Pharmacokinetics and bioavailability of spectinomycin after i.v., i.m., s.c. and oral administration in broiler chickens

A pharmacokinetic and bioavailability study of spectinomycin was conducted in healthy broiler chickens following administration of a single (50 mg/kg bw) intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) dose and oral doses of 50 and 100 mg/kg bw. Following i.v. administration, the elimination half-life (t1/2beta), mean residence time (MRT), volume of distribution at steady-state (Vd(ss)), volume of distribution based on the terminal phase (Vd(z)) and total body clearance (ClB) were 1.46+/-1.10 h, 1.61+/-1.05 h, 0.26+/-0.009 L/kg, 0.34 (0.30-0.38) L/kg and 2.68+/-0.017 mL/min/kg respectively. After i.m. and s.c. dosing, the Cmax was 152.76+/-1.08 and 99.77+/-1.04 microg/mL, achieved at 0.25 (0.25-0.50) and 0.25 (0.25-1.00) h, the t1/2beta was 1.65+/-1.07 and 2.03+/-1.06 h and the absolute bioavailability (F) was 136.1% and 128.8% respectively. A significant difference in Cmax (5.13+/-0.10, 14.26+/-1.12 microg/mL), t1/2beta (3.74+/-1.07, 8.93+/-1.13 h) and ClB/F (22.69+/-0.018, 10.14+/-0.018 mL/min/kg) were found between the two oral doses (50 and 100 mg/kg bw respectively), but there were no differences in the tmax [2.00 (2.00-4.00), 2.00 (2.00-2.00) h] and Vd(z)/F [6.95 (6.34-9.06), 7.98 (4.75-10.62) L/kg). The absolute bioavailability (F) of spectinomycin was 11.8% and 26.4% after oral administration of 50 and 100 mg/kg bw respectively.     

Pharmacokinetics and bioavailability of nimesulide in goats

The pharmacokinetic properties and bioavailability of cyclooxygenase (COX)-2 selective nonsteroidal anti-inflammatory drug nimesulide were investigated in female goats following intravenous (i.v.) and intramuscular (i.m.) administration at a dose of 4 mg/kg BW. Blood samples were collected by jugular venipuncture at predetermined times after drug administration. Plasma concentrations of nimesulide were determined by a validated high-performance liquid chromatography method. Plasma concentration-time data were subjected to compartmental analysis and pharmacokinetic parameters for nimesulide after i.v. and i.m. administration were calculated according to two- and one-compartment open models respectively. Following i.v. administration, a rapid distribution phase was followed by the slower elimination phase. The half-lives during the distribution phase (t1/2alpha) and terminal elimination phase (t1/2beta) were 0.11+/-0.10 and 7.99+/-2.23 h respectively. The steady-state volume of distribution (Vd(ss)), total body clearance (ClB) and mean residence time (MRT) of nimesulide were 0.64+/-0.13 L/kg, 0.06+/-0.02 L/h/kg and 11.72+/-3.42 h respectively. After i.m. administration, maximum plasma concentration (Cmax) of nimesulide was 2.83+/-1.11 microg/mL attained at 3.6+/-0.89 h (tmax). Plasma drug levels were detectable up to 72 h. Following i.m. injection, the t1/2beta and MRT of nimesulide were 1.63 and 1.73 times longer, respectively, than the i.v. administration. The bioavailability of nimesulide was 68.25% after i.m. administration at 4 mg/kg BW. These pharmacokinetic data suggest that nimesulide given intramuscularly may be useful in the treatment of inflammatory disease conditions in goats.     

