics in Dogs

The periods of time that cephalothin and cefazolin serum concentration remained above minimum inhibitory concentration (MIC) for beta hemolytic, coagulase positive staphylococcal, and Escherichia coli clinical isolates were compared. Cephalothin and cefazolin were similarly very effective in vitro against staphylococcal isolates, with an MIC₉₀ of 0.12 μg/mL and 0.25 μg/mL, respectively. In contrast, cefazolin was more effective than cephalothin against E coli isolates; the cefazolin MIC₉₀ for E coli was 16 μg/mL and for cephalothin 64 μg/mL. Cefazolin (20 mg/kg intravenously [IV]) serum concentration remained more than MIC₉₀ for E coli isolates significantly longer than serum concentration of cephalothin (40 mg/kg IV) ( P <.001).     

Intravenous disposition kinetics, oral and intramuscular bioavailability and urinary excretion of norfloxacin nicotinate in donkeys

An aqueous solution of norfloxacin nicotinate (NFN) was administered to donkeys (Aquus astnus) intravenously (once at 10 mg/kg), intramuscularly and orally (both routes once at 10 and 20 mg/kg, and for 5 days at 20 mg/kg/day). Blood samples were collected at predetermined times after each treatment and urine was sampled after intravenous drug administration. Serum NFN concentrations were determined by microbiological assay. Intravenous injection of NFN over 45–60 s resulted in seizures, profuse sweating and tachycardia. The intravenous half-life (t_1/2β was 209 ± 36 min, the apparent volume of distribution (V_d(area)) was 3.34 ± 0.58 L/kg, the total body clearance (Cl_E) was 1.092 ± 0.123 ± 10^--²mL/min/kg and the renal clearance (C1_R) was 0.411 ± 0.057 ± 10^--²mL/min/kg. Oral bioavailability was rather poor (9.6% and 6.4% for the 10 and 20 mg/kg doses respectively). Multiple oral treatments did not result in any clinical gastrointestinal disturbances. After intramuscular administration (20 mg/kg), serum NFN concentrations > 0.25 μg/mL (necessary to inhibit the majority of gram-negative bacteria isolated from horses) were maintained for 12 h. The intramuscular bioavailability was 31.5% and 18.8% for the 10 and 20 mg/kg doses respectively. After multiple dosing some local swelling was observed at the injection site. About 40% of the intravenous dose was recovered in the urine as parent drug. The results of comprehensive haematological and blood biochemistry tests indicated no abnormal findings except elevation in serum CPK (creatine phosphokinase) values after multiple intramuscular dosing. On the basis of the in vitro-determined minimum inhibitory concentrations of the drug and serum concentrations after multiple dosing, the suggested intramuscular dosage schedules for the treatment of gram-negative bacterial infections in Equidae are 10 mg/kg every 12 h or 20 mg/kg every 24 h.     

Pharmacokinetics of voriconazole after single dose intravenous and oral administration to alpacas

Voriconazole is a new antifungal drug that has shown effectiveness in treating serious fungal infections and has the potential for being used in large animal veterinary medicine. The objective of this study was to determine the plasma concentrations and pharmacokinetic parameters of voriconazole after single-dose intravenous (i.v.) and oral administration to alpacas. Four alpacas were treated with single 4 mg/kg i.v. and oral administrations of voriconazole. Plasma voriconazole concentrations were measured by a high-performance liquid chromatography method. The terminal half-lives following i.v. and oral administration were 8.01 ± 2.88 and 8.75 ± 4.31 h, respectively; observed maximum plasma concentrations were 5.93 ± 1.13 and 1.70 ± 2.71 μg/mL, respectively; and areas under the plasma concentration vs. time curve were 38.5 ± 11.1 and 9.48 ± 6.98 mg·h/L, respectively. The apparent systemic oral availability was low with a value of 22.7 ± 9.5%. The drug plasma concentrations remained above 0.1 μg/mL for at least 24 h after single i.v. dosing. The i.v. administration of 4 mg/kg/day voriconazole may be a safe and appropriate option for antifungal treatment of alpacas. Due to the low extent of absorption in alpacas, oral voriconazole doses of 20.4 to 33.9 mg/kg/day may be needed.     

