Comparative Pharmacokinetics of Enrofloxacin, Danofloxacin, and Marbofloxacin After Intravenous and Oral Administration in Japanese Quail ( Coturnix coturnix japonica )

Comparative Pharmacokinetics of Enrofloxacin, Danofloxacin, and Marbofloxacin After Intravenous and Oral Administration in Japanese Quail (Coturnix coturnix japonica) Aneliya Haritova, PhD, Dimitrichka Dimitrova, PhD, Toncho Dinev, PhD, Rumyana Moutafchieva, PhD, and Lubomir Lashev, DSci

Journal of Avian Medicine and Surgery 27(1):23–31, 2013 Ó 2013 by the Association of Avian Veterinarians

Comparative Pharmacokinetics of Enrofloxacin, Danofloxacin, and Marbofloxacin After Intravenous and Oral Administration in Japanese Quail (Coturnix coturnix japonica) Aneliya Haritova, PhD, Dimitrichka Dimitrova, PhD, Toncho Dinev, PhD, Rumyana Moutafchieva, PhD, and Lubomir Lashev, DSci Abstract: A population approach was used to evaluate the pharmacokinetic parameters of 3 fluoroquinolones administered to Japanese quail (Coturnix coturnix japonica). Healthy adult quail (n ¼ 50) were divided into 3 groups, each administered a separate intravenous and oral dose of the compounded drug: enrofloxacin at 10 mg/kg (n ¼ 18; 9 male, 9 female), danofloxacin at 10 mg/kg (n ¼ 12; 6 male, 6 female), and marbofloxacin at 5 mg/kg (n ¼ 20; 10 male, 10 female). A fourth group was used as a control (n ¼ 5). Enrofloxacin was metabolized extensively to ciprofloxacin, while no metabolites of either danofloxacin or marbofloxacin were detected. The volume of distribution was high, greater than 1 in all cases, and highest for danofloxacin, followed by enrofloxacin, then marbofloxacin. The total body clearance was higher in quail than that reported for other avian species with the exception of ostriches. As in mammals, the lowest clearance rate of the 3 fluoroquinolones was observed for marbofloxacin. Enrofloxacin was absorbed most rapidly, followed by marbofloxacin, then danofloxacin. The highest bioavailability was observed for danofloxacin followed by marbofloxacin, while very low bioavailability with significant conversion to ciprofloxacin was observed for enrofloxacin. Population analysis showed low intersubject variability for danofloxacin and marbofloxacin in contrast to that for enrofloxacin and its main metabolite, ciprofloxacin. Because of their more favorable pharmacokinetic properties after oral administration, either danofloxacin or marbofloxacin appears to be preferable to enrofloxacin for the treatment of susceptible bacterial infection in Japanese quail. Key words: pharmacokinetics, fluoroquinolones, enrofloxacin, danofloxacin, marbofloxacin, ciprofloxacin, avian, quail, Coturnix coturnix japonica

enrofloxacin and danofloxacin having larger volumes of distribution than marbofloxacin.2–5 A wide range of values for enrofloxacin clearance, as well as smaller variations for danofloxacin and marbofloxacin, have been reported in avian species.6–14 Metabolites of enrofloxacin and marbofloxacin have been detected in poultry.2,5,10,15 Enrofloxacin, danofloxacin, and marbofloxacin are moderately to slowly absorbed in chickens and turkeys, with peak plasma concentrations occurring 2–6 hours after oral administration.2,4,7,10 In the avian species studied, oral bioavailability of marbofloxacin, danofloxacin, and enrofloxacin is high.2,14,16

Introduction Enrofloxacin, danofloxacin, and marbofloxacin are fluoroquinolones developed exclusively for use in veterinary medicine. They are active against a number of gram-positive and gram-negative microorganisms.1 Fluoroquinolone disposition has been studied in many avian species, and interspecies differences and variation in properties among various fluoroquinolones have been demonstrated. Significant tissue distribution of fluoroquinolones has been shown in poultry and wild birds, with From the Department of Pharmacology, Physiology of Animals and Physiological Chemistry, Faculty of Veterinary Medicine, Trakia University, 6000 Stara Zagora, Bulgaria.