Pharmacokinetics of sarafloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applications

Pharmacokinetics of sarafloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of 5 (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analysed by a noncompartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t1/2beta) were 3.37 +/- 0.46, 4.66 +/- 1.34, 7.20 +/- 1.92 (pigs) and 2.53 +/- 0.82, 6.81 +/- 2.04, 3.89 +/- 1.19 h (broilers), respectively. After i.m. and p.o. doses, bioavailabilities (F) were 81.8 +/- 9.8 and 42.6 +/- 8.2% (pigs) and 72.1 +/- 8.1 and 59.6 +/- 13.8% (broilers), respectively. Steady-state distribution volumes (Vd(ss)) of 1.92 +/- 0.27 and 3.40 +/- 1.26 L/kg and total body clearances (ClB) of 0.51 +/- 0.03 and 1.20 +/- 0.20 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), mean residence times (MRT), and mean absorption times (MAT) were also determined. Sarafloxacin was demonstrated to be more rapidly absorbed, more extensively distributed, and more quickly eliminated in broilers than in pigs. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 10 mg/kg given intramuscularly every 12 h in pigs, or administered orally every 8 h in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC90 are <0.25 microg/mL.     

Pharmacokinetics of levamisole in rabbits after intravenous administration

A compartmental and non-compartmental pharmacokinetic study was carried out on rabbits after intravenous (i.v.) administration of levamisole at the three dose rates: 12.5, 16.0 and 20.0 mg/kg body weight. Using compartmental analysis, the disposition of levamisole best fitted a two-compartmental open model with mean values of alpha = 0.1278, 0.1019 and 0.1282 min-1; beta = 0.0139, 0.0126 and 0.0124 min-1; A = 6.24, 5.27 and 10.58 micrograms/ml and B = 2.14, 3.83 and 5.08 micrograms/ml for each dose, respectively. The statistical moment theory was mainly used for non-compartmental analysis. Values for mean residence time (MRT) of 69.2, 71.7 and 73.1 min were obtained for each dose. The mean values for volume of distribution at steady state (Vd(ss)), determined by compartmental analysis, were 3879, 3279 and 2735 ml/kg for each dose, and values obtained using the statistical moment theory were 3760, 3015 and 2943 ml/kg; there were no statistically significant differences using Student's paired t-test. Identical conclusions were obtained using both methods when the parameters beta, AUC and Cl were compared.     

Pharmacokinetics of diclofenac and its interaction with enrofloxacin in sheep

The pharmacokinetics of diclofenac was investigated in sheep given diclofenac alone (1mgkg(-1), i.v. or i.m.) and in combination with enrofloxacin (5mgkg(-1), i.v.). The plasma concentration-time data following i.v. administration of diclofenac was best described by a two compartment open pharmacokinetic model. The elimination half-life (t(1/2beta)), area under concentration-time-curve (AUC), volume of distribution (Vd(area)), mean residence time (MRT) and total body clearance (Cl(B)) were 1.03+/-0.18h, 12.17+/-1.98microg h ml(-1), 0.14+/-0.02Lkg(-1), 1.36+/-0.16h and 0.10+/-0.02Lkg(-1)h(-1), respectively. Following i.m. administration of diclofenac alone and in conjunction with enrofloxacin, the plasma concentration-time data best fitted to a one compartment open model. The t(1/2beta), AUC, Vd(area), MRT and Cl(B) were 1.33+/-0.10h, 7.32+/-1.01microg h mL(-1), 0.13+/-0.01Lkg(-1) and 0.07+/-0.01Lkg(-1)h(-1), respectively. Co-administration of enrofloxacin did not affect Vd(area) and MRT but absorption rate constant (K(a)), beta, t1/2Ka, t1/2beta, AUC, AUMC, Cl(B) and bioavailability (F) were significantly increased. This may be due to direct inhibition of cytochrome P(450) isozymes by enrofloxacin. A dose of 1.4mgkg(-1) of diclofenac administered every 6h may be appropriate for use in sheep.     

