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Comparative pharmacokinetics of danofloxacin in common pheasants, guinea fowls and Japanese quails after intravenous and oral administration a
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D. J. Dimitrova , A. M. Haritova , T. D. Dinev , R. G. Moutafchieva & L. D. Lashev a
Department of Pharmacology, Physiology of Animals and Physiological Chemistry, Faculty of Veterinary Medicine, Trakia Universiry, Stara Zagora, Bulgaria Accepted author version posted online: 07 Jan 2014.Published online: 16 Apr 2014.
To cite this article: D. J. Dimitrova, A. M. Haritova, T. D. Dinev, R. G. Moutafchieva & L. D. Lashev (2014) Comparative pharmacokinetics of danofloxacin in common pheasants, guinea fowls and Japanese quails after intravenous and oral administration, British Poultry Science, 55:1, 120-125, DOI: 10.1080/00071668.2013.871502 To link to this article: http://dx.doi.org/10.1080/00071668.2013.871502
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British Poultry Science, 2014 Vol. 55, No. 1, 120–125, http://dx.doi.org/10.1080/00071668.2013.871502
Comparative pharmacokinetics of danofloxacin in common pheasants, guinea fowls and Japanese quails after intravenous and oral administration D. J. DIMITROVA, A. M. HARITOVA, T. D. DINEV, R. G. MOUTAFCHIEVA AND L. D. LASHEV
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Department of Pharmacology, Physiology of Animals and Physiological Chemistry, Faculty of Veterinary Medicine, Trakia Universiry, Stara Zagora, Bulgaria
Abstract 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.
INTRODUCTION Danofloxacin, a synthetic antibacterial agent from the class of fluoroquinolone carboxylic acid derivatives, exhibits bactericidal activity against numerous Gram-negative and some Gram-positive bacteria, mycoplasmas and intracellular pathogens, such as Brucella and Chlamydia species (Hannan et al., 1989; Raemdonck et al., 1992; Hannan et al., 1997; Sarasola et al., 2002). It has been registered for use in veterinary medicine, including for treatment of bacterial infection in avian species (Jordan et al., 1993; Charleston et al., 1998; Fiorentin et al., 2003). The information concerning its pharmacokinetics in birds is limited and includes chickens (Knoll et al., 1999; ElGendi et al., 2001), turkeys (Haritova et al., 2006) and ducks (Goudah and Mounier, 2009; Zeng et al., 2010). Species such as common pheasants, quails and guinea fowls are often reared in farms. In these species, it is possible that bacterial
infections such as colibacillosis, mycoplasmosis or fowl cholera may occur and antibacterial treatment to be necessary. The absence of pharmacokinetic data means that allometric calculations or empirical dose extrapolation from other species have to be used. The doses of the drugs used are often extrapolated from the amount used for chickens or other poultry species. Both methods could lead to calculation of unacceptable subtherapeutic or toxic doses of the drug. Although the anatomy and physiology of pheasants is close to that of chickens, there are some differences in the digestive tract of both species, which could cause different drug absorption (Anadon, 1999). The quails have extremely high microsomal protein concentration per g liver reflecting on the content of P450 enzymes, a predisposing factor for species-specific drug metabolism (Craigmill and Cortright, 2004). Therefore, no general principles allow extrapolation from one avian species to another and the rational design of dosage
Correspondence to: Prof. Lubomir D. Lashev, Department of Pharmacology, Physiology of Animals and Physiological Chemistry, Faculty of Veterinary Medicine, Trakia University, 6000 Stara Zagora, Bulgaria. E-mail: [email protected] Accepted for publication 31 October 2013.
© 2014 British Poultry Science Ltd
PHARMACOKINETICS OF DANOFLOXACIN
schedules must be based on data generated separately in each species (Toutain, 2010). The pharmacokinetic investigations concerning pheasants are very few and data for guinea fowls are lacking in the literature. Thus, the aim of the present study was to determine the pharmacokinetic behaviour of danofloxacin after single intravenous (i.v.) and oral (p.o.) administration to common pheasants, guinea fowls and Japanese quails in order to compare it with the respective values obtained for other avian species and to estimate adequate doses.
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Blood samples without anticoagulant (0.5 ml) were collected prior to and at 0.25, 0.5, 1, 2, 4, 6, 8 and 10 h after both administrations from the brachial vein. After i.v. treatments the untreated brachial vein was used. From the separate groups, treated i.v. or p.o. samples were withdrawn at 0.25, 1, 4, and 8 h, respectively at 0.5, 2, 6 and 10 h. The blood samples were allowed to clot at room temperature. Serum samples were obtained after centrifugation at 1800 × g for 15 min and stored at – 70°C until assayed. The studies were approved by the Ethical Committee on the use of animals in experimental trials of Trakia University, Bulgaria.
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MATERIALS AND METHODS Drugs
Drug analysis
Danofloxacin mesylate was used as a powder (Chemos GmbH, Regenstauf, Germany), dissolved ex tempore in distilled water as 1% solution (w/v) for pheasants and guinea fowls and 0.25% for quails.
Serum concentrations of danofloxacin were determined by high-performance liquid chromatography (HPLC) method (Frazier et al., 2000). Extraction of fluoroquinolone was performed using the method described by Garcia et al. (2000). Serum samples (100 μl) were diluted with 400 μl of 0.1 M phosphate buffer (pH 7.4) and vortexed for 0.5 min. After adding 3 ml of dichloromethane, the samples were vortexed for 1 min and centrifuged for 6 min at 1000 × g, at 4° C. The organic layer was evaporated in a vacuum evaporator at 40°C. The residue was dissolved in 100 μl of demineralised Milli-Q-water. A 20 μl aliquot was injected into an HPLC system comprising a Hypersil Spherisorb ODS-2 (C18)250 × 4.6 mm 5 μm column, a Surveyor LC Pump Plus and Surveyor fluorescence detector and Surveyor Autosampler Plus (Thermo Fisher Scientific Inc., USA). These values for danofloxacin were 338 nm and 425 nm, respectively. The mobile phase consisted of acetonitrile in aqueous solution (25:75, v/v) of potassium dihydrogen phosphate (0.05 M) in water. The pH was adjusted to 3.5 with phosphoric acid (85% w/v). The flow rate was 1.0 ml/min. Peak area integrations were measured by the ChromQuest Chromatography Data System (Thermo Fisher Scientific Inc., USA). The limit of quantification was 0.05 μg/ml and the limit of detection was 0.01 μg/ml. Standard dilutions of danofloxacin were prepared in serum obtained from untreated quails, pheasants and guinea fowls at concentrations of 1.0, 0.75, 0.50, 0.25, 0.10, 0.05 and 0.01 μg ml−1 and subjected to HPLC analysis. Enrofloxacin was used as internal standard. Linearity of standard curves was confirmed by the non-significant results of a test for lack of fit with a value of r equal to 0.999 for the tested drugs. The intra-assay and the interassay coefficients of variation (CV) for the tested drugs were lower than 8 and 10, respectively. The mean recovery rate at the concentrations from standard in pheasants was higher than 95% and in quails and guinea fowls was >87%.
