FULL PAPER
Pharmacology
Pharmacokinetics of intravenous and
intramuscular danofloxacin in red-eared
slider turtles (Trachemys scripta elegans)
Orhan CORUM1)*, Duygu Durna CORUM1), Feray ALTAN2), Ayse ER3), Gul CETIN4)
and Kamil UNEY3)
1)Department
of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Kastamonu,
Kastamonu, 37200, Turkey
2)Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Dicle, Diyarbakir,
21280, Turkey
3)Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Selcuk, Konya,
42031, Turkey
4)Department of Pharmacology, Faculty of Pharmacy, University of Erzincan, Erzincan, 25100, Turkey
J. Vet. Med. Sci.
81(5): 753–757, 2019
doi: 10.1292/jvms.18-0609
Received: 14 October 2018
Accepted: 28 February 2019
Published online in J-STAGE:
11 March 2019
ABSTRACT. This study aimed to investigate the pharmacokinetics of danofloxacin in red-eared
slider turtle (Trachemys scripta elegans) following a single intravenous (IV) and intramuscular (IM)
administrations of 6 mg/kg, using a two-way crossover study with 30-day washout period. Eight
clinically healthy red-eared slider turtle weighing 410–600 g (mean 490 g) were used for the study.
Danofloxacin concentrations were measured using the reversed-phase high-performance liquid
chromatography. The plasma concentration-time data were evaluated by a non-compartmental
method. After IV administration, the elimination half-life (t1/2ʎz), mean residence time (MRT0-∞),
area under the concentration-time curve (AUC0-∞), volume of distribution at steady state and
total body clearance in plasma were 24.17 hr, 30.64 hr, 143.31 hr·µg/ml, 1.29 l/kg and 0.04 l/hr/kg,
respectively. Following IM administration, t1/2ʎz, MRT0-∞, AUC0-∞, peak concentration (Cmax), time
to reach Cmax, and bioavailability in plasma were 32.00 hr, 41.15 hr, 198.23 hr·µg/ml, 8.75 µg/ml,
1.5 hr and 139.89%, respectively. Danofloxacin has clinically superior pharmacokinetic properties,
including the complete IM absorption, slow elimination and wide volume of distribution in redeared slider turtles. However, further pharmacokinetics/pharmacodynamics studies are necessary
for the treatment of diseases caused by susceptible bacteria with known minimum inhibitory
concentration values in red-eared slider turtles.
KEY WORDS: bioavailability, danofloxacin, pharmacokinetics, red-eared slider turtles
Currently, red-eared slider turtles (Trachemys scripta elegans) are one of the most preferred pets. These were first used as pets in
the 1950s, and their exportation had considerably increased because they became popular in pet and food trade [22]. The reasons
for the increased popularity of red-eared slider turtles as pets are their characteristics such as small size, long lifetime, low care
costs, and their ability to easily adapt to environmental conditions [5]. However, the widespread use of red-eared slider turtles
has led to some undesired consequences. Conditions such as deterioration of natural environment, rise of dense environments,
reduction of natural habitat of turtles, and stress have weakened their immune system and rendered them vulnerable to infections
[3, 24]. Because red-eared slider turtles were fed at farms to meet the increased demand in pet and food industries, the rate of
bacterial diseases in these turtles increased. Salmonella spp., Mycoplasma spp., Pasteurella spp., and Aeromonas spp. are among
the primary factors causing bacterial diseases in red-eared slider turtles [6, 14]. These bacteria cause several diseases such as
septicemia, respiratory tract disease, abscesses, conjunctivitis, stomatitis, shell infections, osteomyelitis, coelomitis, and skin ulcers
in turtles [6, 14, 21]. In addition, red-eared slider turtles are carriers of zoonotic Salmonella spp. These bacteria cause enteritis and
septicemia in turtles as well as in humans [4].
Fluoroquinolones are one of the most commonly used antibiotic groups for the treatment of bacterial infections in turtles [21].