Pharmacokinetics of tylosin in broiler chickens

Biological availability and pharmacokinetic properties of tylosin were determined in broiler chickens after oral (p.o.) and intravenous (i.v.) administration at a dose of 10 mg/kg. The calculated bioavailability--F%, by comparing AUC values--p.o. and AUC--i.v., ranged from 30%-34%. After intravenous injection tylosin was rapidly distributed in the organism, showing elimination half-life (t1/2 beta) values of 0.52 h and distribution volume (Vd) of 0.69 L/kg, at a clearance rate (Cl) of 5.30 +/- 0.59 ml/min/kg. After oral administration, tylosin has a similar distribution volume (Vd = 0.85 L/kg), while the elimination half-life t1/2 beta of 2.07 h was four times bigger than after i.v. administration at Cl = 4.40 +/- 0.27 ml/min/kg. The obtained value tmax = 1.5 h for tylosin after oral administration indicates that using this antibiotic with drinking water in broiler chickens is the method of choice. However, a relatively low value Cmax = 1.2 micrograms/ml after oral administration of tylosin shows that dosing of this antibiotic in broiler chickens should be higher than in other food producing animals.     

Disposition kinetics of doxycycline in chickens naturally infected with Mycoplasma gallisepticum

1. The pharmacokinetic properties of doxycycline were determined in healthy chickens and chickens naturally infected with Mycoplasma gallisepticum after a single intravenous (i.v.) and oral administration of the drug at 20 mg/kg body weight. Tissue residues of the tested drug after an oral dose of 20 mg/kg given twice daily for 5 consecutive days were also estimated in diseased chickens. 2. The plasma concentrations of doxycycline following single i.v. and oral administration were higher in healthy chickens than in diseased ones. Following i.v. injection, the elimination half-life (t1/2beta), distribution half-life and mean residence time (MRT) were longer in healthy chickens than in diseased birds. The values of total body clearance (ClB) and volume of distribution (Vdss) were larger in healthy chickens than in diseased birds. 3. After single oral administration, the absorption half-life (tl/2ab) and the elimination half-life were longer in normal birds than in diseased ones. The maximum plasma concentration of the drug was higher in normal chickens than in diseased ones. 4. Following repeated oral administration, the concentration of doxycycline in all tissues except muscle was higher than the corresponding concentrations in plasma. Concentrations of doxycycline in different tissues were in the following order: kidney > liver > lung > muscle. The drug was detected in liver and kidney in substantial concentrations on d 5 post administration of the last dose whereas, on d 7, its concentration in all tissues was below the lower limit of the sensitivity of the assay method used. Because of the low sensitivity of the microbiological assay method used in this study, a safe withdrawal time for doxycycline in diseased birds could not be estimated for the meanwhile.     

加丽素红中角黄素在鸡体内的药代动力学研究

本试验旨在探讨加丽素红中角黄素在鸡体内的药代动力学特征.选取19周龄的海兰蛋鸡12只,单次灌胃口服加丽素红9.6 mg/kg BW,在72 h内不同时间段分10次采集静脉血,用高效液相色谱法测定鸡血清中角黄素的质量浓度,并利用3P97药代动力学程序软件处理血药浓度-时间数据.结果如下:加丽素红经口服给药后,角黄素在鸡体内的血药浓度-时间数据符合一级吸收一室模型,其理论方程为C=0.471(e-0.036-e-0.190),主要药代动力学参数为:吸收半衰期t1/2(Ka)=(3.643±0.205)h,消除半衰期t1/2(Ke)=(19.263±1.312)h,达峰时间Tmax=(10.795±1.007)h,达峰浓度Cmax=(0.259±0.048)μg/mL,血药浓度-时间曲线下面积AUC=(10.607±1.029)μg/(mL·h),总体清除率CLB=(0.905±0.076)L/(kg·h),表观分布容积Vd=(2.515±0.133)L/kg.上述结果表明,角黄素在鸡体内血药浓度的变化表征了加丽素红在鸡体内代谢的变化规律,具有吸收分布较迅速、达峰快、体内分布广泛、消除速度较慢等特点.     

