Tissue concentrations and pharmacokinetics of florfenicol in broiler chickens

1. Florfenicol (30 mg/kg body weight) was administered to broiler chickens via intravenous (iv), intramuscular (im) and oral routes to study its plasma concentrations, kinetic behaviour, systemic bioavailability and tissue content.

2. Following a single iv injection, the kinetic disposition of florfenicol followed a 2‐compartmental open model with an elimination half‐life of 173 min, total body clearance of 26.9 ml/kg/min and a steady state volume of distribution of 5.11 1/kg.

3. The highest plasma concentrations of florfenicol were 3.82 and 3.20 μg/ml following single im and oral administration, respectively. The systemic bioavailability was 96.6% and 55.3% after im and oral administration. The plasma protein binding of florfenicol was 18.5%.

4. Following its administration, the highest tissue concentrations of the drug were found in the kidney bile, lung, muscle, intestine, heart, liver, spleen and plasma. Low concentrations of the drug were found in brain, bone marrow and fat. No florfenicol residues were detected in tissues and plasma after 72 h except in the bile from where it disappeared after 96 h.     

Bioavailability and pharmacokinetics of florfenicol in healthy sheep

A study on bioavailability and pharmacokinetics of florfenicol was conducted in 20 crossbred healthy sheep following a single intravenous (i.v.) and intramuscular (i.m.) doses of 20 and 30 mg/kg body weight (b.w.). Florfenicol concentrations in serum were determined by a validated high-performance liquid chromatography method with UV detection at a wavelength of 223 nm in which serum samples were spiked with chloramphenicol as internal standard. Serum concentration-time data after i.v. administration were best described by a three-compartment open model with values for the distribution half-lives (T(1/2alpha)) 1.51 +/- 0.06 and 1.59 +/- 0.10 h, elimination half-lives (T(1/2beta)) 18.83 +/- 6.76 and 18.71 +/- 1.85 h, total body clearance (Cl(B)) 0.26 +/- 0.03 and 0.25 +/- 0.01 L/kg/h, volume of distribution at steady-state (V(d(ss))) 1.86 +/- 0.11 and 1.71 +/- 0.20 L/kg, area under curve (AUC) 76.31 +/- 9.17 and 119.21 +/- 2.05 microg.h/mL after i.v. injections of 20 and 30 mg/kg b.w. respectively. Serum concentration-time data after i.m. administration were adequately described by a one-compartment open model. The pharmacokinetic parameters were distribution half-lives (T(1/2k(a) )) 0.27 +/- 0.03 and 0.25 +/- 0.09 h, elimination half-lives (T(1/2k(e) )) 10.34 +/- 1.11 and 9.57 +/- 2.84 h, maximum concentrations (C(max)) 4.13 +/- 0.29 and 7.04 +/- 1.61 microg/mL, area under curve (AUC) 67.95 +/- 9.61 and 101.95 +/- 8.92 microg.h/mL, bioavailability (F) 89.04% and 85.52% after i.m. injections of 20 and 30 mg/kg b.w. respectively.     

Pharmacokinetics of florfenicol in healthy and Escherichia coli-infected broiler chickens

The aims of this study were to evaluate the effects of a ketamine/propofol anaesthetic protocol in lions (Panthera leo), and to compare it to two commonly used anaesthetic protocols. Seventeen adult lions were anaesthetised using three different protocols. Group XK (n=6) was anaesthetised with intramuscular (i.m.) injections of xylazine and ketamine. Group KD (n=5) was anaesthetised with an i.m. injection of ketamine, followed by an intravenous (i.v.) injection of ketamine and diazepam. Group KP (n=6) was anaesthetised with an i.m. injection of ketamine followed by an i.v. injection of propofol. There was a significant difference in heart rate (P<0.0002), which was lowest in group XK and highest in KD. Jaw tone was significantly lower in Group XK (P<0.05). No undesirable effects were noted following injection of the propofol. Propofol was a suitable and safe drug for maintenance of anaesthesia in adult lions.     

