Pharmacokinetics of enrofloxacin and marbofloxacin in Japanese quails and common pheasants.

The pharmacokinetics of enrofloxacin and marbofloxacin was studied in Japanese quails and common pheasants. Healthy mature birds from both species and both genders were treated intravenously and orally with enrofloxacin (10 mg/kg) and marbofloxacin (5 mg/kg). After intravenous administration enrofloxacin was extensively metabolised to ciprofloxacin. Metabolites of marbofloxacin were not detected. Values of volume of distribution were respectively 4.63 l/kg and 3.67 l/kg for enrofloxacin and 1.56 l/kg and 1.43 l/kg for marbofloxacin. In quails, total body clearance values were higher than those in pheasants and other avian species. After oral application enrofloxacin was rapidly absorbed in quails, more rapidly than marbofloxacin. Pheasants absorbed both antimicrobials at a lower rate. Higher bioavailability was observed for marbofloxacin (118%). Relatively low bioavailability was established in quails for enrofloxacin (26.4%), accompanied by extensive conversion to ciprofloxacin. Generally, quails absorbed and eliminated both fluoroquinolones more rapidly than pheasants; the latter showed pharmacokinetics similar to poultry. Because of favourable pharmacokinetic properties, marbofloxacin should be preferred for oral administration in Japanese quails and pheasants for treatment of infections caused by equally susceptible pathogens.

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.

Expression of MDR1, MRP2 and BCRP mRNA in tissues of turkeys.

MDR1, MRP2 and BCRP are members of the superfamily of ABC membrane transporters that export a large variety of structurally diverse substances out of the cell, hence being an integral part of various biological barriers. Here we report for the first time the tissue distribution of these ABC efflux transporters in the gastrointestinal tract (crop, proventriculus, duodenum, proximal and distal jejunum, ileum, caecum, colon) as well as in liver, kidney, lung, brain, adrenal gland, ovaries, oviduct and testes in BUT9 turkeys. MDR1 and BCRP mRNA expression was detected in all tissue samples, and the highest levels were measured in the small intestines. The tissue distribution of MRP2 mRNA was less consistent and some tissues seemed to lack any significant expression. Moreover, in consideration of previous findings suggesting that fluoroquinolones are substrates and modulators of ABC transporters, the effect of orally administered danofloxacin mesylate on the levels of MDR1, MRP2 and BCRP mRNA expression was investigated. Danofloxacin treatment resulted in a significant up-regulation of the measured transporters at the transcriptional level in the upper part of gastro-intestinal tract, liver and kidneys as well as in barrier-protected organs, such as the brain. However, despite this significant increase in the transcription levels, the pharmacokinetic parameters after repeated application of danofloxacin mesylate were not significantly altered.

Pharmacokinetic studies on tobramycin in horses.

The objective of the study was to evaluate the pharmacokinetics of tobramycin in plasma and urine in the horse (n = 7) after intravenous administration of a dose of 4 mg/kg b.w. Plasma tobramycin concentrations were assayed microbiologically and by means of HPLC analyses. Pharmacokinetic parameters, calculated on the basis of concentrations determined with the microbiological assay were not statistically different from those obtained when data from HPLC analysis were used, but the microbiological assay was more sensitive in the detection of low plasma and urine values. The values of the total body clearance (Cl(B)) were 101.4 +/- 30.1 and 130.0 +/- 49.9 mL/kg/h, respectively. The overall extraction ratio was 2.9%. The determined capacity of elimination of tobramycin in horses was similar to those for other aminoglycosides. Within 24 h after treatment, 57.6 +/- 12.2% of injected antibiotic was excreted in the urine.

Pharmacokinetics of enrofloxacin in turkeys.

The pharmacokinetics of enrofloxacin (EFL) and its active metabolite ciprofloxacin (CIP) was investigated in 7-8 month old turkeys (6 birds per sex). EFL was administered intravenously (i.v.) and orally (p.o.) at a dose 10 mg kg(-1) body weight. Blood was taken prior to and at 0.17, 0.33, 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 h following drug administration. The concentrations of EFL and CIP in blood serum were determined by high-performance liquid chromatography (HPLC). Serum concentrations versus time were analysed by a noncompartmental analysis. The elimination half-live and the mean residence time of EFL after i.v. injection for the serum were after oral administration 6.64+/-0.90 h, 8.96+/-1.18 h and 6.92+/-0.97 h, 11.91+/-1.87 h, respectively. After single p.o. administration, EFL was absorbed slowly (MAT=2.76+/-0.48 h) with time to reach maximum serum concentrations of 6.33+/-2.54 h. Maximum serum concentrations was 1.23+/-0.30 microg mL(-1). Oral bioavailability for for EFL after oral administration was found to be 69.20+/-1.49%. The ratios C(max)/MIC and AUC(0 --> 24)/MIC were respectively from 161.23+/-5.9 h to 12.90+/-0.5 h for the pharmacodynamic predictor C(max)/MIC, and from 2153.44+/-66.6 h to 137.82+/-4.27 h for AUC(0 --> 24)/MIC, for the different clinically significant microorganisms, whose values for MIC varies from 0.008 microg L(-1) to 0.125 microg mL(-1).