Animals and husbandry Six clinically healthy one-year-old common pheasants (Phasianus colchicus) weighing 1.01 ± 0.04 kg (2 male and 4 female) and 6 adult guinea fowls (3 male and 3 female) weighing 1.45–1.67 kg were included in the experiment. The animals were obtained from a private breeding farm. Twenty-four (12 male and 12 female) clinically healthy, mature Japanese quails (Coturnix coturnix japonica) with a mean body weight of 173.7 ± 15 g divided into four groups were involved in the experiments. They were obtained from the breeding centre of Trakia University. All animals were housed under condition according to the species requirements. Standard commercial feed (without antibiotics and coccidiostatics) and water were supplied ad libitum. Experiments were conducted after a 14 d acclimatisation period. Experimental design The experiments with pheasants and guinea fowls followed a two-way crossover design with a washout period of 15 d between both treatments. The i.v. doses were given in the brachial vein and the p.o. doses were given by gavage of the danofloxacin solution into the crop via a plastic tube after 12 h of food (but not water) deprivation at a dose rate of 10 mg kg–1 body weight. Blood samples without anticoagulant (1 ml) were collected prior to and at 0.25, 0.5, 1, 2, 4, 6, 8, 10 and 24 h after both administrations from the brachial vein. Two groups of quails, each containing three male and three female birds, were treated intravenously and the other two were treated orally.
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Figure 2. Serum concentrations (mean ± SEM) of danofloxacin in guinea fowls following single intravenous (i.v., ♦ and tick line) injection and oral (p.o., ▲ and dashed line) administration at a dose of 10 mg kg–1 body weight. Lines represent simulated concentrations and dots show measured concentrations.
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Figure 1. Serum concentrations (mean ± SEM) of danofloxacin in pheasants following single intravenous (i.v., ♦ and tick line) injection and oral (p.o., ▲ and dashed line) administration at a dose of 10 mg kg–1 body weight. Lines represent simulated concentrations and dots show measured concentrations.
Concentration (µg/ml)
Serum danofloxacin curves following i.v. injection were best fit to one-compartmental models in all of the species examined. Although some of the pheasants showed a very short distribution part, the number of points was not sufficient for correct calculations of distribution phases (Figures 1–3). Selected pharmacokinetic parameters are reported in Table 1. Total body clearance (ClB) varied in wide range (0.45–1.61 l kg−1 h−1) between the three species. The elimination half-life and mean residence time depended also on the species. The quails and guinea fowls demonstrated lower values of both parameters. The values of distribution volume were high and best presented in quails (Table 1). Serum concentrations following p.o. administration were determined at 0.25 h in quails and pheasants and remained above 0.34 μg ml−1 for
0.01
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RESULTS
Concentration (µg/ml)
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Compartmental pharmacokinetic analysis of danofloxacin serum curves for each pheasant and guinea fowl was performed using the program WinNonlin 5.1. (Pharsight Corporation, Mountain View, CA, USA). Each curve of the quails’ serum concentrations was constructed of samples of two randomly collected birds (one gender), sampled at different time intervals. The same computer program was used for pharmacokinetic analysis. For i.v. injection, the appropriate pharmacokinetic model was determined by the application of Akaike’s information criterion. The pharmacokinetic/pharmacodynamic (PK/ PD) predictors determined were: the ratio of maximum serum concentrations (Cmax)/MIC (minimal inhibitory concentration) and the ratio of AUC0→∞ /MIC.
Concentration (µg/ml)
Pharmacokinetic analysis
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Figure 3. Serum concentrations (mean ± SEM) of danofloxacin in Japanese quails following single intravenous (i.v., ♦ and tick line) injection and oral (p.o., ▲ and dashed line) administration at a dose of 10 mg kg–1 body weight. Lines represent simulated concentrations and dots show measured concentrations.
24 h only in pheasants (Figure 1). Lack of detectable danofloxacin was obtained in quails at the end of the sampling period (Figure 3). The guinea fowls showed a lag time of about 15 min and lack of determinable concentration at 24 h after treatment (Figure 2). Danofloxacin disposition curves after p.o. administration were best fitted to a one-compartmental open model with first-order absorption and elimination. The maximum serum concentration was achieved earlier in quails, unlike in pheasants where it was registered relatively late at 10.4 h. High p.o. bioavailability was calculated for the three species (between 79.5% and 83.5%) (Table 1). Table 2 presents the estimated values for AUC0→∞/MIC and Cmax/MIC after p.o. administration, for some clinical Gram-positive and Gram-negative bacterial pathogens in birds whose values for MIC90 vary between 0.1 and 0.25 μg ml−1.
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Table 1. Mean (± SEM) of selected pharmacokinetic parameters of danofloxacin in Japanese quail, common pheasant and guinea fowl. (a) after i.v. and (b) after p.o. administration at a dose of 10 mg kg−1 body weight (a) After i.v. administration t1/2β(h)
Vss(l kg−1)
ClB(l h−1 kg−1)
AUC(μg ml−1 h)
MRT(h)
3.84 ± 0.36* 6.82 ± 0.76 3.31 ± 0.13*
8.57 ± 0.32*# 4.20 ± 0.51 5.81 ± 0.22*
1.61 ± 0.14*# 0.45 ± 0.07 1.23 ± 0.07*
6.46 ± 0.57*# 24.58 ± 3.45 8.29 ± 0.45*
5.54 ± 0.52* 9.84 ± 1.10 4.91 ± 0.20*
Species Japanese quail Pheasant Guinea fowl
(b) After p.o. administration Species Japanese quail Pheasant Guinea fowl
t1/2el(h)
Cmax(μg ml−1)
Tmax(h)
AUC((μg ml−1 h)
t1/2abs(h)
F(%)
2.79 ± 0.47* 11.51 ± 3.20 3.59 ± 0.29*
0.78 ± 0.04 0.54 ± 0.11 0.51 ± 0.12
2.04 ± 0.09*# 10.4 ± 2.30 5.35 ± 0.47*
5.40 ± 0.38* 20.20 ± 7.79 6.87 ± 1.47*
0.98 ± 0.20*# 4.90 ± 0.89 3.45 ± 0.36
83.50 82.30 79.46
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t1/2β, t1/2el – elimination half-life; Vss – volume of distribution; ClB – total body clearance; AUC – area under the concentration time curves; MRT – mean residence time; Cmax – maximum serum concentrations; Tmax – time to peak maximum serum concentrations; t1/2abs – absorption half-life; F – bioavailability. * Significantly different compared to pheasants (P < 0.05). # Significantly different compared to guinea fowls (P < 0.05).