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The differences in the pharmacokinetic parameters of fluoroquinolones among avian species require careful evaluation before these drugs are used in clinical situations. Dose extrapolation from other species by using allometric scaling could lead to errors, especially when drugs are subjected to variations in metabolism. Quail species are widespread and can be considered free-ranging birds as well as egg-producing farm animals, and even models for pet birds.17 Japanese quail (Coturnix coturnix japonica) are affected by the same bacterial pathogens that affect chickens. Ideally, fluoroquinolones should be used only if pharmacokinetic parameters are available for a particular species, and these have not been studied in Japanese quail. The goal of our study was to evaluate and compare the disposition of enrofloxacin, danofloxacin, and marbofloxacin after oral and intravenous administration in Japanese quail. The impact of body weight and sex on pharmacokinetic parameters also was evaluated. Materials and Methods Animals Fifty clinically healthy mature Japanese quail (Manchurian breed) with a mean body weight 6 SD of 202.1 6 20.5 g were included in the study. All animals were obtained from the breeding center of Trakia University, Stara Zagora, Bulgaria, and were housed according to species requirements. Standard commercial feed, without antibiotics and coccidiostats, and water were supplied ad libitum. Experiments were conducted after a 14-day acclimatization period. The study was approved by the Ethical Committee of the Faculty of Veterinary Medicine at Trakia University. Drugs Enrofloxacin (enrofloxacin hydrochloride, Chemos GmbH, Regenstauf, Germany) and danofloxacin (danofloxacin mesylate, Chemos GmbH) each were administered IV and PO at a dose of 10 mg/kg. A 5 mg/mL aqueous solution was used for IV administration, and a 2.5 mg/mL aqueous suspension was administered PO. Marbofloxacin (Marbocyl 10% injectable solution, Vetoquinol, Paris, France) was diluted with sterile water to a 5 mg/mL concentration, and administered IV and PO each at a dose of 5 mg/kg. All 3 fluoroquinolones were used as compounded formulations to compare the properties of the drugs without influence by various drug formulations.

Experimental design Birds were divided randomly into 3 groups so that 18 birds (9 male, 9 female) were treated with enrofloxacin, 12 birds (6 male, 6 female) were treated with danofloxacin, and 20 birds (10 male, 10 female) were treated with marbofloxacin. The groups treated with enrofloxacin and danofloxacin were included in a two-way crossover design, so that each animal was treated intravenously (IV) and orally (PO) with the drug routes separated by a 15-day washout interval. A parallel design was used in experiments with marbofloxacin, which was administered IV to 10 quail and PO to another 10 quail, with each group containing 5 male and 5 female birds. A group of untreated quail (n ¼ 5) was used for obtaining control blood samples for the entire study. The body weight of each animal was measured before drug administration. Intravenous solutions were administered in the brachial vein, and PO doses were administered into the crop by using a silicone catheter after 12 hours of food deprivation. Blood samples were collected from the brachial vein, and in cases of IV drug administration, the contralateral wing was used for blood collection. No more than 3 blood samples, each with a maximum volume of 0.5 mL, were obtained from each bird after enrofloxacin administration, and no more than 4 blood samples were collected from each quail after danofloxacin and marbofloxacin administration. Experiments started at 7:30–8:30 AM. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, and 8 hours after enrofloxacin administration. The same scheme was used in the experiments with danofloxacin. In the marbofloxacin study, blood samples were collected at these times in addition to 24 hours after administration of marbofloxacin. Blood samples were collected without an anticoagulant and kept in the dark at room temperature for 2 hours. Serum was separated after centrifugation of samples at 1800g for 15 minutes and was stored at 208C before analysis. Analysis of serum concentrations of fluoroquinolones Serum concentrations of danofloxacin, marboˇ floxacin, enrofloxacin, and ciprofloxacin metabolized from enrofloxacin were determined by highperformance liquid chromatography (HPLC).18 The following substances were used for analysis: enrofloxacin hydrochloride (Batch No. 2002336, 99.3% purity; Chemos GmbH), ciprofloxacin hydrochloride (Batch No. FPCPF070483, 99.7% purity; supplied by Actavis, Sofia, Bulgaria),