Age-related alterations in trimethoprim-sulfadiazine disposition following oral or parenteral administration in calves.

Age-related changes in the absorption and distribution patterns of trimethoprim/sulfadiazine were studied following oral or subcutaneous administration of 15 mg/kg of the drug combination in calves. Following oral administration, the time course of trimethoprim/sulfadiazine appearance and dissipation in serum, synovial fluid and urine was followed for periods up to 48 hours in calves one day, one week and six weeks of age. The profiles of drug appearance-disappearance in these body fluids were also determined after subcutaneous administration in seven week old calves. The peak serum and synovial fluid levels of trimethoprim/sulfadiazine achieved following oral administration were substantially lower with increasing maturation. In ruminating (six and seven week old) calves, subcutaneous or oral administration of the combination led to high serum levels of sulfadiazine but little or no serum trimethoprim was detected in animals at this age. The data indicate that, while therapeutic concentrations and optimum ratios of the drugs may be achieved for extended time periods in neonatal life, this dosage is unable to produce optimum serum and synovial fluid concentrations as the calves mature.     

Pharmacokinetic properties of theophylline given intravenously and orally to ruminating calves

The disposition of theophylline in healthy ruminating calves was best described by a first-order 2-compartment open pharmacokinetic model. The drug had a mean elimination half-life of 6.4 hours and a mean distribution half-life of 22 minutes. Total body clearance averaged 91 ml/kg/h. The mean values for the pharmacokinetic volume of the central compartment, pharmacokinetic volume of distribution during the terminal phase, and volume of distribution at steady state were 0.502, 0.870, and 0.815 L/kg, respectively. Theophylline was readily absorbed after oral administration to the ruminating calf, with a mean fraction of 0.93 absorbed. The plasma concentrations after oral dosing peaked in approximately 5 to 6 hours, with a mean absorption half-life of 3.7 hours. A flip-flop model (rate constant of input is much smaller than the rate constant of output) of drug absorption was not found because the elimination process roughly paralleled that of the study concerning IV administration. In a multiple-dose trial that used a dosage regimen based on single-dose pharmacokinetic values, clinically normal calves responded as predicted. However, diseased calves had higher than expected plasma concentrations after being given multiple oral doses of theophylline at 28 mg/kg once daily. Overt signs of toxicosis were not seen, but this aspect of the drug was not formally investigated. Theophylline can be used as an ancillary therapeutic agent to treat bovine respiratory disease, but not without risk. The suggested oral dose of theophylline at 28 mg/kg of body weight once daily should be tailored to each case.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical pharmacology of apramycin in calves

The minimal inhibitory concentrations (MIC) of apramycin, a unique aminocyclitol antibiotic, were compared with the MIC of dihydrostreptomycin and neomycin for 323 Salmonella, 178 Escherichia coli and twenty-six Pasteurella multocida isolates recovered from newborn calves. Apramycin exhibited better in vitro anti-bacterial activity than dihydrostreptomycin and neomycin; isolates of Salmonella group B and E. coli resistant to the latter were sensitive to apramycin. The two-compartment open model was appropriate for the analysis of serum apramycin concentrations measured after intravenous (i.v.) administration. The distribution half-life (t 1/2 alpha) of the drug was 28 min, the elimination half-life (t 1/2 beta) was 4.4 h, and the apparent volume of distribution (V1) and the distribution volume at steady state (Vdss) were 0.34 and 0.71 l/kg, respectively. The drug was quickly and completely absorbed after intramuscular (i.m.) injection; peak serum drug concentrations were directly related to the dose administered, they were obtained 1-2 h after treatment and the i.m. t 1/2 beta was 5 h. There was no evidence of drug accumulation in the serum after three daily i.m. injections at 20 mg/kg. More than 95% of the i.v. and i.m. doses were recovered in the urine within 96 h post-treatment but the cumulative percentage of drug recovery in the urine after oral treatment was 11%. The durations of free drug concentrations in the tissues after i.v. and i.m. injection were estimated from the serum drug level data, percent of serum protein binding, Vdss, t 1/2 beta, and the MIC. Computations showed that apramycin should be administered i.m. at 20 mg/kg every 24 h in order to maintain in tissues potentially effective drug concentrations sufficient to inhibit 50% of the Salmonella, E. coli, and P. multocida isolates, and at 12-h intervals to inhibit 90% of the isolates.     