The reasons for preferring fluoroquinolones are their low binding activity to plasma proteins, wide distribution volume, and good
tissue penetration [30]. Danofloxacin, which acts by inhibiting the DNA gyrase enzyme of the bacteria, is a fluoroquinolone-group
antibiotic approved for use in cattle, swine, and chicken [7, 15]. Danofloxacin is a broad-spectrum antibiotic covering gramnegative and gram-positive bacteria and Mycoplasma spp. [20, 26]. Danofloxacin is recommended for use in Caretta caretta for
*Correspondence to: Corum, O.: orhancorum46@hotmail.com
©2019 The Japanese Society of Veterinary Science
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd)
License. (CC-BY-NC-ND 4.0: https://creativecommons.org/licenses/by-nc-nd/4.0/)
753
O. CORUM ET AL.
various infections [19] and in tortoises for mycoplasmosis [11]. Although enrofloxacin is used in turtles for many diseases such as
conjunctivitis [13] and lower respiratory diseases [11], it may cause undesired side effects such as skin irritation, hyper salivation,
and anorexia [6]. Danofloxacin exhibited long elimination half-life, wide distribution volume, and high bioavailability in C.
caretta with no side effects [19]. It can also be preferred in bacterial diseases of red-eared slider turtles for its pharmacokinetic
and pharmacodynamic properties. Although danofloxacin pharmacokinetics had been assessed for ectotherm animals species of
C. caretta [19] and some fish species [18, 27], there are no studies in red-eared slider turtles. This study aimed to determine the
pharmacokinetics and bioavailability of danofloxacin following intravenous (IV) and intramuscular (IM) administration at 6 mg/kg
dose in red-eared slider turtles.
MATERIALS AND METHODS
Animals
All experiments on turtles were approved by Selcuk University, Faculty of Veterinary Medicine, Ethics Committee prior to the
study. Eight healthy red-eared slider turtles weighing 410–600 g (mean, 490 g) that had not received any medication in the previous
2 months were used in the study. Turtles were procured from a local pet shop (Konya/Turkey) and were maintained in 450 l
aquariums housing four turtles each. Water temperature was maintained at 22–24°C using aquarium heater. A dry basking area was
heated to 30°C by using an infrared lamp. Aquarium system contained a custom-built mechanical and biological filtration. Turtles
were fed with commercial feed daily (Sera Reptil Raffy P, GmbH, Heinsberg, Germany). The study was conducted following a
2-week acclimatization period after turtles were transferred to the aquariums. At the beginning of and during the study, the health
status of the turtles was evaluated through physical examination, feed consumption, and plasma biochemical parameters.
Experimental design, drug administration, and blood sampling
The study was conducted in a two-way crossover pharmacokinetic design with a 30-day drug washout interval between
administrations (4 × 4). Danofloxacin was administered to the turtles at 6 mg/kg IV and IM doses. The jugular vein was used for
IV administration, and the deltoid muscle was used for IM administration. For IV and IM drug administration to the turtles, the
parenteral formulation of danofloxacin mesylate (Advocin, 25 mg/ml injectable solution, Zoetis, Turkey) was diluted to 10 mg/ml
using sterile water for injection. Blood samples of approximately 0.17 ml were collected from dorsal venous sinus at 0, 0.5, 1, 1.5,
3, 6, 9, 12, 18, 24, 36, 48, 72, 96, 120, and 144 hr by using an insulin injector previously washed with 0.05 ml heparin sodium.
Subsequently, the collected blood samples were centrifuged at 4,000 g for 10 min and the obtained plasma samples were stored at
−70°C until further analysis.
