Pharmacokinetics of danofloxacin and N‐desmethyldanofloxacin in adult horses and their concentration in synovial fluid

The objectives of this study were to investigate the pharmacokinetics of danofloxacin and its metabolite N‐desmethyldanofloxacin and to determine their concentrations in synovial fluid after administration by the intravenous, intramuscular or intragastric routes. Six adult mares received danofloxacin mesylate administered intravenously (i.v.) or intramuscularly (i.m.) at a dose of 5 mg/kg, or intragastrically (IG) at a dose of 7.5 mg/kg using a randomized Latin square design. Concentrations of danofloxacin and N‐desmethyldanofloxacin were measured by UPLC‐MS/MS. After i.v. administration, danofloxacin had an apparent volume of distribution (mean ± SD) of 3.57 ± 0.26 L/kg, a systemic clearance of 357.6 ± 61.0 mL/h/kg, and an elimination half‐life of 8.00 ± 0.48 h. Maximum plasma concentration (C_max) of N‐desmethyldanofloxacin (0.151 ± 0.038 μg/mL) was achieved within 5 min of i.v. administration. Peak danofloxacin concentrations were significantly higher after i.m. (1.37 ± 0.13 μg/mL) than after IG administration (0.99 ± 0.1 μg/mL). Bioavailability was significantly higher after i.m. (100.0 ± 12.5%) than after IG (35.8 ± 8.5%) administration. Concentrations of danofloxacin in synovial fluid samples collected 1.5 h after administration were significantly higher after i.v. (1.02 ± 0.50 μg/mL) and i.m. (0.70 ± 0.35 μg/mL) than after IG (0.20 ± 0.12 μg/mL) administration. Monte Carlo simulations indicated that danofloxacin would be predicted to be effective against bacteria with a minimum inhibitory concentration (MIC) ≤0.25 μg/mL for i.v. and i.m. administration and 0.12 μg/mL for oral administration to maintain an area under the curve:MIC ratio ≥50.     

Comparative pharmacokinetics of acetylsalicylic acid and sodium salicylate in chickens and turkeys

1. Pharmacokinetics of acetylsalicylic acid (ASA) and sodium salicylate (SS) were assessed following single intravenous (i.v.) and oral administration at doses of 50 mg/kg body weight to chickens and turkeys. Plasma drug concentrations were determined using high-performance liquid chromatography with ultraviolet detection and pharmacokinetic variables were calculated using a non-compartmental model.

2. The mean residence time (MRT) of salicylate (SA) after i.v. administration of SS was 6.08 ± 0.59 and 3.32 ± 0.27 h and after oral administration was 6.95 ± 0.72 and 4.55 ± 0.71 h in chickens and turkeys, respectively. The elimination half-life (T _{1/2 e}) was shorter in turkeys compared with chickens. The value of body clearance (Cl_B) was higher in turkeys than in chickens, but the apparent volume of distribution (V _ss) was similarly low in both species. The bioavailability of SS was complete and the maximal plasma concentration of SA (C _max) after oral administration was 96.93 ± 8.06 and 91.76 ± 9.64 µg/ml, respectively, in chickens and turkeys.

3. The MRT of ASA after iv administration was 0.24 ± 0.08 and 0.24 ± 0.02 h and after oral administration was 0.78 ± 0.25 and 0.59 ± 0.13 h, respectively, in chickens and turkeys. In both species, T _{1/2 e} was very short, Cl_B and V _ss were similar and markedly higher than those of salicylate. The bioavailability of unchanged ASA was low and C _max after oral administration was 6.9 ± 3.6 µg/ml in chickens and 8.6 ± 1.3 µg/ml in turkeys.     