Table 2. Mean (±SEM) of selected pharmacokinetic/pharmacodynamic (PK/PD) predictors of danofloxacin antimicrobial activity after p.o.administration in Japanese quail, common pheasant and guinea fowl at a dose of 10 mg kg−1 body weight Species:
Japanese quail
MIC90 (μg ml−1):
0.1
Cmax/MIC (h) AUC0-∞/MIC (h) Doses (mg kg−1)
7.8 ± 0.4 54 ± 3.8 17
Pheasant 0.25 3.1 ± 0.2 21.6 ± 1.5 48
DISCUSSION The information on danofloxacin pharmacokinetics includes data for chickens (Anadon et al., 1997; Knoll et al., 1999; El-Gendi et al., 2001), turkeys (Haritova et al., 2006) and ducks (Goudah and Mounier, 2009). According to these data, danofloxacin penetrates the tissues of the species investigated. The tissue concentrations are higher and persist longer, compared to blood (Zeng et al., 2010). Danofloxacin is eliminated mainly unchanged and relatively slowly, providing a 24 h therapeutic concentration. The p.o. bioavailability in
Table 3.
Guinea fowl
0.1
0.25
0.1
0.25
5.4 ± 1.1 202 ± 78 6
2.5 ± 0.4 69 ± 18 14
5.1 ± 1.2 68.7 ± 15 12
2 ± 0.4 40 ± 9 39
three domestic avian species is high without significant interspecies differences (Table 3). Generally, our data for the quails, pheasants and guinea fowls are similar but with clear interspecies features. Mono-exponential dependence on the time was registered. This is in agreement with the results of Knoll et al. (1999) in chickens. Other authors (Haritova et al., 2006; Goudah and Mounier, 2009) found bi-exponential dependence in turkeys and ducks. This suggests that danofloxacin is distributed rapidly and the arrangement of the blood sampling time could be a reason for these differences.
Mean for selected pharmacokinetic parameters of danofloxacin in birds (a) after i.v. and (b) after p.o. administration
(a) After i.v. administration Species
Dose(mg kg−1)
t1/2β(h)
Vss(l kg−1)
ClB(l h−1 kg−1)
Source
Chicken Duck Turkey
10 5 6
6.73 3.91 8.6
10.2 5.41 6.59
1.43 1.01 0.59
Knoll et al. (1999) Goudah and Mouneir (2009) Haritova et al. (2006)
(b) After p.o. administration Species
Dose(mg kg−1)
Cmax(μg ml−1)
Tmax(h)
t1/2el(h)
F(%)
Source
Chicken Duck Turkey
10 5 6
0.47 0.82 1.17
1.5 1.21 2.13
6.62 2.39 9.74
99.2 89.26 78.37
Knoll et al. (1999) Goudah and Mouneir (2009) Haritova et al. (2006)
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Unexpectedly, the pharmacokinetics in quails and guinea fowls was closer and showed some differences from the pheasants in all parameters (Table 1). Generally, in pheasants, danofloxacin showed lower distribution and clearance values and longer elimination half-life than all other galliform species. This resulted in a longer presence of the drug in the organism and high AUC values. The opposite was seen in guinea fowls that demonstrated a relatively short persistence of danofloxacin. The p.o. administration of danofloxacin is followed rapidly by relatively high concentrations in the blood of the investigated species. In pheasants (present study) and turkeys (Haritova et al., 2006), double serum concentration peaks were registered. Similar results were reported in broiler chickens treated with enrofloxacin (Sumano et al., 2003). This type of curve could not be explained without additional investigation, but possible reasons are biphasic crop and/or stomach emptying, or limited rapid absorption from the crop. In guinea fowls, a lag time of 0.26 ± 0.06 h was found. The data obtained for time to peak maximum serum concentrations (Tmax) are evidence for the delayed process of p.o. absorption of danofloxacin in pheasants, which differs from all other avian species investigated (Knoll et al., 1999; Haritova et al., 2006; Goudah and Mounier, 2009; Zeng et al., 2010). Similar delay is registered in our experiments with guinea fowls. The values of Cmax in the three species are comparable and close to that found in chickens and ducks, but lower than that measured in turkeys (Table 3). If the comparison is consistent with the doses used, it could be concluded that turkeys have the highest values of Cmax. Regardless of interspecies differences in values of various parameters, the p.o. bioavailability in our experiments as well as in other avian species has similar values. It suggests a high degree of absorption in all avian species for which data are available. Generally in all species, the elimination rate of the drug after p.o. administration follows the same pattern as that after i.v. administration. Based on PK/PD parameters, the optimal dosage regimen of danofloxacin to be repeated after a 24 h interval was calculated in pheasants, Japanese quails and guinea fowls using the equation proposed by Toutain et al. (2002): Dose ¼ ClB ðAUC0!∞ =MICÞbreakpoint MIC=fu F 24 h where (AUC0→∞ /MIC)breakpoint is the targeted breakpoint (e.g. 125 h); MIC is the MIC of the targeted pathogen, ClB is the plasma clearance for 24 h; fu is the free fraction of the drug in plasma.
F is the bioavailability factor. We used AUC0→∞ because the values are nearly equal to the respective values of AUC0→24. For calculations of adequate doses, the values of danofloxacin MICs of 0.1 µg ml−1 and 0.25 µg ml−1 were used. They are consistent with the following data about MICs for different microorganisms: Pasteurella multocida and Escherichia coli – 0.015–0.25 µg ml−1 (Raendonck et al., 1992; Tanner et al., 1993; Watts et al., 1997; Ozawa et al., 2010; Zeng et al., 2010); Proteus species – 0.12 µg ml−1 (Watts et al., 1997); Salmonella species – 0.03 µg ml−1 (Watts et al., 1997); Mycoplasma species – 0.008 µg ml−1 (Cooper et al., 1993). It is well known that danofloxacin, like other fluoroquinolones, acts in a concentrationdependent manner (Aliabadi and Lees, 2001; Sarasola et al., 2002; Goudah and Mounier, 2009). For concentration-dependent antimicrobial agents, AUC0→24 h/MIC and Cmax/MIC are perhaps the most important integrated variables determining efficacy. They are also PK/PD predictors, which may be altered by the dose frequency of danofloxacin administration (Toutain et al., 2002; McKellar et al., 2004). For fluoroquinolones Cmax/MIC > 3 produced 99% reduction of bacterial count, and Cmax/MIC > 8 prevented the emergence of resistant organisms (McKellar et al., 2004). Resistance selection may be reduced for fluoroquinolones by achieving an AUC0→24 h/MIC ratio of greater than 125 (Toutain et al., 2002). In the context of these data, our results are clearly species-specific. Guinea fowls need higher doses for therapeutic efficacy, but the dose of 10 mg kg−1 should be effective enough for both Japanese quails and pheasants in the range of microbial sensitivity analysed here.