Drug analysis
Danofloxacin concentration in turtle plasma was analyzed using a high-performance liquid chromatography (HPLC)-UV system
(Shimadzu, Tokyo, Japan). HPLC system contained pump (LC-20AT), degasser (DGU-14A), auto-sampler (SIL-20A), and column
oven (CTO-10A). Danofloxacin analysis was conducted by modifying the pre-specified methods [23, 25]. For analysis, turtle
plasma samples at −70 °C were thawed to room temperature and vortexed before use. Further, 150 µl acetonitrile was added to 75
µl plasma and vortexed for 30 sec. Then, 100 µl of the clean supernatant was transferred to HPLC vial after centrifuging at 10,000
g for 10 min, and 30 µl of the supernatant was injected in the HPLC-UV system. The UV-visible (SPD-10A) detector was set at
280 wavelength. GeminiTM C18 column (250 × 4.6 mm; internal diameter, 5 µm; Phenomenex, Torrance, CA) was used for the
separation of danofloxacin. Further, 18% mobile phase from A (acetonitrile) and 82% mobile phase from B (0.4% triethylamine +
0.4% orthophosphoric acid) were pumped to the HPLC system using a pump containing a low-performance gradient system. The
flow rate was 1 ml/min. The column temperature was kept at 40°C, whereas the auto-sampler was kept at room temperature.
The method was validated in plasma for 6 days in terms of HPLC system selectivity, linearity, sensitivity, recovery, accuracy
and precision. Danofloxacin pure substance (≥98%, Sigma-Aldrich, St. Louis, MO., U.S.A.) was used to prepare working standards
(0.04–20 µg/ml) in water. The peak of danofloxacin did not interfere with endogenous substances, showing the selectivity of
method. Calibration standards were prepared from a pool of turtle plasma spiked with eight concentrations of danofloxacin
between 0.04 and 20 µg/ml. For calibration standards analyzed in six replicate, the correlation coefficients were found to be
>0.9995 indicating functional linear relationship between the concentration of analyte and the area under the peak. The limit of
detection for danofloxacin was 0.02 µg/ml, which was the lowest concentration of danofloxacin resulting in a signal to noise ratio
of 3. The limit of quantification was 0.04 µg/ml, which was the lowest concentration quantified with a coefficient of variation (CV)
of <20%. The recovery, precision and accuracy of assay were determined using quality control samples, which were prepared in
six replicates at three concentration levels (0.1, 1, and 10 µg/ml) and analyzed using the extraction procedure outlined above. The
recovery of danofloxacin from plasma ranged from 94 to 103%. Intra-day and inter-day CVs were <5.3 and 6.8%, respectively.
Intra- and inter-batch accuracy, which were determined by calculating the % bias [Bias (%)=100 × (calculated concentration−
theoretical concentration)/ theoretical concentration] were within acceptable limits of ± 15% at all concentration levels.
Pharmacokinetic calculations
Pharmacokinetic parameters were determined for each turtle following IV and IM administrations. Parameter estimates were
calculated using WinNonlin 6.1.0.173 computer software (Pharsight Corporation, Scientific Consulting Inc., North Carolina,
U.S.A.). In the study, non-compartmental pharmacokinetic parameters including the area under the plasma concentration-versus
doi: 10.1292/jvms.18-0609
754
PHARMACOKINETICS OF DANOFLOXACIN IN TURTLES
Fig. 1. Mean ± SD semi-logarithmic plasma concentration-time curves of danofloxacin following
intravenous and intramuscular administrations at the dose of 6 mg/kg in red-eared slider turtles (n=8).
time curve (AUC), terminal elimination half-life (t1/2ʎz), mean residence time (MRT), mean absorption time (MAT), volume
of distribution at steady state (Vdss), and total clearance (ClT) were measured. The initial concentration (C0), peak plasma
concentration (Cmax), and time to reach Cmax (Tmax) were determined by direct observation of plasma concentration-time plot of the
animals. The t1/2ʎz was calculated by ln 2/kel. MAT was calculated as MAT = MRTIM − MRTIV. AUC was estimated by the linear/log
method. Bioavailability (F) was calculated by using AUC values following IV and IM administration (F = AUC0-∞(IM)/AUC0-∞(IV)
×100).