Pharmacokinetics,urinary excretion and plasma protein binding of danofloxacin following intravenous administration in buffalo calves (Bubalus bubalis)

Pharmacokinetics, urinary excretion and plasma protein binding of danofloxacin was investigated in buffalo calves following intravenous administration at the dose rate of 1.25 mg/kg to select the optimal dosage regimen of danofloxacin. Drug concentrations in plasma and urine were measured by microbiological assaying. In vitro plasma protein binding was determined employing the equilibrium dialysis technique. The distribution and elimination of danofloxacin were rapid, as indicated by values (mean ±SD) of distribution half-life (t_1/2α = 0.16 ± 0.07 h) and elimination half-life (t_1/2β = 4.24 ± 1.78 h), respectively. Volume of distribution at steady state (Vss) = 3.98 ± 1.69 L/kg indicated large distribution of drug. The area under plasma drug concentration versus time curve (AUC) was 1.79 ± 0.28 μg/mlxh and MRT was 8.64 ± 0.61 h. Urinary excretion of danofloxacin was 23% within 48 h of its administration. Mean plasma protein binding was 36% at concentrations ranging from 0.0125 μg/ml to 1 μg/ml. On the basis of pharmacokinetic parameters obtained, it is concluded that the revision of danofloxacin dosage regimen in buffalo calves is needed because the current dosage schedule (1.25 mg/kg) is likely to promote resistance.     

Pharmacokinetics of levofloxacin after single intravenous,oral and subcutaneous administration to dogs

The pharmacokinetic properties of the fluoroquinolone levofloxacin (LFX) were investigated in six dogs after single intravenous, oral and subcutaneous administration at a dose of 2.5, 5 and 5 mg/kg, respectively. After intravenous administration, distribution was rapid (T_½dist 0.127 ± 0.055 hr) and wide as reflected by the volume of distribution of 1.20 ± 0.13 L/kg. Drug elimination was relatively slow with a total body clearance of 0.11 ± 0.03 L kg^?1 hr^?1 and a T_½ for this process of 7.85 ± 2.30 hr. After oral and subcutaneous administration, absorption half‐life and T_max were 0.35 and 0.80 hr and 1.82 and 2.82 hr, respectively. The bioavailability was significantly higher (p ? 0.05) after subcutaneous than oral administration (79.90 vs. 60.94%). No statistically significant differences were observed between other pharmacokinetic parameters. Considering the AUC_24 hr/MIC and C_max/MIC ratios obtained, it can be concluded that LFX administered intravenously (2.5 mg/kg), subcutaneously (5 mg/kg) or orally (5 mg/kg) is efficacious against Gram‐negative bacteria with MIC values of 0.1 μg/ml. For Gram‐positive bacteria with MIC values of 0.5 μg/kg, only SC and PO administration at a dosage of 5 mg/kg showed to be efficacious. MIC‐based PK/PD analysis by Monte Carlo simulation indicates that the proposed dose regimens of LFX, 5 and 7.5 mg/kg/24 hr by SC route and 10 mg/kg/24 hr by oral route, in dogs may be adequate to recommend as an empirical therapy against S. aureus strains with MIC ≤ 0.5 μg/ml and E. coli strains with MIC values ≤0.125 μg/ml.     

Pharmacokinetics of difloxacin in healthy and E. coli-infected broiler chickens

1. The pharmacokinetics of difloxacin were investigated in healthy and E. coli-infected broiler chickens following intravenous and oral administration of a single dose of 10 mg/kg bodyweight.

2. After intravenous injection of difloxacin, the serum concentration–time curves were best described by a two-compartment open model. The distribution and elimination half-lives (t_0.5α) and (t_0.5el), respectively, were 0.10 ± 0.016 h and 3.7 ± 0.08 h in healthy chickens compared with 0.05 ± 0.005 h and 6.42 ± 0.71 h in E. coli-infected birds. The volumes of distribution V_dss were 3.14 ± 0.11 and 9.25 ± 0.43 l/kg, with total body clearance (Cl_tot) of 0.65 ± 0.018 and 1.14 ± 0.1 ml/kg/h, respectively.

3. Following oral administration, difloxacin was absorbed with t_0.5(ab) of 0.57 ± 0.06 and 0.77 ± 0.04 h and was eliminated with t_0.5(el) of 4.7 ± 0.34 and 3.42 ± 0.19, respectively, in normal and infected chickens. The peak serum concentrations were 1.34 ± 0.09 and 1.05 ± 0.06 µg/ml and attained a T_max of 2.27 ± 0.07 and 2.43 ± 0.06 h, respectively. The systemic bioavailability of difloxacin following oral administration was 86.2% in healthy chickens and 90.6% in E. coli-infected birds. The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of difloxacin against the field strain of E. coli O78 in vitro were 0.02 µg and 0.04 µg/ml, respectively.