Pharmacokinetics of buprenorphine following intravenous administration in dogs

OBJECTIVE: To determine pharmacokinetics of buprenorphine in dogs after i.v. administration. ANIMALS: 6 healthy adult dogs. PROCEDURES: 6 dogs received buprenorphine at 0.015 mg/kg, i.v. Blood samples were collected at time 0 prior to drug administration and at 2, 5, 10, 15, 20, 30, 40, 60, 90, 120, 180, 240, 360, 540, 720, 1,080, and 1,440 minutes after drug administration. Serum buprenorphine concentrations were determined by use of double-antibody radioimmunoassay. Data were subjected to noncompartmental analysis with area under the time-concentration curve to infinity (AUC) and area under the first moment curve calculated to infinity by use of a log-linear trapezoidal model. Other kinetic variables included terminal rate constant (k(el)) and elimination half-life (t(1/2)), plasma clearance (Cl), volume of distribution at steady state (Vd(ss)), and mean residence time (MRT). Time to maximal concentration (T(max)) and maximal serum concentration (C(max)) were measured. RESULTS: Median (range) values for T(max) and MRT were 2 minutes (2 to 5 minutes) and 264 minutes (199 to 600 minutes), respectively. Harmonic mean and pseudo SD for t(1/2) were 270+/-130 minutes; mean +/- SD values for remaining pharmacokinetic variables were as follows: C(max), 14+/-2.6 ng/mL; AUC, 3,082+/-1,047 ng x min/mL; Vd(ss), 1.59+/-0.285 L/kg; Cl, 5.4+/-1.9 mL/min/kg; and, k(el), 0.0026+/-0.0,012. CONCLUSIONS AND CLINICAL RELEVANCE: Pharmacokinetic variables of buprenorphine reported here differed from those previously reported for dogs. Wide variations in individual t(1/2) values suggested that dosing intervals be based on assessment of pain status rather than prescribed dosing intervals.     

Interspecies differences in the pharmacokinetics of kanamycin and apramycin

Comparative studies on some selected pharmacokinetic parameters for kanamycin in sheep, goats, rabbits, chickens and pigeons, and for apramycin in sheep, rabbits, chickens and pigeons were carried out after intravenous administration of the two drugs at a dose of 10 mg/kg. The results revealed that a two-compartment open model was most suitable for kanamycin, while for apramycin a one-compartment open model was usually optimal. The log distribution rate constant (alpha) of kanamycin was significantly correlated to the log of the body mass (r = 0.919, n = 5, p < 0.05). Interspecies differences in the apparent volume of distribution (Vda) of kanamycin were small. These differences were larger for apramycin, as were the variations in the area under the serum concentration-time curve (AUC) and in the total body clearance (ClB) of both kanamycin and apramycin, both having almost a threefold difference depending on the species but without any correlation to body mass. The values of the log half-life of kanamycin in the mammals in this study and also those from data in the literature revealed a significant correlation with log body mass between animal species according to the equation: t1/2 beta = 38.47W0.21 (r = 0.7648, n = 10, p < 0.05).     

Pharmacokinetics of oxytetracycline in the American horseshoe crab, Limulus polyphemus

The American horseshoe crab, Limulus polyphemus, is regularly cultured and maintained in research laboratories and public aquaria. Rising concerns over the health of these captive animals makes the diagnosis and treatment of pathological conditions in L. polyphemus essential. This study investigated the kinetics of oxytetracyline following either intravascular or oral dosing. Oxytetracylcine is a broad-spectrum antibiotic used in the treatment of various bacterial diseases of aquatic animals. A noncompartmental model was developed to describe the pharmacokinetics of oxytetracycline (OTC) in the horseshoe crab. The following parameters were determined for a single intravascular bolus of 25 mg/kg OTC: AUC = 9524.60 microg.h/mL, MRT = 443.65 h, Clb = 0.044 mL/min/kg, Vd(ss) = 1.164 L/kg, t(1/2) = 128.3 h, Cmax = 55.90 microg/mL, C(ave) = 27.39 microg/mL. Following a single oral bolus of 25 mg/kg, these parameters were calculated: AUC = 5861.81 microg.h/mL, MRT = 395.89 h, Clb = 0.071 mL/min/kg, Vd(ss) = 1.688 L/kg, t(1/2) = 210.0 h, Cmax = 7.83 microg/mL, C(ave) = 2.89 microg/mL, F = 61.56%.     