REFERENCES ALIABADI, F. & LEES, P. (2001) Pharmacokinetics and pharmacodynamics of danofloxacin in serum and tissue fluids of goats following intravenous and intramuscular administration. American Journal of Veterinary Research, 62: 1979–1989. ANADON, A. (1999) Bioavailability in birds: physiological basis and clinical consequences, in: Materials of the Training Workshop on Pharmacokinetics, 6–10th September, Toulouse, France. ANADON, A., MARTINEZ-LARRANAGA, M.R., DIAZ, M.J., FERNANDEZCRUZ, M.L., FREJO, M.T., FERNANDEZ, R. & MORALES, M.E. (1997) Lung tissue concentrations and plasma pharmacokinetics of danofloxacin following oral administration to broiler chickens. Journal of Veterinary Pharmacology and Therapeutics, 20 (suppl): 197–198. CHARLESTON, B., GATE, J.J., AITKEN, I.A., STEPHAN, B. & FROYMAN, R. (1998) Comparison of the efficacies of three fluoroquinolone antimicrobial agents, given as continuous or pulsedwater medication, against Escherichia coli infection in chickens. Antimicrobial Agents and Chemotherapy, 42: 83–87. COOPER, A.C., FULLER, J.R., WHITTLESTONE, P. & WISE, D.R. (1993) In vitro activity of danofloxacin, tilosin and oxytetracycline against mycoplasmas of veterinary importance. Research in Veterinary Science, 54: 329–334.
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PHARMACOKINETICS OF DANOFLOXACIN CRAIGMILL, A. & CORTRIGHT, K. (2004) Interspecies considerations in the evaluation of human food safety for veterinary drugs. AAPS PharmSci, 4: 1–11. EL-GENDI, A.Y., EL-BANNA, H.A., NORAG, M. & GABER, M. (2001) Disposition kinetics of danofloxacin and ciprofloxacin in broiler chickens. Deutsche Tierärztliche Wochenschrift, 108: 429–434. FIORENTIN, L., SONCINI RA, DA, COSTA, J.L.A., MOREZ, M.A.Z., TREVISOL, I.M., TODA, M. & VIERA, N.D. (2003) Apparent eradication of Mycoplasma synoviae in broiler breeders subjected to intensive antibiotic treatment direct to control Escherichia coli. Avian Pathology, 32: 213–216. FRAZIER, D.L., THOMPSON, L., TRETTIEN, A. & EVANS, E.I. (2000) Comparison of fluoroquinolone pharmacokinetic parameters after treatment with marbofloxacin, enrofloxacin, and difloxacin in dogs. Journal of Veterinary Pharmacology and Therapeutics, 23: 293–302. GARCÍA, M.A., SOLANS, C., ARAMAYONA, J. J., RUEDA, S. & BREGANTE, M.A. (2000) Development of method for the determination of danofloxacin in plasma by HPLC with fluorescence detection. Biomedical Chromatography, 14: 89–92. GOUDAH, A. & MOUNIER, S.M. (2009) Disposition kinetics and tissue residues of danofloxacin in Muscovy ducks. British Poultry Science, 50: 613–619. HANNAN, P.C., O’HANLON, P.J. & ROGERS, N.M. (1989) In vitroevaluation of various quinolone antibacterial agents against veterinary mycoplasmas and porcine respiratory bacterial pathogens. Research in Veterinary Science, 46: 202–211. HANNAN, P.C., WINDSOR, G.D. & DE JONG, N. (1997) Comparative susceptibilities of various animal-pathogenic mycoplasmas to fluoroquinolones. Antimicrobial Agents and Chemotherapy, 41: 2037–2040. HARITOVA, A., RUSENOVA, N., PARVANOV, P., LASHEV, L. & FINKGREMELS, J. (2006) Pharmacokinetic/pharmacodynamic modeling of danofloxacin in Turkeys. Veterinary Research Communications, 30: 775–789. JORDAN, F.T.W., HORROCKS, B.K. & JONES, S.K. (1993) A comparison of the efficacy of danofloxacin and tylosin in the control of Mycoplasma gallisepticum infection in broiler chicks. Journal of Veterinary Pharmacology and Therapeutics, 16: 79–86. KNOLL, U., GLUNDER, G. & KIETZMANN, M. (1999) Comparative study of the plasma pharmacokinetics and tissue concentrations of danofloxacin and enrofloxacin in broiler chickens. Journal of Veterinary Pharmacology and Therapeutics, 22: 239–246.
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MCKELLAR, Q., SANCHEZ BRUNI, S. & JONES, D. (2004) Pharmacokinetic/pharmacodynamic relationships of antimicrobial drugs used in veterinary medicine. Journal of Veterinary Pharmacology and Therapeutics, 27: 503–514. OZAWA, M., BABA, K., SHIMIZU, Y. & ASAI, T. (2010) Comparison of in vitro activities and pharmacokinetics/pharmacodynamics estimations of veterinary fluoroquinolones against avian pathogenic Escherichia coli isolates. Microbial Drug Resistance, 16: 327–332. RAEMDONCK, D.L., TANNER, A.C., TOLLING, S.T. & MICHENER, S.L. (1992) In vitro susceptibility of avian Eschericia coli and Pasteurella multocida to danofloxacin and five other antimicrobials. Avian Diseases, 36: 964–967. SARASOLA, P., LEES, P., ALIABADI, F.S., MCKELLAR, Q.A., DONACHIE, W., MARR, K.A., SUNDERLAND, S.J. & ROWAN, T.G. (2002) Pharmacokinetic and pharmacodynamic profiles of danofloxacin administered by two dosing regimens in calves infected with Mannheimia (Pasteurella) haemolytica. Antimicrobial Agents and Chemotherapy, 46: 3013–3019. SUMANO, L.H., GUTIERREZ, O.L. & ZAMORA, Q.M. (2003) Strategic administration of enrofloxacin in poultry to achieve higher maximal serum concentrations. The Veterinary Journal, 165: 143–148. TANNER, A.C., AVAKIAN, A.P., BARNES, H.J., LEY, D.H., MIGAKI, T.T. & MAGONIGLE, R.A. (1993) A comparison of danofloxacin and tylosin in the control of induced Mycoplasma Gallisepticum infection in broiler chickens. Avian Diseases, 37: 515–522. TOUTAIN, P.L. (2010) Species differences in pharmacokinetics and Pharmacodinamics, in: CUNNINGHAM, F., ELLIOT, J., LEES, P. (Eds) Handbook of Experimental Pharmacology, Vol. 199, pp. 19–48 (Berlin, Heidelberg, Springer-Verlag). TOUTAIN, P.L., DEL CASTILLO, J.R.E. & BOUSQUET-MÉLOU, A. (2002) The pharmacokinetic/pharmacodynamic approach to a dosage regimen for antibiotics. Research in Veterinary Science, 73: 105–114. WATTS, J.L., SALMON, S.A., SANCHEZ, M.S. & YANCEY, R.J. (1997) In vitro activity of premafloxacin, a new extended-spectrum fluoroquionolone, against pathogens of veterinary importance. Antimicrobial Agents and Chemotherapy, 41: 1190–1192. ZENG, Z., DENG, G., SHEN, X., RIZWAN-UL HAG, M., ZENG, D. & DING, H. (2010) Plasma and tissue pharmacokinetics of danofloxacin in healthy and in experimentally infected chickens with Pasteurella multocida. Journal of Veterinary Pharmacology and Therapeutics, 34: 101–104.