4. These results show that administration of a therapeutic dose of difloxacin is effective in the treatment of E. coli infection in chickens. The serum concentration of the drug was much higher than the MIC of the E. coli O78 strain in both healthy and infected chickens.     

Pharmacokinetics and bioavailability of danofloxacin in chukar partridge (Alectoris chukar) following intravenous,intramuscular, subcutaneous,and oral administrations

The aim of the present study was to determine the pharmacokinetics (PKs) and bioavailability of danofloxacin in chukar partridge (Alectoris chukar) following intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations at a dose of 10 mg/kg. A total of eight clinically healthy chukar partridges weighing 480 ± 45 g were used for the investigation. The study was performed in a crossover design (2 × 2 × 2 × 2) with a 15‐day washout period between two administrations in four periods. The plasma concentrations of danofloxacin were determined using reversed‐phase high‐performance liquid chromatography. Noncompartmental PK parameters were also estimated. No local or systemic adverse drug effects were observed in any of the chukar partridges. The mean elimination half‐life ranged between 8.18 and 12.08 hr and differed statistically among administration routes. The mean peak plasma concentrations of danofloxacin following IM, SC, and PO administrations were 8.05, 9.58, and 3.39 μg/ml at 0.5, 1, and 4 hr, respectively. Following IM, SC, and PO administrations, the mean bioavailability was 86.33%, 134.40%, and 47.62%, respectively. The mean total clearance and volume of distribution at steady‐state following IV administration were 0.13 L hr^?1 kg^?1 and 0.96 L/kg, respectively. These data, including favorable PKs and the absence of adverse drug effects, suggest that danofloxacin is a useful antibiotic in chukar partridges.     

Pharmacokinetics of the novel COX‐2 selective inhibitor vitacoxib in cats: The effects of feeding and dose

The purpose of this study was to determine the pharmacokinetics and dose‐scaling model of vitacoxib in either fed or fasted cats following either oral or intravenous administration. The concentration of the drug was quantified by UPLC‐MS/MS on plasma samples. Relevant parameters were described using noncompartmental analysis (WinNonlin 6.4 software). Vitacoxib is relatively slowly absorbed and eliminated after oral administration (2 mg/kg body weight), with a T_max of approximately 4.7 hr. The feeding state of the cat was a statistically significant covariate for both area under the concentration versus time curve (AUC) and mean absorption time (MAT_fed). The absolute bioavailability (F) of vitacoxib (2 mg/kg body weight) after oral administration (fed) was 72.5%, which is higher than that in fasted cats (F = 50.6%). Following intravenous administration (2 mg/kg body weight), Vd (ml/kg) was 1,264.34 ± 343.63 ml/kg and Cl (ml kg^?1 hr^?1) was 95.22 ± 23.53 ml kg^?1 hr^?1. Plasma concentrations scaled linearly with dose, with C_max (ng/ml) of 352.30 ± 63.42, 750.26 ± 435.54, and 936.97 ± 231.27 ng/ml after doses of 1, 2, and 4 mg/kg body weight, respectively. No significant undesirable behavioral effects were noted throughout the duration of the study.     

Pharmacokinetics and pharmacodynamics of danofloxacin in serum and tissue fluids of goats following intravenous and intramuscular administration

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of danofloxacin in goats and the concentrations required to induce bacteriostasis, bactericidal activity, and bacterial elimination. ANIMALS: 6 healthy British Saanen goats. PROCEDURE: Danofloxacin (1.25 mg/kg of body weight) was administered i.v. and i.m. in a cross-over design with 14 days between treatments. A tissue cage was used for evaluation of drug distribution into transudate and exudate. The ex vivo antibacterial activity of danofloxacin in serum, exudate, and transudate against a caprine isolate of Mannheimia haemolytica was determined. Pharmacokinetic and pharmacodynamic data were integrated to determine the ratio of the area under the concentration versus time curve to the minimum inhibitory concentration of danofloxacin (AUIC). RESULTS: Elimination half-lives of danofloxacin in serum were 4.67 and 4.41 hours after i.v. and i.m. administration, respectively. Volume of distribution was high after administration via either route, and bioavailability was 100% after i.m. administration. Rate of penetration into exudate and transudate was slow, but elimination half-lives from both fluids were approximately twice that from serum. Drug concentrations in serum, exudate, and transudate for 9 to 12 hours after administration induced marked ex vivo antibacterial activity. For serum, AUIC24h values required for bacteriostasis, bactericidal effect, and bacterial elimination were 22.6, 29.6, and 52.4, respectively. Similar values were obtained for exudate and transudate. CONCLUSIONS AND CLINICAL RELEVANCE: Integration of danofloxacin pharmacokinetic and pharmacodynamic data obtained in goats may provide a new approach on which to base recommendations for therapeutic dosages.     