Pharmacokinetic-pharmacodynamic modelling of danofloxacin in turkeys.

Colibacillosis is a systemic disease responsible for important economic losses in poultry breeding; fluoroquinolones, including danofloxacin, are used to treat diseased animals. The purpose of the present study was to estimate pharmacokinetic-pharmacodynamic (PK-PD) surrogates for bacteriostasis, bactericidal activity and bacterial elimination against Escherichia coli O78/K80, using a PK-PD approach, for danofloxacin in turkeys after oral administration. Eight healthy turkeys, breed BUT 9, were included in a two-way crossover study. The drug was administered intravenously (i.v.) and orally at a dose rate of 6 mg/kg bw. The values of the elimination half-life and the total body clearance after i.v. administration were 8.64 +/- 2.35 h and 586.76 +/- 136.67 ml kg(-1)h(-1), respectively. After oral administration, the values of the absolute bioavailability and the elimination half-life were 78.37+/- 17.35% and 9.74+/- 2.93 h, respectively. The minimum inhibitory concentration against the investigated strain in turkey serum was 0.25 microg/ml, four times higher than in broth. The lowest effective ex vivo AUC(24)/MIC ratios required for bacteriostasis, bactericidal activity, and total killing of E. coli O78/K80 were 0.416 h, 1.9 h and 6.73 h, respectively. The oral dose of 6 mg/kg used in the present study could be interpreted as being sufficient to eliminate E. coli with an MIC 0.25 microg/ml. However, considering the demand that antimicrobial resistance should be avoided by complete bacterial elimination, PK-PD considerations suggest that an even higher dose of 32 mg/kg per day or 0.7 mg/kcal per day should be evaluated in clinical trials.

Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin in male and female turkeys following intravenous and oral administration.

The pharmacokinetics of enrofloxacin (EFL) was investigated in turkeys (6 male and 6 female; 7-month-old at the start of the experiment), after intravenous and oral administration at a dose of 10 mg/kg body weight. The serum concentrations of EFL and its active metabolite ciprofloxacin (CFL) were determined by high-performance liquid chromatography. The serum concentrations vs time were analysed by a compartmental analysis. The mean values of EFL pharmacokinetic parameters showed differences only between values of V(d,ss) (3.46+/-0.19 for the females and 4.53+/-0.11 L/kg for the males, p>0.05). The metabolite CFL was eliminated more slowly than its parent compound. There were no statistically significant differences between the values of the CFL pharmacokinetic parameters calculated for both sexes, excluding the higher values (p>0.05) of C(max) in the females. The ratio AUC(CFL)/AUC(EFL)x100 was 4.4% in the male and 6.84% in the female birds. After oral administration of EFL the values of F(%) were 77.83 in the female and 79.61 in the male turkeys. Higher CFL serum concentrations were measured in females (p>0.05). The pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin in turkeys can be characterized as similar to that in chickens and very similar between both sexes.

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.

Pharmacokinetics of enrofloxacin in lactating sheep.

The pharmacokinetics of enrofloxacin (ENR) was investigated after its intravenous (iv) and intramuscular (im) administration in six healthy lactating sheep. After iv ENR injection (as a bolus), the elimination half-life (t(1/2beta)), the volume of distribution (Vd(area)), and the area under the concentration vs. time curve (AUC) were 3.30 (0.36)h, 2.91 (0.17)l/kg and 4.19 (0.18) microg h/ml, respectively. The maximum milk concentrations of ENR (C(max)), the area under the milk concentration vs. time curve (AUC(milk)) and the ratio AUC(milk)/AUC(serum) were 2.38 (0.14)microg/ml, 23.76 (2.21) microg h/ml and 5.62 (0.30), respectively. After im administration of ENR the t(1/2beta), C(max), time of C(max) (t(max)) and absolute bioavailability (F(abs)) were 3.87 (0.10)h, 0.74 (0.07) microg/ml, 0.83 (0.12)h and 75.35%, respectively. The C(max), AUC(milk) and the ratio AUC(milk)/AUC(serum) were 1.94 (0.13) microg/ml, 24.81 (2.25) microg h/ml and 8.15 (0.96), respectively.

Pharmacokinetics of oleandomycin in dogs after intravenous or oral administration alone and after pretreatment with metamizole or dexamethasone.