Bioavailability and pharmacokinetics of ibuprofen in the broiler chicken

The intravenous, intramuscular and oral pharmacokinetics of ibuprofen in broiler chickens were investigated. In a preliminary study, plasma ibuprofen concentration-time profiles, following i.v. (25 mg/kg) dosing were best described by a 2-compartment model. After intravenous administration, the volume of distribution at steady-state ( V _d(ss)), the total systemic clearance ( Cl _B), the elimination half-life (t_1/2p) and the MRT were 0.303 L/kg, 482.3 ml/h-kg, 2.71 h and 1.02 h, respectively. After intramuscular administration of ibuprofen, the t _max and C _max were 0.37 h, and 42.2μg/mL, respectively, with an estimated bioavailability of 46.7%. After oral administration of ibuprofen, the t _max and C _max were 0.31 h and 23.91 μg/mL, respectively, with an estimated bioavailability of 24.2%. This is a preliminary study, examining the use of ibuprofen in broiler chickens, and should be followed by tissue residue and efficacy studies in different disease states.     

氟苯尼考磺酸盐在肉鸡体内的药物动力学初步研究

研究氟苯尼考磺酸盐在肉鸡体内的血药浓度及药动学特征。将12只健康三黄肉鸡,单次肌肉注射推荐治疗剂量（20mg／kg）的自制2％氟苯尼考磺酸盐。采用高效液相色谱法测定血浆药物浓度,所得数据用3P97药动软件进行分析后发现,血药浓度和时间关系符合一级吸收一室模型,选择的权重为1／C。主要药动学参数为T1／2kα：（0．28±0．04）h,T1/2Ke：（2．06±0．06）h,Cmax：（4．17±0．12）μg／mL,Tmax：（0．92±0．09）h,AUC：（16．89±0,35）μg／mL,V／F（c）：（3．52±0．13）L／kg,CL／F（s）：（1．19±0．03）L／（kg·h）,Ke：（0．34±0．01）／h,kα：（2．57±0．37）／h,A：（6．56±0．38）μg／mL。结果提示,氟苯尼考磺酸盐在肉鸡体内具有吸收迅速,分布广泛、峰浓度较高以及消除较快的动力学特征。     

Physicochemical characterization and pharmacokinetics in broiler chickens of a new recrystallized enrofloxacin hydrochloride dihydrate

Enrofloxacin, a key antimicrobial agent in commercial avian medicine, has limited bioavailability (60%). This prompted its chemical manipulation to yield a new solvate‐recrystallized enrofloxacin hydrochloride dihydrate entity (enro_C). Its chemical structure was characterized by means of mass spectroscopy, Fourier transformed infrared spectroscopy, X‐ray powder diffraction, and thermal analysis. Comparative oral pharmacokinetics (PK) of reference enrofloxacin (enro_R) and enro_C in broiler chickens after oral administration revealed noticeable improvements in key parameters and PK/PD ratios. Maximum serum concentration values were 2.61 ± 0.21 and 5.9 ± 0.42 μg/mL for enro_R and enro_C, respectively; mean residence time was increased from 5.50 ± 0.26 h to 6.20 ± 0.71 h and the relative bioavailability of enro_C was 336%. Considering C_max/MIC and AUC/MIC ratios and the MIC values for a wild‐type Escherichia coli O78/H12 (0.25 μg/mL), optimal ratios will only be achieved by enro_C (C_max/MIC = 23.6 and AUC/MIC = 197.7 for enro_C; vs. C_max/MIC = 10.4 and AUC/MIC = 78.1 for enro_R). Furthermore, enro_C may provide in most cases mutant prevention concentrations (C_max/MIC ≥ 16). Ready solubility of powder enro_C in drinking water at concentrations regularly used (0.01%) to provide an additional advantage of enro_C in the field. Further development of enro_C is warranted before it can be recommended for clinical use in veterinary medicine.     