A comparative study of the pharmacokinetics of intravenous and oral trimethoprim/sulfadiazine formulations in the horse

The biopharmaceutical properties of four fuced trimethoprim/sulfonamide combinations were investigated in the horse. Eight fasted horses were dosed at 1 week intervals in a sequentially designed study with one intravenous (i.v.) and three oral trimethoprim/sulfadiazine (TMP/SDZ) formulations (1, 2 and 3) administered at a dose of 5 mg/kg trimethoprim (TMP) and 25 mg/kg sulfadiazine (SDZ). Plasma concentrations of each compound were monitored for 48 h. Pharmacokinetic parameters (volume of distribution, bioavailability and total body clearance) for TMP and SDZ were calculated and compared. After oral administration plasma concentrations of TMP and SDZ increased rapidly. With all three paste formulations, TMP peak plasma concentrations were attained within 2 h. SDZ mean peak plasma concentrations were reached at 2.59 ± 0.48 h for a commercial paste (l), and at 1.84 ± 0.66 h and 1.95 ± 0.61 h for the two self-made formulations (2 and 3). Mean peak plasma TMP concentrations (± SD) were 1.72 ± 0.36 μg/ml, 1.42 ± 0.37 μg/ml and 1.31 ± 0.36 μ g/d, and mean peak plasma SDZ concentrations 12.11 ± 4.5 5 μg/ml, 12.72 ± 3.47 μg/ml and 15.45 ± 4.74 μg/ml for preparations 1, 2 and 3. The bioavailability of TMP was 67.0 ± 20.3%, 57.7 ±21.6% and 60.9 f 18.9% and of SDZ 57.6 ± 14.8%, 59.3 ± 19.5% and 65.9 ± 5.8% for SDZ for 1, 2 and 3, respectively. Following i.v. administration TMP/SDZ plasma concentration ratios approached the optimal 1:20 ratio (It 10%) for about 5 h, but following the oral administrations this ratio was only achieved for a very short time-span. No adverse effects were seen following i.v. and oral administration. In considering the pharmacokinetic data in combination with in vitro antibacterial sensitivity data, it is concluded that treatment at a dose of 5 mg/kg TMP and 25 mg/kg SDZ with a dosing interval of 12 h can be regarded as therapeutically effective for susceptible bacteria (MIC₉₀ 0.25/4.75) for all three oral formulations. It is concluded that neither the formulation nor the addition of different excipients result in significantly different bioavailabilities.     

Influence of <Emphasis Type="Italic">E. coli</Emphasis> lipopolysaccharide induced fever on the plasma kinetics of cefepime in cross-bred calves

The pharmacokinetic behavior of cefepime was studied in healthy and febrile cross-bred calves after single intravenous administration (10 mg/kg). The fever was induced with E. coli lipopolysaccharide (1 μg/kg, IV). The drug concentration in plasma was detected by microbiological assay method using E. coli (MTCC 739) test organism. Pharmacokinetic analysis of disposition data indicated that intravenous administration data were best described by 2 compartment open model. At 1 min the concentration of cefepime in healthy and febrile animals were 55.3 ± 0.54 μg/ml and 50.0 ± 0.48 μg/ml, respectively and drug was detected up to 12 h. The elimination half-life of cefepime was increased from 1.26 ± 0.01 h in healthy animals to 1.62 ± 0.09 h in febrile animals. Drug distribution was altered by fever as febrile animals showed volume of distribution (0.27 ± 0.02 L/kg) higher than normal animal (0.19 ± 0.01 L/kg). Total body clearances in healthy and febrile animals were 104.4 ± 2.70 and 114.2 ± 1.20 ml/kg/h, respectively. To maintain minimum therapeutic concentration of 1 μg/ml, a satisfactory dosage regimen of cefepime in healthy and febrile cross-bred calves would be 15.5 mg/kg and 8.2 mg/kg body weight, respectively, to be repeated at 8 h intervals. The T>MIC values (8 h) of cefepime suggested that this agent is clinically effective in the treatment of various infections.     