Statistical analysis
Statistical analysis were conducted using SPSS 22.0 commercial software (IBM Corp, Armonk, NY, U.S.A.). All values were
presented as mean ± SD. Paired t-test was used for the evaluation of differences between pharmacokinetic parameters based on the
route of administration. Harmonic mean was calculated for t1/2ʎz
and MRT values, which were compared with Wilcoxon’s Rank
Sum test. P<0.05 was considered to be statistically significant.
RESULTS
Following IV and IM administration of danofloxacin at a dose
of 6 mg/kg in red-eared slider turtles, no adverse drug effects were
observed either locally or systematically. The semi-logarithmic
plasma concentration-time curves and pharmacokinetic parameters
following IV and IM administration of danofloxacin at a dose
of 6 mg/kg to red-eared slider turtles are presented in Fig. 1 and
Table 1, respectively. Danofloxacin was detected in all turtles
up to 144 hr following IV and IM administration. Following IV
administration, C0 was 10.57 µg/ml at 0.5 hr and Cmax, which
was reached with Tmax of 1.5 hr following IM administration, was
8.75 µg/ml. Danofloxacin exhibited higher AUC and longer t1/2ʎz
and MRT0–∞ after IM administration than after IV administration.
Following IV administration, Vdss and ClT were 1.29 l/kg and 0.04
l/hr/kg, respectively. The bioavailability after IM administration
was 139.89%.
DISCUSSION
There were no local or systemic side effects in turtles following
IV and IM administration of danofloxacin at the dose of 6 mg/kg.
doi: 10.1292/jvms.18-0609
Table 1. Mean ± SD plasma pharmacokinetic parameters
of danofloxacin following intravenous (IV) and intramuscular (IM) administrations at the dose of 6 mg/kg in
red-eared slider turtles (n=8)
Parameter
t1/2ʎz (hr) HM
AUC0–24 (hr.µg/ml)
AUC0–144 (hr.µg/ml)
AUC0-∞ (hr.µg/ml)
MRT0-∞ (hr) HM
MAT (hr)
ClT (l/hr/kg)
Vdss (l/kg)
Tmax (hr) M
Cmax (µg/ml)
C0 (µg/ml)
F%
IV
IM
24.17 ± 1.21
86.10 ± 7.59
140.75 ± 13.30
143.31 ± 13.80
30.64 ± 1.58
0.04 ± 0.00
1.29 ± 0.11
10.57 ± 0.75
-
32.00 ± 1.50 a)
98.27 ± 8.89 a)
190.03 ± 23.41 a)
198.23 ± 25.41 a)
41.15 ± 2.26 a)
10.50 ± 2.94
1.5
8.75 ± 0.72
139.89 ± 25.16
a) Statistically different from IV administration (P<0.05). t1/2ʎz,
terminal elimination half-life; AUC, area under the plasma
concentration-versus time curve; MRT, mean residence time; MAT,
mean absorption time; ClT, total clearance; Vdss, volume of distribution
at steady state; Tmax, time to reach the peak concentration; Cmax, peak
concentration; C0, initial concentration; F, absolute bioavailability;
HM, harmonic mean; M, median.
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O. CORUM ET AL.
No side effects were reported following IV, IM, subcutaneous (SC), and oral administration of danofloxacin at the dose of 6–15
mg/kg to C. caretta [19], tilapia [8], sea bass [29], and crucian carp [27].