Antimicrobial use in the treatment of calf diarrhea

Calves with diarrhea often have small intestinal overgrowth with Escherichia coli bacteria, regardless of the inciting cause for the diarrhea, and 30% of systemically ill calves with diarrhea have bacteremia, predominantly because of E coli. Antimicrobial treatment of diarrheic calves should therefore be focused against E coli in the small intestine and blood, the 2 sites of infection. Fecal bacterial culture and antimicrobial susceptibility testing is not recommended in calves with diarrhea because fecal bacterial populations do not accurately reflect small intestinal or blood bacterial populations and because the break points for susceptibility test results have not been validated. Antimicrobial efficacy is therefore best evaluated by the clinical response of a number of calves to treatment, with calves randomly assigned to treatment groups. Amoxicillin, chlortetracycline, neomycin, oxytetracycline, streptomycin, sulfachloropyridazine, sulfamethazine, and tetracycline administered PO are currently labeled in the United States for the treatment of calf diarrhea. On the basis of published evidence for the oral administration of these antimicrobial agents, only amoxicillin can be recommended for the treatment of diarrhea. Dosage recommendations are amoxicillin trihydrate (10 mg/kg PO q12h) or amoxicillin trihydrate-clavulanate potassium (12.5 mg combined drug/kg PO q12h) for at least 3 days; the latter constitutes extra-label drug use. Parenteral administration of broad-spectrum beta-lactam antimicrobials--ceftiofur (2.2 mg/kg IM or SC q12h) and amoxicillin or ampicillin (10 mg/kg IM q12h)--or potentiated sulfonamides (25 mg/kg IV or IM q24h) is recommended for treating calves with diarrhea and systemic illness; both constitute extra-label drug use. In calves with diarrhea and no systemic illness (normal appetite for milk, no fever), it is recommended that the health of the calf be monitored and that oral or parenteral antimicrobials not be administered.     

Pharmacokinetic evaluation of ceftiofur in serum, tissue chamber fluid and bronchial secretions from healthy beef-bred calves.

Ceftiofur is a new broad spectrum cephalosporin marketed for the treatment of acute bovine respiratory disease. In this investigation ceftiofur was administered by intramuscular injection, at 24 h intervals, to healthy beef-bred calves for four days at dosages of 2.2 and 4.4 mg/kg of body weight, with 4 wk intervals between dosing regimens. Serum, tissue chamber fluid (TCF), and bronchial secretion (BS) concentrations of ceftiofur were measured by microbiological assay after the first and fourth dose of each dosing regimen. Peak serum concentrations (Cmax) of 8.8 micrograms/mL and 17.3 micrograms/mL were obtained approximately 2 h (Tmax), the time of mean peak concentration) after single injections of 2.2 mg/kg and 4.4 mg/kg, respectively. The Cmax was increased approximately twofold following multiple doses of 2.2 mg/kg (Cmax = 13.1 micrograms/mL) and 4.4 mg/kg (Cmax = 24.1 micrograms/mL). Ceftiofur accumulated slowly into TCF and peak concentrations were found to be approximately 14% of those observed in serum after the first dose and approximately 24% after multiple dosing. Concentrations of ceftiofur in BS were obtained rapidly with peak concentrations reaching 45% of the serum Cmax after the first dose. After multiple dosing the Cmax for BS was approximately 25% of the serum Cmax. This study found that both the 2.2 mg/kg and 4.4 mg/kg dosing regimens resulted in continuous serum, TCF and BS concentrations of ceftiofur that exceeded the minimal concentration required to inhibit the bacteria most frequently isolated from calves with acute bovine respiratory disease.     