British Poultry Science Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/cbps20
Comparative pharmacokinetics of danofloxacin in common pheasants, guinea fowls and Japanese quails after intravenous and oral administration a
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D. J. Dimitrova , A. M. Haritova , T. D. Dinev , R. G. Moutafchieva & L. D. Lashev a
Department of Pharmacology, Physiology of Animals and Physiological Chemistry, Faculty of Veterinary Medicine, Trakia Universiry, Stara Zagora, Bulgaria Accepted author version posted online: 07 Jan 2014.Published online: 16 Apr 2014.
To cite this article: D. J. Dimitrova, A. M. Haritova, T. D. Dinev, R. G. Moutafchieva & L. D. Lashev (2014) Comparative pharmacokinetics of danofloxacin in common pheasants, guinea fowls and Japanese quails after intravenous and oral administration, British Poultry Science, 55:1, 120-125, DOI: 10.1080/00071668.2013.871502 To link to this article: http://dx.doi.org/10.1080/00071668.2013.871502
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British Poultry Science, 2014 Vol. 55, No. 1, 120–125, http://dx.doi.org/10.1080/00071668.2013.871502
Comparative pharmacokinetics of danofloxacin in common pheasants, guinea fowls and Japanese quails after intravenous and oral administration D. J. DIMITROVA, A. M. HARITOVA, T. D. DINEV, R. G. MOUTAFCHIEVA AND L. D. LASHEV
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Department of Pharmacology, Physiology of Animals and Physiological Chemistry, Faculty of Veterinary Medicine, Trakia Universiry, Stara Zagora, Bulgaria
Abstract 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.
INTRODUCTION Danofloxacin, a synthetic antibacterial agent from the class of fluoroquinolone carboxylic acid derivatives, exhibits bactericidal activity against numerous Gram-negative and some Gram-positive bacteria, mycoplasmas and intracellular pathogens, such as Brucella and Chlamydia species (Hannan et al., 1989; Raemdonck et al., 1992; Hannan et al., 1997; Sarasola et al., 2002). It has been registered for use in veterinary medicine, including for treatment of bacterial infection in avian species (Jordan et al., 1993; Charleston et al., 1998; Fiorentin et al., 2003). The information concerning its pharmacokinetics in birds is limited and includes chickens (Knoll et al., 1999; ElGendi et al., 2001), turkeys (Haritova et al., 2006) and ducks (Goudah and Mounier, 2009; Zeng et al., 2010). Species such as common pheasants, quails and guinea fowls are often reared in farms. In these species, it is possible that bacterial
infections such as colibacillosis, mycoplasmosis or fowl cholera may occur and antibacterial treatment to be necessary. The absence of pharmacokinetic data means that allometric calculations or empirical dose extrapolation from other species have to be used. The doses of the drugs used are often extrapolated from the amount used for chickens or other poultry species. Both methods could lead to calculation of unacceptable subtherapeutic or toxic doses of the drug. Although the anatomy and physiology of pheasants is close to that of chickens, there are some differences in the digestive tract of both species, which could cause different drug absorption (Anadon, 1999). The quails have extremely high microsomal protein concentration per g liver reflecting on the content of P450 enzymes, a predisposing factor for species-specific drug metabolism (Craigmill and Cortright, 2004). Therefore, no general principles allow extrapolation from one avian species to another and the rational design of dosage
Correspondence to: Prof. Lubomir D. Lashev, Department of Pharmacology, Physiology of Animals and Physiological Chemistry, Faculty of Veterinary Medicine, Trakia University, 6000 Stara Zagora, Bulgaria. E-mail: [email protected] Accepted for publication 31 October 2013.
© 2014 British Poultry Science Ltd
PHARMACOKINETICS OF DANOFLOXACIN
schedules must be based on data generated separately in each species (Toutain, 2010). The pharmacokinetic investigations concerning pheasants are very few and data for guinea fowls are lacking in the literature. Thus, the aim of the present study was to determine the pharmacokinetic behaviour of danofloxacin after single intravenous (i.v.) and oral (p.o.) administration to common pheasants, guinea fowls and Japanese quails in order to compare it with the respective values obtained for other avian species and to estimate adequate doses.
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Blood samples without anticoagulant (0.5 ml) were collected prior to and at 0.25, 0.5, 1, 2, 4, 6, 8 and 10 h after both administrations from the brachial vein. After i.v. treatments the untreated brachial vein was used. From the separate groups, treated i.v. or p.o. samples were withdrawn at 0.25, 1, 4, and 8 h, respectively at 0.5, 2, 6 and 10 h. The blood samples were allowed to clot at room temperature. Serum samples were obtained after centrifugation at 1800 × g for 15 min and stored at – 70°C until assayed. The studies were approved by the Ethical Committee on the use of animals in experimental trials of Trakia University, Bulgaria.
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MATERIALS AND METHODS Drugs
Drug analysis
Danofloxacin mesylate was used as a powder (Chemos GmbH, Regenstauf, Germany), dissolved ex tempore in distilled water as 1% solution (w/v) for pheasants and guinea fowls and 0.25% for quails.
Serum concentrations of danofloxacin were determined by high-performance liquid chromatography (HPLC) method (Frazier et al., 2000). Extraction of fluoroquinolone was performed using the method described by Garcia et al. (2000). Serum samples (100 μl) were diluted with 400 μl of 0.1 M phosphate buffer (pH 7.4) and vortexed for 0.5 min. After adding 3 ml of dichloromethane, the samples were vortexed for 1 min and centrifuged for 6 min at 1000 × g, at 4° C. The organic layer was evaporated in a vacuum evaporator at 40°C. The residue was dissolved in 100 μl of demineralised Milli-Q-water. A 20 μl aliquot was injected into an HPLC system comprising a Hypersil Spherisorb ODS-2 (C18)250 × 4.6 mm 5 μm column, a Surveyor LC Pump Plus and Surveyor fluorescence detector and Surveyor Autosampler Plus (Thermo Fisher Scientific Inc., USA). These values for danofloxacin were 338 nm and 425 nm, respectively. The mobile phase consisted of acetonitrile in aqueous solution (25:75, v/v) of potassium dihydrogen phosphate (0.05 M) in water. The pH was adjusted to 3.5 with phosphoric acid (85% w/v). The flow rate was 1.0 ml/min. Peak area integrations were measured by the ChromQuest Chromatography Data System (Thermo Fisher Scientific Inc., USA). The limit of quantification was 0.05 μg/ml and the limit of detection was 0.01 μg/ml. Standard dilutions of danofloxacin were prepared in serum obtained from untreated quails, pheasants and guinea fowls at concentrations of 1.0, 0.75, 0.50, 0.25, 0.10, 0.05 and 0.01 μg ml−1 and subjected to HPLC analysis. Enrofloxacin was used as internal standard. Linearity of standard curves was confirmed by the non-significant results of a test for lack of fit with a value of r equal to 0.999 for the tested drugs. The intra-assay and the interassay coefficients of variation (CV) for the tested drugs were lower than 8 and 10, respectively. The mean recovery rate at the concentrations from standard in pheasants was higher than 95% and in quails and guinea fowls was >87%.