Pharmacokinetics of pentobarbital and thiamylal as combined anesthetics in sheep

This study was performed to investigate the possible mechanisms underlying prolongation of anesthesia times in sheep caused by the sequential administration of thiamylal and pentobarbital. Sodium thiamylal was injected as an intravenous bolus dose (13.2 mg/kg) followed in 7 min by sodium pentobarbital (14.3 mg/kg) by the same route to seven sheep. Separate studies were conducted for each of the two drugs administered separately to the same animals at the same doses. Mean anesthesia times (to the return of the palpebral reflex) were 7.89 min (thiamylal), 5.39 min (pentobarbital) and 34.1 min (the sequential combination). The kinetic parameters Vd(area), Vd(ss), t 1/2 beta, and ClB for either drug were not affected by the other when given in combination. The t 1/2 alpha was shorter, and the Vc was smaller, for pentobarbital when administered with thiamylal, while there were no changes in thiamylal disposition for the combination regimen. Computer-generated curves, associated with the two-compartment open model showing the fraction of dose in each compartment as a function of time, illustrated that pentobarbital rapidly achieved higher concentrations in the peripheral compartment after prior thiamylal administration. Protein-binding studies showed that this could not be attributed to displacement of pentobarbital from plasma albumin by thiamylal. Calculation of total and free drug concentrations at the time of awakening showed that, when the drugs were combined, the concentration of each drug was less than half of that observed at awakening when they were studied separately. It can be concluded that the prolonged sleeping times associated with the sequential combination of the two agents were not due to an alteration in kinetic parameters of either drug caused by the other, but rather to an additive effect of the subanesthetic concentrations of the two drugs when combined. The fact that sleeping times were supra-additive is attributed to a shift of awakening time from the distribution (alpha) phase, when given independently, to the elimination (beta) phase when administered in combination.     

Pharmacokinetics and pharmacodynamics of A77 1726 and leflunomide in domestic cats

The pharmacokinetics and pharmacodynamics of A77 1726 and leflunomide after intravenous (i.v.) and oral (p.o.) administration were evaluated in adult cats. Three treatments were administered: a single i.v. dose of A77 1726 (4 mg/kg), a single oral dose of leflunomide (4 mg/kg), and multiple oral doses of leflunomide (2 mg/kg). Mean pharmacokinetic parameter values after a single i.v. dose of A77 1726 were distribution (A) and elimination (B) intercepts (15.2 μg/mL and 34.5 μg/mL, respectively), distribution and elimination half-lives (1.5 and 71.8 h, respectively), area under the curve (AUC(0 → ∞); 3723 μg*h/mL), mean residence time (MRT; 93 h), clearance (Cl(obs); 1.1 mL/kg/h), and volume of distribution at steady state (Vd(ss); 97 mL/kg). Mean pharmacokinetic parameter values after a single oral dose of leflunomide were absorption and elimination rate constants (0.3 1/h and 0.01 1/h, respectively), absorption and elimination half-lives (2.3 and 59.1 h, respectively), AUC(0 → ∞) (3966 μg*h/mL), and maximum observed plasma concentration (C(max); 38 μg/mL). The bioavailability after a single oral dose of leflunomide was 100%. The mean ± SD A77 1726 concentration that inhibited 50% lymphocytes (EC(50) ) was 16 ± 13.5 μg/mL. The mean ± SD maximum A77 1726 concentration (EC(max)) was 61.0 ± 23.9 μg/mL.     