The mean t1/2ʎz (24.17 hr) obtained after the IV administration of danofloxacin to red-eared slider turtles was longer than that
reported in C. caretta (15.4 hr) [19] and consistent with previously reported value in Amur sturgeon (22.19 hr) [18]. Because t1/2λz
is a hybrid parameter, it is difficult to evaluate the differences in the elimination half-life between species [28]. The different t1/2λz
in the interspecies can be related to the differences in the elimination or distribution processes. In red-eared slider turtles, mean
ClT (0.04 l/hr/kg) and Vdss (1.29 l/kg) were lower (0.11 l/hr/kg) and partially similar (1.02 l/kg) to previously reported values in C.
caretta, respectively [19]. Danofloxacin has large Vdss owing to its lipophilic structure and low binding activity to plasma proteins
[12]. Although plasma protein binding activity of danofloxacin is unknown for reptiles, it ranges from 17% to 49% in other animals
[10, 12]. The larger Vdss value in this study than that observed in C. caretta may be related to the difference in the binding activity
of danofloxacin to plasma protein. Danofloxacin is metabolized into N-desmethyldanofloxacin, N-oxide, and glucuronide-conjugate
metabolites, and this metabolism differs among species [2]. In this study, lower ClT than that observed with C. caretta may be
related to the species difference in the metabolism and excretion of danofloxacin.
The t1/2ʎz and MRT0-∞ following IM administration of danofloxacin were longer than those following IV administration.
Turtles are ectotherm animals that can adapt to lower temperatures, and they can regulate their physiological and biochemical
functions based on the temperature. Therefore, cardiac output and tissue perfusion depend on ambient temperatures [16]. In this
study, maintaining turtles at 22–24°C ambient temperature may have reduced cardiac output and tissue perfusion. Reduced tissue
perfusion may have led to the restriction of elimination by causing slow absorption of danofloxacin. In addition, the long t1/2ʎz of
danofloxacin after extravascular administration may be caused by biphasic absorption process or flip–flop kinetics. However, MAT
values obtained during the study do not support the flip–flop kinetics. Biphasic absorption process or flip–flop kinetics following
the extravascular administration of danofloxacin has been reported in some species [9, 17].
The mean AUC0-∞ following IM administration of danofloxacin was higher than that following IV administration. Following
IV administration, C0 (0.5 hr) was 10.57 µg/ml, and Cmax, reached with 1.5 hr Tmax, following IM administration was 8.75 µg/
ml. Danofloxacin was detected up to 144 hr following administration via both routes. Plasma concentration at the time of last
sampling for IV and IM administrations were 0.07 and 0.18 µg/ml, respectively. In this study, Cmax and Tmax obtained following
IM administration were lower (10.25 µg/ml) and longer (1.2 hr) than previously reported values in C. caretta, respectively [19].
The mean bioavailability following IM administration in red-eared slider turtles was 139.89%. This was higher than what was
previously reported for C. caretta (104.81%) [19]. In this study, high bioavailability of danofloxacin following IM administration
may be caused by extended t1/2ʎz and increased AUC owing to the slow absorption rate related with the biphasic absorption
process.
In veterinary medicine, danofloxacin is recommended for use at the dose of 1.25–15 mg/kg [1, 27]. Because 6 mg/kg of
danofloxacin was reported to be effective against various infections in C. caretta [19], this dose level was selected for this study.
Serial blood samples were collected from dorsal cervical sinus (left and right) instead of the jugular vein because of the small sizes
of red-eared slider turtles. However in turtles, vessels except for jugular vein are contaminated with lymphatic fluid. Cmax (8.75
µg/ml) value of danofloxacin obtained in red-eared slider turtles following IM administration at 6 mg/kg dose was lower than that
reported in C. caretta (10.25 µg/ml) [19] and higher than that reported in rabbits (1.87 µg/ml) [9]. In turtles, higher plasma Cmax
level in turtles than in other animal species may be due to the lymphatic fluid being mixed into the plasma.
In conclusion, danofloxacin has clinically superior pharmacokinetic properties including the complete IM bioavailability, slow
elimination and wide volume of distribution in red-eared slider turtles. Further pharmakinetics/pharmacodynamics studies are
necessary for the treatment of diseases caused by susceptible bacteria with known MIC values in red-eared slider turtles.
ACKNOWLEDGMENT. This study was presented as an abstract at the International Health Sciences Conference (IHSC) Diyarbakir, Turkey, 14–17 November, 2018.