Animals and husbandry Six clinically healthy one-year-old common pheasants (Phasianus colchicus) weighing 1.01 ± 0.04 kg (2 male and 4 female) and 6 adult guinea fowls (3 male and 3 female) weighing 1.45–1.67 kg were included in the experiment. The animals were obtained from a private breeding farm. Twenty-four (12 male and 12 female) clinically healthy, mature Japanese quails (Coturnix coturnix japonica) with a mean body weight of 173.7 ± 15 g divided into four groups were involved in the experiments. They were obtained from the breeding centre of Trakia University. All animals were housed under condition according to the species requirements. Standard commercial feed (without antibiotics and coccidiostatics) and water were supplied ad libitum. Experiments were conducted after a 14 d acclimatisation period. Experimental design The experiments with pheasants and guinea fowls followed a two-way crossover design with a washout period of 15 d between both treatments. The i.v. doses were given in the brachial vein and the p.o. doses were given by gavage of the danofloxacin solution into the crop via a plastic tube after 12 h of food (but not water) deprivation at a dose rate of 10 mg kg–1 body weight. Blood samples without anticoagulant (1 ml) were collected prior to and at 0.25, 0.5, 1, 2, 4, 6, 8, 10 and 24 h after both administrations from the brachial vein. Two groups of quails, each containing three male and three female birds, were treated intravenously and the other two were treated orally.
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Figure 2. Serum concentrations (mean ± SEM) of danofloxacin in guinea fowls following single intravenous (i.v., ♦ and tick line) injection and oral (p.o., ▲ and dashed line) administration at a dose of 10 mg kg–1 body weight. Lines represent simulated concentrations and dots show measured concentrations.
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Figure 1. Serum concentrations (mean ± SEM) of danofloxacin in pheasants following single intravenous (i.v., ♦ and tick line) injection and oral (p.o., ▲ and dashed line) administration at a dose of 10 mg kg–1 body weight. Lines represent simulated concentrations and dots show measured concentrations.
Concentration (µg/ml)
Serum danofloxacin curves following i.v. injection were best fit to one-compartmental models in all of the species examined. Although some of the pheasants showed a very short distribution part, the number of points was not sufficient for correct calculations of distribution phases (Figures 1–3). Selected pharmacokinetic parameters are reported in Table 1. Total body clearance (ClB) varied in wide range (0.45–1.61 l kg−1 h−1) between the three species. The elimination half-life and mean residence time depended also on the species. The quails and guinea fowls demonstrated lower values of both parameters. The values of distribution volume were high and best presented in quails (Table 1). Serum concentrations following p.o. administration were determined at 0.25 h in quails and pheasants and remained above 0.34 μg ml−1 for
0.01
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Compartmental pharmacokinetic analysis of danofloxacin serum curves for each pheasant and guinea fowl was performed using the program WinNonlin 5.1. (Pharsight Corporation, Mountain View, CA, USA). Each curve of the quails’ serum concentrations was constructed of samples of two randomly collected birds (one gender), sampled at different time intervals. The same computer program was used for pharmacokinetic analysis. For i.v. injection, the appropriate pharmacokinetic model was determined by the application of Akaike’s information criterion. The pharmacokinetic/pharmacodynamic (PK/ PD) predictors determined were: the ratio of maximum serum concentrations (Cmax)/MIC (minimal inhibitory concentration) and the ratio of AUC0→∞ /MIC.
Concentration (µg/ml)
Pharmacokinetic analysis
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Figure 3. Serum concentrations (mean ± SEM) of danofloxacin in Japanese quails following single intravenous (i.v., ♦ and tick line) injection and oral (p.o., ▲ and dashed line) administration at a dose of 10 mg kg–1 body weight. Lines represent simulated concentrations and dots show measured concentrations.
24 h only in pheasants (Figure 1). Lack of detectable danofloxacin was obtained in quails at the end of the sampling period (Figure 3). The guinea fowls showed a lag time of about 15 min and lack of determinable concentration at 24 h after treatment (Figure 2). Danofloxacin disposition curves after p.o. administration were best fitted to a one-compartmental open model with first-order absorption and elimination. The maximum serum concentration was achieved earlier in quails, unlike in pheasants where it was registered relatively late at 10.4 h. High p.o. bioavailability was calculated for the three species (between 79.5% and 83.5%) (Table 1). Table 2 presents the estimated values for AUC0→∞/MIC and Cmax/MIC after p.o. administration, for some clinical Gram-positive and Gram-negative bacterial pathogens in birds whose values for MIC90 vary between 0.1 and 0.25 μg ml−1.
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Table 1. Mean (± SEM) of selected pharmacokinetic parameters of danofloxacin in Japanese quail, common pheasant and guinea fowl. (a) after i.v. and (b) after p.o. administration at a dose of 10 mg kg−1 body weight (a) After i.v. administration t1/2β(h)
Vss(l kg−1)
ClB(l h−1 kg−1)
AUC(μg ml−1 h)
MRT(h)
3.84 ± 0.36* 6.82 ± 0.76 3.31 ± 0.13*
8.57 ± 0.32*# 4.20 ± 0.51 5.81 ± 0.22*
1.61 ± 0.14*# 0.45 ± 0.07 1.23 ± 0.07*
6.46 ± 0.57*# 24.58 ± 3.45 8.29 ± 0.45*
5.54 ± 0.52* 9.84 ± 1.10 4.91 ± 0.20*
Species Japanese quail Pheasant Guinea fowl
(b) After p.o. administration Species Japanese quail Pheasant Guinea fowl
t1/2el(h)
Cmax(μg ml−1)
Tmax(h)
AUC((μg ml−1 h)
t1/2abs(h)
F(%)
2.79 ± 0.47* 11.51 ± 3.20 3.59 ± 0.29*
0.78 ± 0.04 0.54 ± 0.11 0.51 ± 0.12
2.04 ± 0.09*# 10.4 ± 2.30 5.35 ± 0.47*
5.40 ± 0.38* 20.20 ± 7.79 6.87 ± 1.47*
0.98 ± 0.20*# 4.90 ± 0.89 3.45 ± 0.36
83.50 82.30 79.46
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t1/2β, t1/2el – elimination half-life; Vss – volume of distribution; ClB – total body clearance; AUC – area under the concentration time curves; MRT – mean residence time; Cmax – maximum serum concentrations; Tmax – time to peak maximum serum concentrations; t1/2abs – absorption half-life; F – bioavailability. * Significantly different compared to pheasants (P < 0.05). # Significantly different compared to guinea fowls (P < 0.05).