The pharmacokinetics of cefadroxil over a range of oral doses and animal ages in the foal

To evaluate the effect of foal age on the pharmacokinetics of cefadroxil, five foals were administered cefadroxil in a single intravenous dose (5 mg/kg) and a single oral dose (10 or 20 mg/kg) at ages of 0.5, 1, 2, 3 and 5 months. Pharmacokinetic parameters of terminal elimination rate constant (β_po), oral mean residence time (MRT_po), mean absorption time (MAT), rate constant for oral absorption (K_a), bioavailability F, peak serum concentrations(C_max) and time of peak concentration (t_max), were evaluated in a repeated measures analysis over dose. Across animal ages, parameters for the intravenous dose did not change significantly over animal age (P 0.05). Mean values ± SEM were: β_IV = 0.633 ± 0.038 h^?1; Cl = 0.316 ± 0.010 L/kg/h; V_c = 0.196 ± 0.008 L/kg; V_area = 0.526 ± 0.024 L/kg; V_SS =0.374 ± 0.014 L/kg; MRT_iv = 1.22 ± 0.07 h; K_el = 1.67 ± 0.08 ^h?1. Following oral administration, drug absorption became faster with age (P < 0.05), as reflected by MRT_po, MAT, K_a and t_max. However, oral bioavailability (±SE) declined significantly (P < 0.05) from 99.6 ± 3.69% at 0.5 months to 14.5 ± 1.40% at 5 months of age. To evaluate a dose effect on the pharmacokinetic parameters, a series of oral doses (5, 10, 20 and 40 mg/kg) were administered to these foals at 1 month of age. β_po (0.548 ± 0.023 h^?1) and F (68.26 ± 2.43%) were not affected significantly by the size of the dose. C_max was approximately doubled with each two-fold increase in dose: 3.15 ± 0.15, 5.84 ± 0.48, 12.17 ± 0.93 and 19.71 ± 2.19 μg/mL. Dose-dependent kinetics were observed in MRT_po, MAT, K_a and t_max.     

The pharmacokinetics of levetiracetam in healthy dogs concurrently receiving phenobarbital

Moore, S.A., Muñana, K.R., Papich, M.G., Nettifee‐Osborne, J.A. The pharmacokinetics of levetiracetam in healthy dogs concurrently receiving phenobarbital. J. vet. Pharmacol. Therap. 34 , 31–34. Levetiracetam (LEV) is a commonly used add‐on medication in dogs with refractory epilepsy. The objective of this study was to determine if the pharmacokinetics of LEV are altered by concurrent administration of phenobarbital (PB). Six healthy dogs received a single oral dose of LEV (16.7–27.8 mg/kg). Blood samples were collected at baseline and intermittently for 24 h. The study was repeated after the dogs received oral PB (2.0–3.3 mg/kg) twice daily for 21 days. Plasma LEV levels were evaluated by high pressure liquid chromatography, and data analyzed using a compartmental model. Compared with values determined when LEV was administered alone, concurrent administration of PB resulted in a decrease in LEV peak concentration (C_max) from 32.39 ± 6.76 to 18.22 ± 8.97 (P = 0.0071), a decrease in elimination half‐life (T_1/2) from 3.43 ± 0.47 to 1.73 ± 0.22 (P = 0.0005), and an increase in oral clearance from 124.93 ± 26.93 to 252.99 ± 135.43 ml/h/kg (P < 0.0001). Concurrent PB administration significantly alters the pharmacokinetics of LEV in the dog, indicating that dosage adjustments might be necessary when the drug is administered with PB.     

The influence of growth and E. coli endotoxaemia on amoxicillin pharmacokinetics in turkeys

1. This experiment aimed to determine if the pharmacokinetics of amoxicillin (AMO) was affected by rapid growth or intravenous (i.v.) injection of Escherichia coli lipopolysaccharide (LPS).