HARITOVA ET AL—COMPARATIVE PHARMACOKINETICS IN QUAIL

danofloxacin mesylate (Batch No. 20090509, 98.5% purity; Chemos GmbH), and marbofloxacin hydrochloride (Batch No. 22428; Marbocyl, Vetoquinol). Fluoroquinolones were extracted using the method described by Garcia et al.19 Serum samples (100 lL) were diluted with 400 lL of 0.1 M phosphate buffer at pH 7.4 and vortexed for 0.5 minute. After adding 3 mL of dichloromethane, the samples were vortexed again for 1 minute and then centrifuged for 6 minutes at 1000g at 48C. The organic layer was evaporated in a vacuum evaporator at 408C. The residue was dissolved in 100 lL of demineralized Milli-Q water. A 20 lL aliquot was injected into an HPLC system comprising a Hypersil Spherisorb ODS-2 (C18)-250 3 4.6 mm 5 lM column, a Surveyor LC Pump Plus, and Surveyor fluorescence detector, and Surveyor Autosampler Plus (Thermo Scientific, West Palm Beach, FL, USA). Excitation and emission wavelengths for enrofloxacin and ciprofloxacin were set at 277 and 418 nm, respectively. The quantification of marbofloxacin was performed at an excitation wavelength of 295 nm and an emission wavelength of 500 nm, while these values for danofloxacin were 338 and 425 nm, respectively. The mobile phase consisted of acetonitrile in aqueous solution (75:25, vol/vol) of potassium dihydrogenophosphate (0.05 M) in water. The pH was adjusted to 3.5 with phosphoric acid (85%). The flow rate was 1.0 mL/min. Peak area integrations were measured by the ChromQuest Chromatography Data System (Thermo Scientific). The limit of quantification was 0.05 lg/mL, and the limit of detection was 0.01 lg/ mL. Standard dilutions of enrofloxacin hydrochloride and ciprofloxacin hydrochloride were prepared in serum obtained from untreated quail at concentrations of 0.01, 0.05, 0.10, 0.25, 0.50, 0.75, and 1.0 lg/mL, and subjected to HPLC analysis. Enrofloxacin was used as an internal standard for the marbofloxacin and danofloxacin assays. Linearity of standard curves was confirmed by the nonsignificant results of test for lack of fit, with a value of r ¼ 0.999 for the tested drugs. The intraassay and the interassay coefficients of variation for the tested drugs were lower than 8 and 10, respectively. Pharmacokinetic analysis By analyzing the study results with Akaike information criteria delivered by specialized software (WinNonlin 5.0.1., Pharsight, Mountain View, CA, USA), the curves of serum concentrations after IV and PO administration were characterized best by a one-compartmental model.