Table 2. Mean (±SEM) of selected pharmacokinetic/pharmacodynamic (PK/PD) predictors of danofloxacin antimicrobial activity after p.o.administration in Japanese quail, common pheasant and guinea fowl at a dose of 10 mg kg−1 body weight Species:
Japanese quail
MIC90 (μg ml−1):
0.1
Cmax/MIC (h) AUC0-∞/MIC (h) Doses (mg kg−1)
7.8 ± 0.4 54 ± 3.8 17
Pheasant 0.25 3.1 ± 0.2 21.6 ± 1.5 48
DISCUSSION The information on danofloxacin pharmacokinetics includes data for chickens (Anadon et al., 1997; Knoll et al., 1999; El-Gendi et al., 2001), turkeys (Haritova et al., 2006) and ducks (Goudah and Mounier, 2009). According to these data, danofloxacin penetrates the tissues of the species investigated. The tissue concentrations are higher and persist longer, compared to blood (Zeng et al., 2010). Danofloxacin is eliminated mainly unchanged and relatively slowly, providing a 24 h therapeutic concentration. The p.o. bioavailability in
Table 3.
Guinea fowl
0.1
0.25
0.1
0.25
5.4 ± 1.1 202 ± 78 6
2.5 ± 0.4 69 ± 18 14
5.1 ± 1.2 68.7 ± 15 12
2 ± 0.4 40 ± 9 39
three domestic avian species is high without significant interspecies differences (Table 3). Generally, our data for the quails, pheasants and guinea fowls are similar but with clear interspecies features. Mono-exponential dependence on the time was registered. This is in agreement with the results of Knoll et al. (1999) in chickens. Other authors (Haritova et al., 2006; Goudah and Mounier, 2009) found bi-exponential dependence in turkeys and ducks. This suggests that danofloxacin is distributed rapidly and the arrangement of the blood sampling time could be a reason for these differences.
Mean for selected pharmacokinetic parameters of danofloxacin in birds (a) after i.v. and (b) after p.o. administration
(a) After i.v. administration Species
Dose(mg kg−1)
t1/2β(h)
Vss(l kg−1)
ClB(l h−1 kg−1)
Source
Chicken Duck Turkey
10 5 6
6.73 3.91 8.6
10.2 5.41 6.59
1.43 1.01 0.59
Knoll et al. (1999) Goudah and Mouneir (2009) Haritova et al. (2006)
(b) After p.o. administration Species
Dose(mg kg−1)
Cmax(μg ml−1)
Tmax(h)
t1/2el(h)
F(%)
Source
Chicken Duck Turkey
10 5 6
0.47 0.82 1.17
1.5 1.21 2.13
6.62 2.39 9.74
99.2 89.26 78.37
Knoll et al. (1999) Goudah and Mouneir (2009) Haritova et al. (2006)
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Unexpectedly, the pharmacokinetics in quails and guinea fowls was closer and showed some differences from the pheasants in all parameters (Table 1). Generally, in pheasants, danofloxacin showed lower distribution and clearance values and longer elimination half-life than all other galliform species. This resulted in a longer presence of the drug in the organism and high AUC values. The opposite was seen in guinea fowls that demonstrated a relatively short persistence of danofloxacin. The p.o. administration of danofloxacin is followed rapidly by relatively high concentrations in the blood of the investigated species. In pheasants (present study) and turkeys (Haritova et al., 2006), double serum concentration peaks were registered. Similar results were reported in broiler chickens treated with enrofloxacin (Sumano et al., 2003). This type of curve could not be explained without additional investigation, but possible reasons are biphasic crop and/or stomach emptying, or limited rapid absorption from the crop. In guinea fowls, a lag time of 0.26 ± 0.06 h was found. The data obtained for time to peak maximum serum concentrations (Tmax) are evidence for the delayed process of p.o. absorption of danofloxacin in pheasants, which differs from all other avian species investigated (Knoll et al., 1999; Haritova et al., 2006; Goudah and Mounier, 2009; Zeng et al., 2010). Similar delay is registered in our experiments with guinea fowls. The values of Cmax in the three species are comparable and close to that found in chickens and ducks, but lower than that measured in turkeys (Table 3). If the comparison is consistent with the doses used, it could be concluded that turkeys have the highest values of Cmax. Regardless of interspecies differences in values of various parameters, the p.o. bioavailability in our experiments as well as in other avian species has similar values. It suggests a high degree of absorption in all avian species for which data are available. Generally in all species, the elimination rate of the drug after p.o. administration follows the same pattern as that after i.v. administration. Based on PK/PD parameters, the optimal dosage regimen of danofloxacin to be repeated after a 24 h interval was calculated in pheasants, Japanese quails and guinea fowls using the equation proposed by Toutain et al. (2002): Dose ¼ ClB ðAUC0!∞ =MICÞbreakpoint MIC=fu F 24 h where (AUC0→∞ /MIC)breakpoint is the targeted breakpoint (e.g. 125 h); MIC is the MIC of the targeted pathogen, ClB is the plasma clearance for 24 h; fu is the free fraction of the drug in plasma.
F is the bioavailability factor. We used AUC0→∞ because the values are nearly equal to the respective values of AUC0→24. For calculations of adequate doses, the values of danofloxacin MICs of 0.1 µg ml−1 and 0.25 µg ml−1 were used. They are consistent with the following data about MICs for different microorganisms: Pasteurella multocida and Escherichia coli – 0.015–0.25 µg ml−1 (Raendonck et al., 1992; Tanner et al., 1993; Watts et al., 1997; Ozawa et al., 2010; Zeng et al., 2010); Proteus species – 0.12 µg ml−1 (Watts et al., 1997); Salmonella species – 0.03 µg ml−1 (Watts et al., 1997); Mycoplasma species – 0.008 µg ml−1 (Cooper et al., 1993). It is well known that danofloxacin, like other fluoroquinolones, acts in a concentrationdependent manner (Aliabadi and Lees, 2001; Sarasola et al., 2002; Goudah and Mounier, 2009). For concentration-dependent antimicrobial agents, AUC0→24 h/MIC and Cmax/MIC are perhaps the most important integrated variables determining efficacy. They are also PK/PD predictors, which may be altered by the dose frequency of danofloxacin administration (Toutain et al., 2002; McKellar et al., 2004). For fluoroquinolones Cmax/MIC > 3 produced 99% reduction of bacterial count, and Cmax/MIC > 8 prevented the emergence of resistant organisms (McKellar et al., 2004). Resistance selection may be reduced for fluoroquinolones by achieving an AUC0→24 h/MIC ratio of greater than 125 (Toutain et al., 2002). In the context of these data, our results are clearly species-specific. Guinea fowls need higher doses for therapeutic efficacy, but the dose of 10 mg kg−1 should be effective enough for both Japanese quails and pheasants in the range of microbial sensitivity analysed here.