氟苯尼考在猪的群体药动学

收集临床消化道和呼吸道细菌性疾病猪 2 15头 ,其中原种猪 91头 ,杂交商品猪 12 4头 ;公猪 112头 ,母猪 10 3头 ;体重范围 5～ 4 1kg,平均为 18.6 8± 0 .4 7;日龄 6 3～ 117天 ,平均为 85 .2 4± 0 .78。动物随机分为两组 ,第 1组动物数量为总体数量的 2 / 3,共 14 6头 ,为模型组 ,用于建立群体药动学模型 ;第 2组动物数量为总体动物数量的 1/ 3,共 6 9头 ,为验证组。给药前测定每头猪血清生化指标。试验猪颈部肌肉注射 30 %氟苯尼考注射液 ,剂量为 2 0 mg· kg- 1体重。给药前采一次空白血浆及血清 (测定血清生化指标 ) ,给药后随机采样 ,每只猪采样 2～ 4次 ,就整个群体而言使采样时间均匀分布于药物的吸收相、分布相和消除相内 ,采样时间为给药后 0 .183～ 4 8.36 7h,以高效液相色谱法测定血浆药物浓度 ,应用 NONMEM程序处理所收集的数据 ,包括药时数据、猪只的体重、日龄、性别、种属及血清生化指标、对研究组数据拟合发现最佳药动学模型为一级吸收一室模型 ,药动学参数随机效应及自身变异的最佳模型均为对数加法模型。体重对机体清除率、表观分布容积有显著影响 ,机体清除率、表观分布容积随体重的增加而增加 ,基本呈线性关系。种属对吸收速率常数有显著影响。把研究组得到的群体药动学参数值应用     

Estimating danofloxacin withdrawal time in broiler chickens based on physiologically based pharmacokinetics modeling

In this study, a physiologically based pharmacokinetics (PBPK) model was firstly developed for danofloxacin in healthy broiler chickens after a single oral administration at 5 mg/kg bw. Then, the model extrapolation from healthy chickens to those infected with Pasteurella multocidaones was performed. The healthy model was validated through a comparison of predicted and previously published concentrations, which indicated that the healthy PBPK model had good predictive ability in plasma, lung, muscle, liver, and kidney, especially at the later sampling time points. Multiple dosing of administration was incorporated into the healthy and infected models. In addition, a Monte Carlo simulation (MCS) included 1000 iterations was further incorporated into both models to predict the withdrawal times of danofloxacin in healthy and infected chickens, which were estimated to be 3 and 2 days, respectively.     

Comparative study of the plasma pharmacokinetics and tissue concentrations of danofloxacin and enrofloxacin in broiler chickens

The plasma pharmacokinetics of danofloxacin and enrofloxacin in broiler chickens was investigated following single intravenous (i.v.) or oral administration (p.o.) and the steady-state plasma and tissue concentrations of both drugs were investigated after continuous administration via the drinking water. The following dosages approved for the treatment of chickens were used: danofloxacin 5 mg/kg and enrofloxacin 10 mg/kg of body weight. Concentrations of danofloxacin and enrofloxacin including its metabolite ciprofloxacin were determined in plasma and eight tissues by specific and sensitive high performance liquid chromatography methods. Pharmacokinetic parameter values for both application routes calculated by noncompartmental methods were similar for danofloxacin compared to enrofloxacin with respect to elimination half-life (t1/2: approximately 6-7 h), mean residence time (MRT; 6-9 h) and mean absorption time (MAT; 1.44 vs. 1.20 h). However, values were twofold higher for body clearance (ClB; 24 vs. 10 mL/min. kg) and volume of distribution at steady state (VdSS; 10 vs. 4 L/kg). Maximum plasma concentration (Cmax) after oral administration was 0.5 and 1.9 micrograms/mL for danofloxacin and enrofloxacin, respectively, occurring at 1.5 h for both drugs. Bioavailability (F) was high: 99% for danofloxacin and 89% for enrofloxacin. Steady-state plasma concentrations (mean +/- SD) following administration via the drinking water were fourfold higher for enrofloxacin (0.52 +/- 0.16 microgram/mL) compared to danofloxacin (0.12 +/- 0.01 microgram/mL). The steady-state AUC0-24 h values of 12.48 and 2.88 micrograms.h/mL, respectively, derived from these plasma concentrations are comparable with corresponding area under the plasma concentration-time curve (AUC) values after single oral administration. For both drugs, tissue concentrations markedly exceeded plasma concentrations, e.g. in the target lung, tissue concentrations of 0.31 +/- 0.07 microgram/g for danofloxacin and 0.88 +/- 0.24 microgram/g for enrofloxacin were detected. Taking into account the similar in vitro activity of danofloxacin and enrofloxacin against important pathogens in chickens, a higher therapeutic efficacy of water medication for enrofloxacin compared to danofloxacin can be expected when given at the approved dosages.     