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Parameters computed included elimination (k10) and absorption (k01) rate constants, total body clearance (ClB), area volume of distribution (Vd), area under the serum-concentration-time curve (AUC), mean residence time (MRT), maximum serum concentration (Cmax), and time to reach Cmax (Tmax). Absolute bioavailability (F) was calculated by using the following equation: Fð%Þ ¼ AUCpo =AUCiv 3 100; where iv indicates IV administration and po indicates PO administration. Population pharmacokinetic analysis also was performed using the Monolix V2.2 (Lixoft, Orsay, France). Population parameters were estimated using the Stochastic Approximation Expectation Maximization (SAEM) algorithm. Data obtained after IV administration were processed with one-compartmental analysis using Model No 2 from the Monolix V2.2 program’s library. ClB and Vd both were computed. Pharmacokinetic parameters after PO administration of the fluoroquinolones, including k10, k01, and apparent Vd, were computed with one-compartmental analysis by applying Model No 7 from the Monolix V2.2 program’s library. Interindividual variances for each pharmacokinetic parameter (x2) also were computed. Regression models were developed to examine potential relationships between individual subject characteristics (such as body weight and sex) and pharmacokinetic parameters. These models were constructed by using a stepwise procedure, starting with a model without covariables and subsequently adding covariates one by one while testing their significance. The covariates then were included one by one in the population model by using the likelihood ratio test to compare the models. The concentration-time profile was described by the following equation: yij ¼ f ðxij ; /i Þ þ gðxij ; /i Þeij ; 1  i  N ; 1  j  ni ; where f and g are mathematical symbols for function, yij is the jth observation of subject i , N is the number of subjects, ni is the number of observations of subject i, xij are the regression variables, eij is within-group errors, and ui is a vector, modeled by unknown vectors of population parameters or so-called random unexplained effects that vary among subjects, among occasions, or within a subject. Results Serum concentrations of each fluoroquinolone administered IV and PO are shown in Figure 1. All

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Table 1. Mean pharmacokinetic parameters estimated on the basis of mean serum concentrations by onecompartmental analysis and population mean (PM) 6 SEM after intravenous and oral administration of enrofloxacin (10 mg/kg), danofloxacin (10 mg/kg), and marbofloxacin (5 mg/kg) in healthy Japanese quail; parameters of ciprofloxacin, the main metabolite of enrofloxacin, also are shown.

Pharmacokinetic parameters

Intravenous administration N samples Vd (L/kg1) x2 Vd (%) ClB( L/h 3 kg) x2 ClB (%) k10 (h1) t1/2k10 (h) MRT (h) AUC (lg 3 h/mL) Oral administration N samples k01 (/h) x2 k01 (%) t1/2k01 (h) k10 (/h) x2 k10 (%) t1/2k10 (h) Cmax (lg/mL) Tmax (h) AUC (lg 3g/mL) F (%)

Enrofloxacin

Ciprofloxacin

Danofloxacin

Marbofloxacin

10 mg/kg, n ¼ 18

n ¼ 18

10 mg/kg, n ¼ 12

5 mg/kg, n ¼ 20

Mean

PM 6 SEM

Mean

PM 6 SEM

5.36 — 1.52 — 0.28 2.45 3.53 6.59

33 5.63 6 0.68 22.5 1.52 6 0.13 5.4 — — — —

— — — — — — — 1.08

32 — — — — — — — —

— — — 0.27 — 2.56 0.29 0.35 1.00 15.16

28 — — — 0.29 6 0.04 29.7 — — — — —

— — — 0.34 — — 0.19 1.19 0.83 —

32 — — — 0.47 6 0.37 38.1 — — — — —

Mean

8.67 1.64 0.19 3.66 5.28 6.09

0.84 0.82 0.24 — 2.86 0.79 2.08 5.36 88.08

PM 6 SEM

Mean

PM 6 SEM

36 9.52 6 0.53 0.32 1.48 6 0.17 4.09 — — — —

0.35 2.01 2.90 11.55

35 1.18 6 0.05 1.42 0.47 6 0.03 2.54 — — — —

40 0.65 6 0.2 2.67 — 0.33 6 0.1 1.43 — — — — —

1.52 — 0.46 0.28 — 2.46 1.25 1.36 6.60 56.28

35 1.61 6 0.18 7.44 — 0.12 6 0.04 0.27 — — — — —

1.25 0.43

Abbreviations: Vd indicates volume of distribution; x2 Vd, interindividual variances of volume of distribution; ClB, total body clearance; x2ClB, interindividual variances of total body clearance; k10, elimination rate constant; t1/2k10, half-life of elimination; MRT, mean residence time; AUC, area under the serum-concentration-time curve; k01, absorption rate constant; x2 k01, interindividual variances of absorption rate constant; t1/2k01, half-life of absorption; x2 k10, interindividual variances of elimination rate constant; Cmax, maximum serum concentration; Tmax, time to reach maximum serum concentration; F, absolute bioavailability.