Pharmacokinetics of Amikacin in Lactating Sheep

The pharmacokinetics of amikacin (AMK) were investigated after intravenous (i.v.) and intramuscular (i.m.) administration of 7.5 mg/kg bw in 6 healthy lactating sheep. After i.v. AMK injection (as a bolus), the elimination half-life (t1/2beta), the volume of distribution (Vd,area), the total body clearance (ClB) and the area under the concentration-time curve (AUC) were 1.64 +/- 0.06 h, 0.19 +/- 0.02 L/kg, 1.36 +/- 0.1 ml/min per kg and 94.09 +/- 6.95 (microg.h)/ml, respectively. The maximum milk concentration of AMK (Cmax), the area under the milk concentration-time curve (AUCmilk) and the ratio AUCmilk/AUCserum were 1.18 +/- 0.22 microg/ml, 22.45 +/- 3.21 (micro.h)/ml and 0.24 +/- 0.02, respectively. After i.m. administration of AMK the t1/2beta, Cmax, time of Cmax (tmax) and absolute bioavailability (Fabs) were 1.29 +/- 0.1 h, 16.97 +/- 1.54 microg/ml, 1.0 +/- 0 h and 64.88% +/- 6.16%, respectively. The Cmax, AUCmilk and the ratio AUCmilk/AUCserum were 0.33 microg/ml, 1.67 (microg.h)/ml and 0.036, respectively.     

Enrofloxacin‐based therapeutic strategy for the prevention of endometritis in susceptible mares

González, C., Moreno, L., Fumuso, E., García, J., Rivulgo, M., Confalonieri, A., Sparo, M., Sanchez Bruni, S. Enrofloxacin‐based therapeutic strategy for the prevention of endometritis in susceptible mares. J. vet. Pharmacol. Therap. 33 , 287–294. Enrofloxacin (EFX) is often used empirically to prevent uterine infections in mares in order to improve efficiency on Commercial Embryo Transfer Farms. This study investigated the uterine distribution of EFX and its metabolite ciprofloxacin (CFX) in mares and assessed the minimal inhibitory concentrations (MIC) of EFX against various common pathogens as a basis for establishing a rational dosing schedule. Plasma and uterine pharmacokinetic (PK) studies were performed in two groups (n = 5) of healthy mares following intravenous (i.v.) administration of EFX at either 2.5 and at 5 mg/kg bodyweight. Plasma and endometrial tissue samples, taken before for up to 48 h after treatment were analysed by Reverse Phase HPLC. MIC values for wild strains of Gram‐negative (Escherichia coli, Pseudomonas aeruginosa) and Gram‐positive bacteria (β‐haemolytic streptococci) ranged from 0.25–2 and 1.5–3.0 μg/mL respectively. In terms of tissue distribution, the sum of the endometrial concentrations of the parent drug (EFX) and its active metabolite (CFX) (in terms of AUC), exceeded those in plasma by 249% and 941% following administration of EFX at 2.5 and 5 mg/kg respectively. After i.v. treatment with EFX at 5 mg/kg, endometrial concentrations of EFX and CFX above the MIC value were detected for 36–48 and 22–43 h posttreatment for Gram‐negative and ‐positive isolates respectively. Concentrations above MIC were maintained for much shorter periods at the lower (2.5 mg/kg) treatment dose. Based on these results, a conventional dose (5 mg/kg) of EFX given prebreeding followed by two further doses at 36–48 h postbreeding are proposed as a rational strategy for using of EFX as a preventative therapy against a variety of common bacterial strains associated with equine endometritis.     

喹烯酮在鸡体内的代谢及药物动力学研究

以HPLC-MS/MS为定量手段,研究了喹烯酮经静脉注射(2.5 mg/kg)、口服(30 mg/kg)两种给药途径在鸡体内的代谢及药物动力学特征.鸡静脉注射喹烯酮后,血浆中检测到喹烯酮原药和1-脱氧喹烯酮;口服灌注喹烯酮后,血浆中检测到喹烯酮原药和3-甲基喹噁啉-2-羧酸(MQCA).喹烯酮在鸡体内的药动学数据采用统...     