Intravenous and subcutaneous pharmacokinetics of florfenicol in sheep

Pharmacokinetic parameters of florfenicol were determined in 10 adult sheep (five wethers and five ewes) after a single 40 mg/kg intravenous (i.v.) dose, and three daily subcutaneous (s.c.) doses of 40 mg/kg of a commercial preparation (Nuflor((R))). The concentration of florfenicol in serum samples was assayed using a proprietary HPLC assay method, and pharmacokinetic parameters derived for individual animal data by each route using compartmental and noncompartmental approaches. Two animals (one male and one female) were excluded due to observed i.v. dosing problems, and a biexponential model was found to fit the i.v. data well for six of the other eight animals. Data from two males showed prolonged low concentrations of florfenicol in serum and were better fit by a three-compartment model. The mean +/- SD for the half-lives of the distribution and elimination phases for the six sheep best fit with a two-compartment model were 0.069 +/- 0.018 and 1.01 +/- 0.09 h respectively, and for the V(d(ss)) and clearances were 0.503 +/- 0.035 L/kg and 366 +/- 53 mL/h/kg respectively. The data collected during the s.c. multiple dose study were analyzed using noncompartmental methods only. The bioavailability (F%) after s.c. dosing was calculated in three ways to compare estimation methods as steady-state had not been reached and single dose s.c. data were not obtained past 24 h. Using the AUC(0--24) and AUC(0--> infinity ) from the first dose, the F% values averaged 27 and 40% respectively. Using the AUC(0--> infinity ) for all doses, the F% was 65%. Calculations of the mean time during which the serum concentration exceeded 0.5 and 1.0 microg/mL were 105 +/- 3.9 and 74.7 +/- 12.2 h respectively.     

Mycoplasma gallisepticum and Escherichia coli mixed infection model in broiler chickens for studying valnemulin pharmacokinetics

A Mycoplasma gallisepticum–Escherichia coli mixed infection model was developed in broiler chickens, which was applied to pharmacokinetics of valnemulin in the present experiment. The velogenic M. gallisepticum standard strain S6 was rejuvenated to establish the animal model, and the wild E. coli strain O78 was injected as supplementary inoculum to induce chronic respiratory disease in chickens. The disease model was evaluated based on its clinical signs, histopathological examination, bacteriological assay, and serum plate agglutination test. The pharmacokinetics of valnemulin in infected chickens was determined by intramuscular (i.m.) injection and oral administration (per os, p.o.) of a single dose of 10 mg/kg body weight (BW). Plasma samples were analyzed by liquid chromatography–tandem mass spectrometry. The plasma concentration–time curve of valnemulin was analyzed using the noncompartmental method. After the i.m. administration, the mean values of C_max, T_max, AUC_last, MRT, CL_β/F, V_z/F, and t_1⁄2β, were 27.94 μg/mL, 1.57 h, 171.63 μg·h/mL, 4.51 h, 0.06 L/h/kg, 0.56 L/kg, and 6.50 h, respectively. By contrast, the corresponding values after p.o. administration were 5.93 μg/mL, 7.14 h, 47.60 μg·h/mL, 9.80 h, 0.22 L/h/kg, 3.35 L/kg, and 10.60 h. The disposition of valnemulin was retarded in infected chickens after both modes of extravascular administration as compared to the healthy controls. More attention should be given to monitoring the therapeutic efficacy and adverse effects of mixed infection because of higher required plasma drug concentration and enlarged AUC with valnemulin treatment.     