the substances, including ciprofloxacin metabolized from enrofloxacin, were detectable in serum 15 minutes after IV and PO drug administration. Neither enrofloxacin nor ciprofloxacin was detectable in a measurable concentration by 8 hours after PO treatment, whereas the serum level of marbofloxacin, administered IV or PO, was below the limit of quantification by 24 hours after drug administration. Pharmacokinetic parameters, estimated on the basis of mean serum concentrations, are shown in Table 1. Danofloxacin showed the highest values for Vd and ClB, while the lowest values were found with marbofloxacin. Only the k01 could be calculated for danofloxacin and marbofloxacin after their oral administration. The k10 values were similar for all 3 compounds. Higher Cmax and Tmax values were found for danofloxacin and marbofloxacin compared with the total for enrofloxacin and ciprofloxacin. A low

F% was found for enrofloxacin relative to marbofloxacin and danofloxacin. Because of the small size of the quail and ethical reasons, only a relatively small number of blood samples could be obtained from each bird. Therefore, pharmacokinetic parameters and their variability were calculated by population pharmacokinetic analysis. The population mean values of Vd and ClB were very close to those estimated by a conventional pharmacokinetic approach (Table 1). Negligible interindividual variations were found for values of ClB after intravenous administration. The highest interindividual variations were determined for Vd after intravenous administration, and for k10 after oral administration of enrofloxacin and ciprofloxacin compared to danofloxacin and marbofloxacin. The inclusion of body weight and sex as covariates did not

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Figure 1. Mean serum concentrations and 90% prediction intervals for 3 fluoroquinolones and 1 metabolite after IV and PO administration to Japanese quail. (A) Enrofloxacin after IV administration (10 mg/kg). (B) Enrofloxacin after PO administration (10 mg/kg). (C) Ciprofloxacin metabolite after IV administration of enrofloxacin (10 mg/kg). (D) Ciprofloxacin metabolite after PO administration of enrofloxacin (10 mg/kg). (E) Danofloxacin after IV administration (10 mg/kg). (F) Danofloxacin after PO administration (10 mg/kg). (G) Marbofloxacin after IV administration (5 mg/ kg). (H) Marbofloxacin after PO administration (5 mg/kg). Dots represent individual serum concentrations.

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Table 2. Reference citations for pharmacokinetic parameters of enrofloxacin, danofloxacin, and marbofloxacin in various avian species. Enrofloxacin Species

Parameter

Intravenous administration Chicken t1/2k10 (h) Vdss ( L/kg) Cl (L/h 3 kg) Turkey t1/2k10 (h) Vdss (L/kg) Cl (L/h 3 kg) Duck

Ostrich

Buzzard

Vulture

Macaw

t1/2k10 (h) Vdss (L/kg) Cl (L/h 3 kg) t1/2k10 (h) Vdss (L/kg) Cl (L/h 3 kg) t1/2k10 (h) Vdss (L/kg) Cl (L/h 3 kg) t1/2k10 (h) Vdss (L/kg) Cl (L/h 3 kg) t1/2k10 (h) Vdss (L/kg) Cl (L/h 3 kg)

Oral administration Chicken Cmax (lg/mL) Tmax (h) F (%) Turkey Cmax (lg/mL) Tmax (h) F (%) Duck