REFERENCES ALIABADI, F. & LEES, P. (2001) Pharmacokinetics and pharmacodynamics of danofloxacin in serum and tissue fluids of goats following intravenous and intramuscular administration. American Journal of Veterinary Research, 62: 1979–1989. ANADON, A. (1999) Bioavailability in birds: physiological basis and clinical consequences, in: Materials of the Training Workshop on Pharmacokinetics, 6–10th September, Toulouse, France. ANADON, A., MARTINEZ-LARRANAGA, M.R., DIAZ, M.J., FERNANDEZCRUZ, M.L., FREJO, M.T., FERNANDEZ, R. & MORALES, M.E. (1997) Lung tissue concentrations and plasma pharmacokinetics of danofloxacin following oral administration to broiler chickens. Journal of Veterinary Pharmacology and Therapeutics, 20 (suppl): 197–198. CHARLESTON, B., GATE, J.J., AITKEN, I.A., STEPHAN, B. & FROYMAN, R. (1998) Comparison of the efficacies of three fluoroquinolone antimicrobial agents, given as continuous or pulsedwater medication, against Escherichia coli infection in chickens. Antimicrobial Agents and Chemotherapy, 42: 83–87. COOPER, A.C., FULLER, J.R., WHITTLESTONE, P. & WISE, D.R. (1993) In vitro activity of danofloxacin, tilosin and oxytetracycline against mycoplasmas of veterinary importance. Research in Veterinary Science, 54: 329–334.
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PHARMACOKINETICS OF DANOFLOXACIN CRAIGMILL, A. & CORTRIGHT, K. (2004) Interspecies considerations in the evaluation of human food safety for veterinary drugs. AAPS PharmSci, 4: 1–11. EL-GENDI, A.Y., EL-BANNA, H.A., NORAG, M. & GABER, M. (2001) Disposition kinetics of danofloxacin and ciprofloxacin in broiler chickens. Deutsche Tierärztliche Wochenschrift, 108: 429–434. FIORENTIN, L., SONCINI RA, DA, COSTA, J.L.A., MOREZ, M.A.Z., TREVISOL, I.M., TODA, M. & VIERA, N.D. (2003) Apparent eradication of Mycoplasma synoviae in broiler breeders subjected to intensive antibiotic treatment direct to control Escherichia coli. Avian Pathology, 32: 213–216. FRAZIER, D.L., THOMPSON, L., TRETTIEN, A. & EVANS, E.I. (2000) Comparison of fluoroquinolone pharmacokinetic parameters after treatment with marbofloxacin, enrofloxacin, and difloxacin in dogs. Journal of Veterinary Pharmacology and Therapeutics, 23: 293–302. GARCÍA, M.A., SOLANS, C., ARAMAYONA, J. J., RUEDA, S. & BREGANTE, M.A. (2000) Development of method for the determination of danofloxacin in plasma by HPLC with fluorescence detection. Biomedical Chromatography, 14: 89–92. GOUDAH, A. & MOUNIER, S.M. (2009) Disposition kinetics and tissue residues of danofloxacin in Muscovy ducks. British Poultry Science, 50: 613–619. HANNAN, P.C., O’HANLON, P.J. & ROGERS, N.M. (1989) In vitroevaluation of various quinolone antibacterial agents against veterinary mycoplasmas and porcine respiratory bacterial pathogens. Research in Veterinary Science, 46: 202–211. HANNAN, P.C., WINDSOR, G.D. & DE JONG, N. (1997) Comparative susceptibilities of various animal-pathogenic mycoplasmas to fluoroquinolones. Antimicrobial Agents and Chemotherapy, 41: 2037–2040. HARITOVA, A., RUSENOVA, N., PARVANOV, P., LASHEV, L. & FINKGREMELS, J. (2006) Pharmacokinetic/pharmacodynamic modeling of danofloxacin in Turkeys. Veterinary Research Communications, 30: 775–789. JORDAN, F.T.W., HORROCKS, B.K. & JONES, S.K. (1993) A comparison of the efficacy of danofloxacin and tylosin in the control of Mycoplasma gallisepticum infection in broiler chicks. Journal of Veterinary Pharmacology and Therapeutics, 16: 79–86. KNOLL, U., GLUNDER, G. & KIETZMANN, M. (1999) Comparative study of the plasma pharmacokinetics and tissue concentrations of danofloxacin and enrofloxacin in broiler chickens. Journal of Veterinary Pharmacology and Therapeutics, 22: 239–246.
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MCKELLAR, Q., SANCHEZ BRUNI, S. & JONES, D. (2004) Pharmacokinetic/pharmacodynamic relationships of antimicrobial drugs used in veterinary medicine. Journal of Veterinary Pharmacology and Therapeutics, 27: 503–514. OZAWA, M., BABA, K., SHIMIZU, Y. & ASAI, T. (2010) Comparison of in vitro activities and pharmacokinetics/pharmacodynamics estimations of veterinary fluoroquinolones against avian pathogenic Escherichia coli isolates. Microbial Drug Resistance, 16: 327–332. RAEMDONCK, D.L., TANNER, A.C., TOLLING, S.T. & MICHENER, S.L. (1992) In vitro susceptibility of avian Eschericia coli and Pasteurella multocida to danofloxacin and five other antimicrobials. Avian Diseases, 36: 964–967. SARASOLA, P., LEES, P., ALIABADI, F.S., MCKELLAR, Q.A., DONACHIE, W., MARR, K.A., SUNDERLAND, S.J. & ROWAN, T.G. (2002) Pharmacokinetic and pharmacodynamic profiles of danofloxacin administered by two dosing regimens in calves infected with Mannheimia (Pasteurella) haemolytica. Antimicrobial Agents and Chemotherapy, 46: 3013–3019. SUMANO, L.H., GUTIERREZ, O.L. & ZAMORA, Q.M. (2003) Strategic administration of enrofloxacin in poultry to achieve higher maximal serum concentrations. The Veterinary Journal, 165: 143–148. TANNER, A.C., AVAKIAN, A.P., BARNES, H.J., LEY, D.H., MIGAKI, T.T. & MAGONIGLE, R.A. (1993) A comparison of danofloxacin and tylosin in the control of induced Mycoplasma Gallisepticum infection in broiler chickens. Avian Diseases, 37: 515–522. TOUTAIN, P.L. (2010) Species differences in pharmacokinetics and Pharmacodinamics, in: CUNNINGHAM, F., ELLIOT, J., LEES, P. (Eds) Handbook of Experimental Pharmacology, Vol. 199, pp. 19–48 (Berlin, Heidelberg, Springer-Verlag). TOUTAIN, P.L., DEL CASTILLO, J.R.E. & BOUSQUET-MÉLOU, A. (2002) The pharmacokinetic/pharmacodynamic approach to a dosage regimen for antibiotics. Research in Veterinary Science, 73: 105–114. WATTS, J.L., SALMON, S.A., SANCHEZ, M.S. & YANCEY, R.J. (1997) In vitro activity of premafloxacin, a new extended-spectrum fluoroquionolone, against pathogens of veterinary importance. Antimicrobial Agents and Chemotherapy, 41: 1190–1192. ZENG, Z., DENG, G., SHEN, X., RIZWAN-UL HAG, M., ZENG, D. & DING, H. (2010) Plasma and tissue pharmacokinetics of danofloxacin in healthy and in experimentally infected chickens with Pasteurella multocida. Journal of Veterinary Pharmacology and Therapeutics, 34: 101–104.