The pharmacokinetics of oleandomycin (OLD) after intravenous and oral administration, both alone and after intramuscular pretreatment with metamizole or dexamethasone, were studied in healthy dogs. After intravenous injection of OLD alone (10 mg/kg as bolus), the elimination half-life (t 1/2 beta, volume of distribution (Vd,area), body clearance (ClB) and area under the concentration time curve (AUC) were 1.60 h, 1.11 L/kg. 7.36 (ml/kg)/min and 21.66 microg h/ml, respectively. There were no statistically significant differences following pretreatment with metamizole or dexamethasone. After oral administration of OLD alone, the t 1/2 beta, maximum plasma concentrations (Cmax), time of Cmax (tmax), mean absorption time (MAT) and absolute bioavailability (Fabs) were 1.6 h, 5.34 microg/ml, 1.5 h, 1.34 h and 84.29%, respectively. Pretreatment with metamizole caused a significantly decreased value for Cmax (2.93 microg/ml) but the MAT value (2.23 h) was significantly increased. Statistically significant changes in the pharmacokinetic parameters of OLD following oral administration were also observed as a result of pretreatment with dexamethasone. The Cmax was increased (8.24 microg/ml) and the tmax (0.5 h) and MAT (0.45 h) were lower.

Interspecies comparisons of plasma half-life of trimethoprim in relation to body mass.

The relationship between body mass and plasma half-life of trimethoprim was studied in 10 different species of animals and man using published data. Log half-life was positively and significantly correlated to log body mass based on individual measurements in herbivorous animals (n = 23, P < 0.01), in herbivorous animals+pigs (n = 29, P < 0.01), in ungulates (n = 27, P < 0.01), in ruminants (n = 16, P < 0.01) and in non-herbivorous mammals, except pigs (n = 6, P < 0.05). The correlation was described by the allometric equations: t 1/2 beta = 27 W0.26 in herbivorous animals and t 1/2 beta = 125 W0.32 in non-herbivorous animals except pigs.

Species specific pharmacokinetics of rolitetracycline.

Comparative studies on some selected pharmacokinetic parameters of rolitetracycline (effective antimicrobial activity levels) in sheep, pigs, rabbits, chickens and pigeons were carried out after intravenous administration of the drug at a dose of 5 mg/kg. The results revealed that a two-compartment open model was usually optimal. Interspecies differences in the rate (alpha) and the volume of distribution (Vda), the area under the serum concentration time curve (AUC) and the total body clearance (ClB) were small. The values of the elimination half-life (t1/2 beta) found in sheep, pigs, rabbits, chickens and pigeons were 1.51, 3.06, 2.18, 4.33 and 2.51 h respectively. These results and data in mice, rabbits and man taken from literature were analysed to determine any correlation to body mass (W). The log of the elimination half-life values (log t1/2 beta) of rolitetetracycline revealed a significant correlation with log values of (W) between animal species. This relationship was described by the equation t1/2 beta = 1.27.W0.29 (r = 0.93, P < 0.01, n = 5) for mammal species and t1/2 beta = 1.81.W0.24 (r = 0.78, P < 0.05, n = 7) for mammal and bird species.

Pharmacokinetics of sulphamethoxazole and trimethoprim administered intravenously and orally to Japanese quails.

The pharmacokinetic behaviour of sulphamethoxazole and trimethoprim was studied after combined intravenous (i.v.) administration at doses of 20 mg/kg and 4 mg/kg, respectively, and after oral administration at doses of 50 mg/kg and 10 mg/kg. The serum concentration versus time data after i.v. administration were best described by the biexponential equations C = 34.77.e-2.655.t + 39.03.e-0.241.t for sulphamethoxazole and C = 3.29.e-3.878.t + 0.83.e-0.306.t for trimethoprim. Mean biological half-lives of the drugs were 2.89 +/- 0.11 and 2.38 +/- 0.33 h, respectively. The distribution volumes (V area) were 0.475 +/- 0.026 l/kg (sulphamethoxazole) and 3.89 +/- 0.61 l/kg (trimethoprim). Orally administered sulphamethoxazole and trimethoprim were rapidly absorbed. The maximum serum concentrations were reached 0.5-1 h after administration. The bioavailability was 81% for sulphamethoxazole and 41% for trimethoprim.

Interspecies variations in plasma half-life of ampicillin, amoxycillin, sulphadimidine and sulphacetamide related to variations in body mass.

The relationships between the half-lives during the elimination phase (t1/2 minutes) of ampicillin, amoxycillin, sulphadimidine and sulphacetamide and body mass (W, kg) between species of mammals and birds were examined using data from the authors' experiments and collected from the literature. Linear regression of the log half-lives of ampicillin, amoxycillin and sulphadimidine following intravenous injection on the log body mass for a variety of species of mammals and birds revealed significant correlations (r = 0.7709, n = 8, r = 0.7712, n = 8, r = 0.7749, n = 10). The interspecies relationships were described by the allometric equations t1/2 = 31.3 W0.16, t1/2 = 32.7 W0.12 and t1/2 = 129.2 W0.28, respectively. These equations may be of value for estimating dose intervals in species for which no relevant pharmacokinetic data are available.