Hawk Owl Bustard

Danofloxacin

Value

Reference

Value

5.56–10.29 2.77–3.9 0.25–0.62 6.92 3.66 0.57

7, 16, 22 7, 16, 22 7, 16, 22 5 5 5

6.73 10.2 1.43 8.64 6.59 0.59 3.91 5.41 1.01 — — — — — — — — — — — —

— — — 0.78 3.4 4.56 — — — — — — — — — 0.99–2.44 1.5–2.5 80.1–89.2 1.23 6.33 69.2

— — — 9 9 9 — — — — — — — — — 7, 16, 22 7, 16, 22 7, 16, 22 5 5 5

0.47–0.51 1.5–2.33 99.2 1.17 2.13 78.37

Reference

Marbofloxacin Value

Reference

22 22 22 10 10 10

5.26 0.77 0.17 7.38 1.41 0.16

2 2 2 4 4 4

11 11 11 — — — — — — — — — — — —

3.28 0.80 0.23 1.47 3.22 2.19 4.11 1.16 0.18 12.51 1.51 0.11 4.3 1.3 0.29

23 23 23 3 3 3 12 12 12 13 13 13 14 14 14

1.05 1.48 63.9 0.67 6 84.37

2 2 2 4 4 4

22, 27 22, 27 22, 27 10 10 10

Cmax (lg/mL) Tmax (h) F (%) Cmax (lg/mL) Tmax (h)

0.99 1.38 — 2.8 5.4

26 26 26 8 8

0.82 1.21 82.26 — —

11 11 11 — —

1.13 1.41 87.75 — —

23 23 23 — —

Cmax (lg/mL) Tmax (h) Cmax (lg/mL) Tmax (h) F (%)

2.6 7.1 1.84 0.66 62.7

8 8 21 21 21

— — — — —

— — — — —

— — — — —

— — — — —

Abbreviations: t1/2k10 indicates half-life of elimination; Vdss, steady-state volume of distribution; Cl, total body clearance; Cmax, maximum serum concentration; Tmax, time to reach maximum serum concentration; F, bioavailability.

improve the pharmacokinetic modeling (estimations are not shown). Discussion Our study used population kinetics because of the limited amount of blood that could be obtained safely from individual quail. This approach al-

lowed evaluation of the impact of covariates, such as sex, body weight, and others, on pharmacokinetic modeling. The data showed that none of the tested covariates impacted individual pharmacokinetic parameters. Similarly, Guo et al,20 who for the first time to our knowledge applied the population approach to the investigation of enrofloxacin pharmacokinetics in chickens, did not

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observe a relationship between body weight and pharmacokinetic parameters. Their results and ours can be explained by the homogeneity of the groups of chickens or quail, and the absence of a clear dependence of fluoroquinolone disposition on body weight and sex within the same animal species, and populations with similar body weight and age. High values for the Vd found in quail after intravenous administration of enrofloxacin, danofloxacin, and marbofloxacin suggested that the highest concentrations of these drugs are found in tissues. Population analysis showed that considerable interindividual variations in Vd could be expected for enrofloxacin in contrast with those for danofloxacin and marbofloxacin. Comparing the Vd values of these 3 fluoroquinolones in quail demonstrated data similar to those in other species for Vdss, with danofloxacin having the highest value, followed by enrofloxacin then marbofloxacin (Table 2).7,8,10,11,21–23 The ClB of the studied fluoroquinolones was higher in quail than in other avian species referenced.4,5,7,10,11,20,23 Rapid clearance of orbifloxacin also was reported in quail by Hawkins et al.24 These results suggest that a relatively faster clearance rate of fluoroquinolones is typical for quail, which could be related to the faster metabolic rates of small animal species.25–27 The slower elimination rate for marbofloxacin in comparison with the other 2 fluoroquinolones has been found in quail as well as other avian species. Interindividual variations in ClB for the studied fluoroquinolones were negligible. Among the investigated fluoroquinolones, ciprofloxacin, a metabolite from enrofloxacin, was determined by the HPLC method. Anadon et al7 reported for first time the conversion of enrofloxacin to ciprofloxacin in chickens. Later, Intorre et al28 found less than 10% ciprofloxacin after enrofloxacin administration to muscovy ducks. In the literature, it generally is accepted that enrofloxacin is metabolized to an insignificant extent in poultry.5 Our results with quail were similar, although the metabolic pathway is not well known in this species. Measurable concentrations of metabolites of danofloxacin have not been detected. Although a metabolite of marbofloxacin has been detected in chicken and turkey, it has not been found in quail.2,4 Pharmacokinetic parameters after oral administration of enrofloxacin differed from those observed in other avian species, especially for Cmax, AUC, and F%.5,7 However, because of insufficient data points recorded during the first 15 minutes of