REFERENCES
1. Aliabadi, F. and Lees, P. 2003. Pharmacokinetic-pharmacodynamic integration of danofloxacin in the calf. Res. Vet. Sci. 74: 247–259. [Medline]
[CrossRef]
2. Anonymous. 2018. http://www.fao.org/docrep/W8338E/w8338e07.htm [accessed on July 15, 2018].
3. Ariel, E. 2011. Viruses in reptiles. Vet. Res. (Faisalabad) 42: 100. [Medline] [CrossRef]
4. Bosch, S., Tauxe, R. V. and Behravesh, C. B. 2016. Turtle-Associated Salmonellosis, United States, 2006–2014. Emerg. Infect. Dis. 22: 1149–1155.
[Medline]
5. Burger, J. 2009. Red-eared slider turtles (Trachemys scripta elegans). http://depts.washington.edu/oldenlab/wordpress/wp-content/uploads/2013/03/
Trachemys-scripta elegans_ Burger.pdf [accessed on June 15, 2018].
6. Chitty, J. and Raftery, A. 2013. Essentials of Tortoise Medicine and Surgery, Wiley Blackwell, West Sussex.
7. CVMP 2002. Danofloxacin (extension to all food producing species) summary report (6). European Agency for the Evaluation of Medicinal
Products. EMEA/MRL/818/02-FINAL. https://www.ema.europa.eu/en/documents/mrl-report/danofloxacin-extension-all-food-producing-speciessummary-report-6-committee-veterinary-medicinal_en.pdf [accessed on July 25, 2018].
8. Fan, Y. C., Sheu, S. Y., Lai, H. T., Chang, M. H., Chen, P. H., Lei, Y. C., Kuo, T. F. and Wang, C. Y. 2015. Residue depletion study of danofloxacin
in cultured tilapia (Oreochromis mossambicus). J. AOAC Int. 98: 575–579. [Medline] [CrossRef]
9. Fernández-Varón, E., Marin, P., Escudero, E., Vancraeynest, D. and Cárceles, C. M. 2007. Pharmacokinetic-pharmacodynamic integration of
danofloxacin after intravenous, intramuscular and subcutaneous administration to rabbits. J. Vet. Pharmacol. Ther. 30: 18–24. [Medline] [CrossRef]
doi: 10.1292/jvms.18-0609
756
PHARMACOKINETICS OF DANOFLOXACIN IN TURTLES
10. Friis, C. 1993. Penetration of danofloxacin into the respiratory tract tissues and secretions in calves. Am. J. Vet. Res. 54: 1122–1127. [Medline]
11. Gibbons, G. M. 2014. Advances in reptile clinical therapeutics. J. Exot. Pet Med. 23: 21–38. [CrossRef]
12. Goudah, A. and Mouneir, S. M. 2009. Disposition kinetics and tissue residues of danofloxacin in Muscovy ducks. Br. Poult. Sci. 50: 613–619.
[Medline] [CrossRef]
13. Isler, C. T., Altug, M. E., Secer, F. S. and Cantekin, Z. 2015. Treatment of bath with enrofloxacin in red-eared sliders (Trachemys scripta elegans)
suffer from conjunctivitis and its results. Kafkas Univ. Vet. Fak. Derg. 21: 429–431.
14. Jacobson, E. R., Brown, M. B., Wendland, L. D., Brown, D. R., Klein, P. A., Christopher, M. M. and Berry, K. H. 2014. Mycoplasmosis and upper
respiratory tract disease of tortoises: a review and update. Vet. J. 201: 257–264. [Medline] [CrossRef]
15. Janecko, N., Pokludova, L., Blahova, J., Svobodova, Z. and Literak, I. 2016. Implications of fluoroquinolone contamination for the aquatic
environment-A review. Environ. Toxicol. Chem. 35: 2647–2656. [Medline] [CrossRef]
16. Kik, M. J. L. and Mitchell, M. A. 2005. Reptile cardiology: a review of anatomy and physiology, diagnostic approaches, and clinical disease. J.