Salt poisoning in broiler chickens

The incident occurred on a small, owner-operated broiler unit that used home-mixed feed. Two flocks of broilers, one aged 6 weeks and one aged 6 days, developed signs of watery diarrhoea, thirst and weakness. Over 3 days the mortality increased considerably and many birds were noticed to show laboured breathing. The majority of dead birds had an excess of clear fluid in the pericardial sac, oedematous lungs and pale swollen kidneys. Cystic dilation of the testes was conspicuous in several birds from the younger flock killed at 12 days of age. This lesion is a specific indication of sodium toxicity in young broilers. Histological lesions were those associated with cardiovascular collapse and hypoxia. Liver levels of sodium chloride were 4 g/kg of wet weight. Broiler feed samples contained more than 7% sodium chloride whereas the nutritional specifications were for 0.4%. The rations had been correctly mixed and the problem was traced to a faulty batch of meatmeal that had been contaminated by salt used for curing hides.     

Campylobacter succession in broiler chickens

The competitive ability of Campylobacter coli OR12 over C. jejuni OR1 has been examined in experimental broiler chickens following the observation that C. coli replaced an established C. jejuni intestinal colonisation within commercial chicken flocks reared outdoors [El-Shibiny, A., Connerton, P.L., Connerton, I.F., 2005. Enumeration and diversity of campylobacters and bacteriophages isolated during the rearing cycles of free-range and organic chickens. Appl. Environ. Microbiol. 71, 1259-1266]. Co-cultures of C. coli OR12 with C. jejuni OR1, revealed that the two species were able to grow together at similar growth rates in exponential growth phase but if the disparity of the inoculum ratios were >log(10)4 in favour of C. coli OR12, C. jejuni OR1 was observed to prematurely enter decline phase. Chickens were pre-colonised with C. jejuni OR1 at 21-days-old to examine succession in vivo. The birds were inoculated between 2 and 12 days later with C. coli OR12, to determine if the second isolate could efficiently colonise and compete with an established C. jejuni strain. C. coli OR12 were able to co-colonise before replacing C. jejuni OR1 as the dominant species when the birds were more than 27 days of age at the time of administration over a 4-day period. If these criteria were met C. coli OR12 became the dominant isolate otherwise co-colonisation occurred until they were met. C. coli OR12 was also found to displace three alternative C. jejuni strains from pre-colonised chickens challenged with C. coli OR12 at 30 days of age and tested at 40 days. These data raise the possibility of manipulating populations of Campylobacter colonising chickens through competition.     

Swollen-head syndrome in broiler chickens

Swollen-head syndrome is a disease seen in broiler chickens between 4 and 6 weeks of age in Southern Africa. It appears to be caused by a mixed coronavirus and Escherichia coli infection. The coronavirus appears to be of a hitherto unrecorded serotype. The disease is controlled by an attenuated live-virus vaccine and antibacterial medication.     

Salt poisoning in broiler chickens

The clinical signs of salt poisoning in young chickens are thirst, diarrhoea and weakness. When 13 500 broilers are simultaneously affected, the deterioration that occurs in their physical condition and in the litter beneath their feet is dramatic. Two flocks of meat chickens on a small unit in North Otago were affected in this way.