2. Turkeys of 2.0, 5.5 and 12.0 kg were administered i.v. or orally with AMO sodium at the dose of 15 mg/kg. Another group (5.7 kg) was treated with LPS prior to i.v. AMO administration. Plasma drug concentrations were determined using high-performance liquid chromatography and pharmacokinetic parameters were calculated using a non-compartmental model. To assess the haemodynamic effects of endotoxaemia, turkeys were subjected to echocardiography.

3. During growth from 2.0 to 5.5 kg, the area under the drug concentration-time curve after i.v. AMO administration increased from 9.37 ± 2.43 to 21.29 ± 5.49 mg×h/ml. Total body clearance decreased from 1.72 ± 0.55 to 0.75 ± 0.12 l/h/kg. Growth to 12.0 kg did not further affect these parameters. Mean residence time and elimination half-life gradually increased. Pharmacokinetics of orally administered drug followed a similar pattern. LPS injection affected stroke volume, heart rate and resistance index. However, it did not affect the pharmacokinetic profile of AMO in survivors.

4. It is concluded that rapid growth in turkeys affects AMO pharmacokinetics. Endotoxaemia, on the other hand, does not affect AMO elimination if compensatory mechanisms develop.     

Pharmacokinetics of oxytetracycline and therapeutic implications in veal calves

Pharmacokinetic parameters of oxytetracycline were analysed in healthy preruminant veal calves after intravenous, intramuscular and oral administration. The serum half-lives in the β-elimination phase of both 10% and 20% solutions after i.v. injection of 10 mg/kg were similar (7.07 ± 1.36 h and 7.16 ± 1.17 h, mean ± SD), whereas the total body clearance and the apparent volume of distribution were higher for the 20% solution. Serum concentrations above 0.5 μg/ml were maintained with both formulations during 12–24 h but were only above 4 μg/ml to 5 h. Intramuscular administration of the 20% solution gave a complete absorption with two rate constants of absorption, a faster (t_1/2a1= 0.27 h) and a slower one (t_1/2a2= 10.90 h) responsible for the delayed elimination half-life after this route of application (t_1/2β= 9.83 ± 1.35 h). Mean serum concentrations reached a maximum level of 3.01 ± 0.72 μg/ml at 4.01 ± 2.84 h and decreased to 0.5 μg/ml between 12 and 24 h. 50 mg/kg given orally with a milk replacer were found to have a mean bioavailability of 46.35%. A mean serum peak level of 4.99 ± 1.37 μg/ml was achieved at 9.16 ± 1.99 h and the mean concentration was still above 0.5 μg/ml after 48 h. The elimination half-life (t_1/2β= 10.66 ± 3.15 h) reflected the slow absorption step (t_1/2a2= 10.15 h) following that responsible for the initial faster absorption (t_1/2a2= 1.99 h). Comparison of the area under the serum curves gave mean values of 117% for tetracycline and of 53% for chlortetracycline relative to oxytetracycline (arbitrarily fixed at 100%) after identical oral dosage of the three tetracyclines. We also propose and discuss a dosage schedule based on minimal inhibitory concentrations of different susceptible pathogens     

Pharmacokinetics of doxycycline in laying hens after intravenous and oral administration

1. The pharmacokinetics of doxycycline in laying hens was investigated after a single intravenous (IV) or an oral (PO) dose at 20 mg/kg body weight.

2. The concentrations of doxycycline in plasma samples were determined by high-performance liquid chromatography with an ultraviolet detector, and pharmacokinetic parameters were calculated using a compartmental model method.

3. The disposition of doxycycline after one single IV injection was best described by a two-compartment open model and the main pharmacokinetic parameters were as follows: volume of distribution (V_d) was 865.15 ± 127.64 ml/kg, distribution rate constant (α) was (2.28 ± 0.38) 1/h, elimination rate constant (β) was 0.08 ± 0.02 1/h and total body clearance (Cl) was104.11 ± 18.32 ml/h/kg, while after PO administration, the concentration versus time curve was best described by a one-compartment open model and absorption rate constant (K_a), peak concentration (C_max), time to reach C_max (t_max) and absolute bioavailability (F) were 2.55 ± 1.40 1/h, 5.88 ± 0.70 μg/ml, 1.73 ± 0.75 h and 52.33%, respectively.