Exot. Pet Med. 14: 52–60.
17. Lopez, B. S., Giguère, S., Berghaus, L. J., Mullins, M. A. and Davis, J. L. 2015. Pharmacokinetics of danofloxacin and N-desmethyldanofloxacin in
adult horses and their concentration in synovial fluid. J. Vet. Pharmacol. Ther. 38: 123–129. [Medline] [CrossRef]
18. Lu, T. Y. 2004. The assessment of danofoxacin used against Amur sturgeon infected by Aeromonas hydrophila, PhD thesis, Northeast Agricultural
University, HarBin.
19. Marín, P., Bayón, A., Fernández-Varón, E., Escudero, E., Clavel, C., Almela, R. and Cárceles, C. M. 2008. Pharmacokinetics of danofloxacin after
single dose intravenous, intramuscular and subcutaneous administration to loggerhead turtles Caretta caretta. Dis. Aquat. Organ. 82: 231–236.
[Medline] [CrossRef]
20. Nakamura, S. 1995. Veterinary use of new quinolones in Japan. Drugs 49 Suppl 2: 152–158. [Medline] [CrossRef]
21. Norton, T. M. 2005. Chelonian emergency and critical care. J. Exot. Pet Med. 14: 106–130.
22. O’Keeffe, M. S. 2006. Red-eared slider turtles in Australia and New Zealand. Brisbane, Queensland 3–7 April, 2006. https://www.pestsmart.org.au/
wp-content/uploads/2010/11/REST_Workshop_April2006.pdf [accessed on June 25, 2018].
23. Potter, T., Illambas, J., Pelligand, L., Rycroft, A. and Lees, P. 2013. Pharmacokinetic and pharmacodynamic integration and modelling of
marbofloxacin in calves for Mannheimia haemolytica and Pasteurella multocida. Vet. J. 195: 53–58. [Medline] [CrossRef]
24. Rataj, A. V., Lindtner-Knific, R., Vlahović, K., Mavri, U. and Dovč, A. 2011. Parasites in pet reptiles. Acta Vet. Scand. 53: 33. [Medline]
[CrossRef]
25. Real, R., Egido, E., Pérez, M., González-Lobato, L., Barrera, B., Prieto, J. G., Alvarez, A. I. and Merino, G. 2011. Involvement of breast cancer
resistance protein (BCRP/ABCG2) in the secretion of danofloxacin into milk: interaction with ivermectin. J. Vet. Pharmacol. Ther. 34: 313–321.
[Medline] [CrossRef]
26. Summa, N. M. and Guzman, D. S. 2017. Evidence-based advances in avian medicine. Vet. Clin. North Am. Exot. Anim. Pract. 20: 817–837.
[Medline] [CrossRef]
27. Tan, C. 2008. Pharmacokinetics and residues studies of danofloxacin mesylate in crucian carps (Carassius auratus Linnaeus), Phd thesis, Hunan
Agricultural University, Hunan.
28. Toutain, P. L. and Bousquet-Mélou, A. 2004. Bioavailability and its assessment. J. Vet. Pharmacol. Ther. 27: 455–466. [Medline] [CrossRef]
29. Vardali, S. C., Kotzamanis, Y. P., Tyrpenou, A. E. and Samanidοu, V. F. 2017. Danofloxacin depletion from muscle plus skin tissue of European sea
bass (Dicentrarchus labrax) fed danofloxacin mesylate medicated feed in seawater at 16°C and 27°C. Aquaculture 479: 538–543. [CrossRef]
30. Walker, R. D. 2000. The use of fluoroquinolones for companion animal antimicrobial therapy. Aust. Vet. J. 78: 84–90. [Medline] [CrossRef]
doi: 10.1292/jvms.18-0609
757