The lack of effect of inoculation with equine influenza vaccine on theophylline pharmacokinetics in the horse

Several studies conducted during the past few years have shown that the pharmacokinetics of a variety of drugs may be altered following viral infection or vaccination. The elimination of drugs which are extensively metabolized, such as theophylline, may be prolonged, especially following exposure to RNA viruses such as Type A influenza or similar orthomyxoviruses. The purpose of this study was to determine whether vaccination of horses with equine influenza virus affected pharmacokinetic parameters describing the distribution and elimination of intravenously administered theophylline. Three thoroughbred horses and three ponies were vaccinated with a trivalent vaccine containing inactivated strains of A/Equi 1 (Prague), A/Equi 2 (Miami) and A/Equi 2 (Kentucky 81). Antibody titre, serum interferon concentrations, and the pharmacokinetic parameters t1/2 beta, Vc, Vd(ss), Vd(area) and ClB were measured at various intervals after vaccination. Antibody titre increased substantially in only two animals, while plasma interferon was detectable in low concentrations in four subjects. There was no significant change in any parameter describing the pharmacokinetics of theophylline when measured 2, 6, or 12 days after vaccination. It is suggested that the failure of vaccination to substantially increase plasma interferon concentrations, and thereby alter theophylline elimination, was related to the use of an inactivated viral vaccine, the only type available for vaccination of horses against infection with equine influenza. Regular use of such vaccines, as is required by most Racing Authorities, is therefore unlikely to affect drug withdrawal times.     

Effects of experimentally induced Theileria annulata infection on the pharmacokinetics of oxytetracycline in cross-bred calves

The effects of an experimental Theileria annulata infection on the intravenous (10 mg kg-1) pharmacokinetics of oxytetracycline (OTC) were investigated in crossbred calves. The serum concentration-time curve of oxytetracycline before and after the experimental infection was best described by an open two-compartment model. The experimental infection was induced by a subcutaneous administration of ground-up tick supernate (GUTS) equivalent to 30 Hyalomma anatolicum anatolicum ticks infected with Theileria annulata. It produced a definite temperature rise and symptoms of clinical disease in the calves. The haemoglobin, packed cell volume (PCV), white blood cell (WBC) counts and serum Cu, Fe and Zn concentrations decreased after onset of the infection. The distribution and elimination half-lives (t1/2 alpha and t1/2 beta), volume of the central compartment (Vc), AUC0-infinity, AUMC and mean residence time (MRT), were significantly reduced (P < or = 0.05) and the hybrid rate constants K12, Kel, K12/K21 ratio and total body clearance (ClB) of oxytetracycline were significantly (P < or = 0.05) increased after infection. The infection, however, had no effect on the C0, K21, apparent and steady-state volumes of distribution (Vd(area) and Vdss) of the drug. The above changes may necessitate changes in the dosage regimen of oxytetracycline used to treat Theileria infections in cattle under field conditions.     

Lack of inhibitory effects of several fluoroquinolones on cytochrome P-450 3A activities at clinical dosage in dogs

Inhibitory effects of several fluoroquinolones (FQs) on liver CYP3A activities were examined by in vitro and in vivo tests in dogs. Midazolam (MDZ) hydroxylation rate was used to determine the CYP3A activities in liver microsomes. Enrofloxacin (EFX), ofloxacin (OFX) orbifloxacin (OBFX) and ciprofloxacin (CFX) were tested. None of the FQs changed Vmax, Km or intrinsic clearance (Vmax/Km) of MDZ. For in vivo test, we examined the effects of oral administration of EFX and OFX on the pharmacokinetics of quinidine (QN), a CYP3A substrate. EFX or OFX (10 mg/kg) was administered once a day for 3 days. QN (2 mg/kg) was intravenously injected at 2 h after the final dose of FQs administration. The same dose of QN was intravenously injected 3 weeks before the start of FQs administration for control. Neither EFX nor OFX changed the pharmacokinetic parameters of QN. These in vitro and in vivo consisted results suggest that these FQs lack the inhibitory effects on CYP3A activities in dogs. Hence, given these results, the risk of drug-drug interaction is unlikely to occur between FQs and CYP3A substrates in clinical situation in dogs.     

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.