4. The profile of doxycycline exhibited favourable pharmacokinetic characteristics in laying hens, such as quick absorption and slow distribution and elimination, though oral bioavailability was relatively low. A multiple-dosing regimen (a dose of 20 mg/kg/d for 3 consecutive days) of doxycycline was recommended to treat infections in laying hens. But a further study should be conducted to determine the withdrawal time of doxycycline in eggs.

     

Pharmacokinetics of an intravenous and oral dose of enrofloxacin in white rhinoceros (Ceratotherium simum)

South Africa currently loses over 1000 white rhinoceros (Ceratotherium simum) each year to poaching incidents, and numbers of severely injured victims found alive have increased dramatically. However, little is known about the antimicrobial treatment of wounds in rhinoceros. This study explores the applicability of enrofloxacin for rhinoceros through the use of pharmacokinetic‐pharmacodynamic modelling. The pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin were evaluated in five white rhinoceros after intravenous (i.v.) and after successive i.v. and oral administration of 12.5 mg/kg enrofloxacin. After i.v. administration, the half‐life, area under the curve (AUC_tot), clearance and the volume of distribution were 12.41 ± 2.62 hr, 64.5 ± 14.44 μg ml^?1 hr^?1, 0.19 ± 0.04 L h^?1 kg^?1, and 2.09 ± 0.48 L/kg, respectively. Ciprofloxacin reached 26.42 ± 0.05% of the enrofloxacin plasma concentration. After combined i.v. and oral enrofloxacin administration oral bioavailability was 33.30 ± 38.33%. After i.v. enrofloxacin administration, the efficacy marker AUC₂₄: MIC exceeded the recommended ratio of 125 against bacteria with an MIC of 0.5 μg/mL. Subsequent intravenous and oral enrofloxacin administration resulted in a low Cmax: MIC ratio of 3.1. The results suggest that intravenous administration of injectable enrofloxacin could be a useful drug with bactericidal properties in rhinoceros. However, the maintenance of the drug plasma concentration at a bactericidal level through additional per os administration of 10% oral solution of enrofloxacin indicated for the use in chickens, turkeys and rabbits does not seem feasible.     

Pharmacokinetics and toxicity of ciprofloxacin in adult horses

Yamarik, T. A., Wilson, W. D., Wiebe, V. J., Pusterla, N., Edman, J., Papich, M. G. Pharmacokinetics and toxicity of ciprofloxacin in adult horses. J. vet. Pharmacol. Therap. 33 , 587–594. Using a randomized, cross‐over study design, ciprofloxacin was administered i.g. to eight adult mares at a dose of 20 mg/kg, and to seven of the eight horses at a dose of 5 mg/kg by bolus i.v. injection. The mean C₀ was 20.5 μg/mL (±8.8) immediately after i.v. administration. The C_max was 0.6 μg/mL (±0.36) at T_max 1.46 (±0.66) h after the administration of oral ciprofloxacin. The mean elimination half‐life after i.v. administration was 5.8 (±1.6) h, and after oral administration the terminal half‐life was 3.6 (±1.7) h. The overall mean systemic availability of the oral dose was 10.5 (±2.8)%. Transient adverse effects of mild to moderate severity included agitation, excitement and muscle fasciculation, followed by lethargy, cutaneous edema and loss of appetite developed in all seven horses after i.v. administration. All seven horses developed mild transient diarrhea at 36–48 after i.v. dosing. All eight horses dosed intragastrically experienced adverse events attributable to ciprofloxacin administration. Adverse events included mild transient diarrhea to severe colitis, endotoxemia and laminitis necessitating euthanasia of three horses on humane grounds. The high incidences of adverse events preclude oral and rapid i.v. push administration of ciprofloxacin.     