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this study, the k01 for the quail could not be estimated. Enrofloxacin was absorbed in quail to a much lower extent than in other bird species, which could be attributed to significant metabolism of enrofloxacin to ciprofloxacin with a first-pass effect.5,8 The high interindividual variations in the k10 of enrofloxacin compared with those for danofloxacin and marbofloxacin also could be related to the metabolism of enrofloxacin. Danofloxacin was absorbed highly with very low interindividual variations after oral administration in quail. A similar disposition pattern of danofloxacin was found in chickens and turkeys, but the k10 was higher in quail. This also was observed after intravenous administration of danofloxacin in chickens and turkeys.10,22,29 The elimination phase pharmacokinetics of danofloxacin in ducks is highly similar to that in quail, but danofloxacin is absorbed faster in muscovy ducks.11 For marbofloxacin, Anadon et al2 reported similar values of Cmax and Tmax in chickens, and a slightly lower value for k10. Ducks again showed a significant similarity to quail if Cmax and Tmax were compared, with the exception of a higher value for bioavailability.23 The population analysis in quail revealed a very high similarity among subjects in the disposition of orally administered marbofloxacin. In conclusion, analysis of the pharmacokinetics of enrofloxacin, danofloxacin, and marbofloxacin administered intravenously and orally to quail shows a clear tendency for faster elimination of all 3 of these drugs in quail compared with other avian species. Because of a significant degree of metabolism and possible differences in the activity of the metabolizing enzymes between animals, enrofloxacin disposition showed the highest interindividual variations. In contrast, marbofloxacin and danofloxacin behaved similarly among individual birds. Lower bioavailability was observed for enrofloxacin and marbofloxacin in quail compared with other avian species. Because of favorable pharmacokinetic properties after oral administration in quail, either danofloxacin or marbofloxacin is preferable to enrofloxacin for treatment of infections with susceptible bacteria. Because of its low bioavailability, oral treatment with enrofloxacin cannot ensure high therapeutic concentrations. The significant conversion of enrofloxacin to ciprofloxacin results in a higher total concentration of enrofloxacin plus ciprofloxacin, but the level still is lower than with either of the 2 other fluoroquinolones. The higher oral bioavailability and Cmax of danofloxacin and marbofloxacin along with the

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lower minimum inhibitory concentrations of these fluoroquinolones compared with those of enrofloxacin plus ciprofloxacin support their use in quail. Multiple drug resistance was reported recently in Escherichia coli strains isolated from Japanese quail. The rate of resistance against ampicillin/ cloxacillin, cotrimoxazole, chloramphenicol, and tetracycline was 100%, against ciprofloxacin 68%, and against nitrofurantoin 52%. However, the last drug is prohibited from use in veterinary medicine. In addition, the use of fluoroquinolones is prohibited in food animals in the United States.30 These data require a very selective use of antibacterial drugs in quail after isolation and determination of the sensitivity of pathogenic strains. Results of our study revealed the considerable metabolism of enrofloxacin to ciprofloxacin in quail. This finding should be clarified further by investigation of the metabolism and transport of enrofloxacin in the gastrointestinal tract and liver of quail. The suitability of using these granivorous gallinaceous animals as universal models for granivorous psittacine birds when studying the disposition of significantly metabolized drugs also should be investigated.

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