Pharmacokinetics and tissue distribution of enrofloxacin and its active metabolite ciprofloxacin in calves

The purpose of this study was to establish the pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin in the plasma and interstitial fluid (ISF) following subcutaneous (s.c.) administration of enrofloxacin. Ultrafiltration probes were placed in the s.c. tissue, gluteal musculature, and pleural space of five calves. Each calf received 12.5 mg/kg of enrofloxacin. Plasma and ISF samples were collected for 48 h after drug administration and analyzed by high pressure liquid chromatography. Plasma protein binding of enrofloxacin and ciprofloxacin was measured using a microcentrifugation system. Tissue probes were well tolerated and reliably produced fluid from each site. The mean +/- SD plasma half-life was 6.8 +/- 1.2 and 7.3 +/- 1 h for enrofloxacin and ciprofloxacin, respectively. The combined (ciprofloxacin + enrofloxacin) peak plasma concentration (Cmax) was 1.52 microg/mL, and the combined area under the curve (AUC) was 25.33 microg/mL. The plasma free drug concentrations were 54% and 81% for enrofloxacin and ciprofloxacin, respectively, and free drug concentration in the tissue fluid was higher than in plasma. We concluded that Cmax/MIC and AUC/MIC ratios for free drug concentrations in plasma and ISF would meet suggested ratios for a targeted MIC of 0.06 microg/mL.     

Disposition of metronidazole in hens (Gallus gallus) and quails (Coturnix coturnix japonica): pharmacokinetics and whole-body autoradiography

Hens were given single intravenous or oral doses (30 mg/kg body weight) of metronidazole and the plasma concentrations of the drug were determined by high-performance liquid chromatography (HPLC) at intervals from 10 min to 24 h after drug administration. Pharmacokinetic variables were calculated by the Lagrange algorithm technique. The elimination half-life ( t _1/2β) after the intravenous injection was 4.2 ± 0.5 h, the volume of distribution ( V _d(ss)) 1.1±0.2 L/kg and the total body clearance ( Cl _B) 131.2 ± 20 mL/h.kg. Oral bioavailability of the metronidazole was 78 ± 16%. The plasma maximum concentration ( C _max) 31.9 ± 2.3 μg/mL was reached 2 h after the oral administration and the oral elimination half-life ( t ₁/2β) was 4.7 ± 0.2 h. The binding of metronidazole to proteins in hen plasma was very low (less than 3%). Whole body autoradiography of [³H] metronidazole in hens and quails showed an even distribution of labelled material in various tissues at short survival intervals (1-4 h) after oral or intravenous administration. A high labelling was seen in the contents of the small and large intestines. In the laying quails a labelling was also seen in the albumen and in a ring in the periphery of the yolk at long survival intervals. Our results show that a concentration twofold above the MIC is maintained in the plasma of hens for at least 12 h at an oral dose of 30 mg/kg metronidazole.     

Pharmacokinetics of phenoxymethyl penicillin (penicillin V) in calves

Phenoxymethyl penicillin (penicillin V) was administered intravenously (i.v.) and orally to pre-ruminant calves and the distribution and elimination kinetics, as well as the oral bioavailability, were determined. After i.v. injection, the drug was distributed rapidly in the body, the elimination half-life (t1/2 beta) was 34 min and the apparent volume of distribution at steady-state (Vd ss) was 0.30 l/kg. Mean peak serum drug concentrations were directly related to the oral dose administered, i.e. 0.22 microgram/ml, 1.06 micrograms/ml and 2.14 micrograms/ml after dosing at 10, 20 and 40 mg/kg, respectively. The elimination t1/2 of the drug after oral dosing varied between 90 and 110 min, and the oral bioavailability was approximately 30% of the dose. The co-administration of phenoxymethyl penicillin and probenecid resulted in elevation and prolongation of serum drug concentration. The percentage of drug bound to serum proteins was 78.8% +/- 8.2%. Phenoxymethyl penicillin was probably inactivated and degraded in the gastrointestinal tract of 6-week-old calves fed exclusively hay, silage and concentrates as very low and erratic serum drug concentrations were measured after these calves were dosed orally with the drug at 40 mg/kg. In view of the narrow antibacterial spectrum of the drug and the relatively high dose required, it appears that phenoxymethyl penicillin can only be of limited practical value for the treatment of bacterial infections in preruminant calves.