Effect of dose on the intravenous pharmacokinetics of tolfenamic acid in goats

The objective of this study was to determine the pharmacokinetics of tolfenamic acid (TA) following intravenous (IV) administration at doses of 2 and 4 mg/kg in goats. In this study, six healthy goats were used. TA was administered intravenously to each goat at 2 and 4 mg/kg doses in a cross-over pharmacokinetic design with a 15-day washout period. Plasma concentrations of TA were analyzed using the high performance liquid chromatography with ultraviolet detector, and pharmacokinetic parameters were assigned by noncompartmental analysis. Following IV administration at dose of 2 mg/kg, area under the concentration–time curve (AUC_0−∞), elimination half-life (t_1/2ʎz), total clearance (Cl_T) and volume of distribution at steady state (V_dss) were 6.64 ± 0.81 hr^*µg/ml, 1.57 ± 0.14 hr, 0.30 ± 0.04 L h^-1 kg^-1 and 0.40 ± 0.05 L/kg, respectively. After the administration of TA at a dose of 4 mg/kg showed prolonged t_1/2ʎz, increased dose-normalized AUC_0-∞, and decreased Cl_T. In goats, TA at 4 mg/kg dose can be administered wider dose intervals compared to the 2 mg/kg dose. However, further studies are needed to determine the effect of different doses on the clinical efficacy of TA in goats.     

Comparative pharmacokinetics of danofloxacin in common pheasants,guinea fowls and Japanese quails after intravenous and oral administration

1. The pharmacokinetics of danofloxacin was investigated in common pheasants, guinea fowls and Japanese quails after intravenous (i.v.) and oral (p.o.) administration at a dose of 10 mg kg^?1 body weight. Concentrations of the drug in serum were determined by high-performance liquid chromatography. The values of the pharmacokinetic parameters after both applications were calculated on the basis of a one-compartment model.

2. The elimination half-lives after i.v. injection were 6.82 ± 1.87, 3.31 ± 0.13 and 3.84 ± 0.89 h in pheasants, guinea fowls and quails, respectively. Total body clearance values were 0.45 ± 0.16, 1.23 ± 0.07 and 1.61 ± 0.34 l h^?1 kg^?1 in pheasants, guinea fowls and quails, respectively.

3. After p.o. administration, maximum serum concentrations were 0.54 ± 0.26, 0.51 ± 0.12 and 0.78 ± 0.11 μg ml^?1 respectively, reached at 2.04 ± 0.23, 10.4 ± 5.64 and 5.35 ± 0.47 h. Oral bioavailability values were 82.32% for pheasants, 79.46% for guinea fowls and 83.5% for Japanese quails. Pharmacokinetic/pharmacodynamic (PK/PD) predictive indices were also calculated and compared.     

Pharmacokinetics of cefpodoxime in plasma and subcutaneous fluid following oral administration of cefpodoxime proxetil in male beagle dogs

Kumar, V., Madabushi, R., Lucchesi, M. B. B., Derendorf, H. Pharmacokinetics of cefpodoxime in plasma and subcutaneous fluid following oral administration of cefpodoxime proxetil in male beagle dogs. J. vet. Pharmacol. Therap. 34 , 130–135. Pharmacokinetics of cefpodoxime in plasma (total concentration) and subcutaneous fluid (free concentration using microdialysis) was investigated in dogs following single oral administration of prodrug cefpodoxime proxetil (equivalent to 5 and 10 mg/kg of cefpodoxime). In a cross over study design, six dogs per dose were utilized after a 1 week washout period. Plasma, microdialysate, and urine samples were collected upto 24 h and analyzed using high performance liquid chromatography. The average maximum concentration (C_max) of cefpodoxime in plasma was 13.66 (±6.30) and 27.14 (±4.56) μg/mL with elimination half‐life (t_1/2) of 3.01 (±0.49) and 4.72 (±1.46) h following 5 and 10 mg/kg dose, respectively. The respective average area under the curve (AUC_0–∞) was 82.94 (±30.17) and 107.71 (±30.79) μg·h/mL. Cefpodoxime was readily distributed to skin and average free C_max in subcutaneous fluid was 1.70 (±0.55) and 3.06 (±0.93) μg/mL at the two doses. Urinary excretion (unchanged cefpodoxime) was the major elimination route. Comparison of subcutaneous fluid concentrations using pharmacokinetic/pharmacodynamic indices of fT_>MIC indicated that at 10 mg/kg dose; cefpodoxime would yield good therapeutic outcome in skin infections for bacteria with MIC₅₀ upto 0.5 μg/mL while higher doses (or more frequent dosing) may be needed for bacteria with higher MICs. High urine concentrations suggested cefpodoxime use for urinary infections in dogs.