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Intravenous pharmacokinetics of moxifloxacin following simultaneous administration with flunixin meglumine or diclofenac in sheep

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© 2020 John Wiley & Sons Ltd wileyonlinelibrary.com/journal/jvp J vet Pharmacol Therap. 2020;43:108–114.

1 | INTRODUCTION

Moxifloxacin, a fourth generation fluoroquinolone, is a broad-spec-trum antibiotic that acts against Gram-negative and Gram-positive bacteria and atypical organisms (such as Mycoplasma spp. and

Chlamydia spp.). It exhibits a higher efficacy against Streptococcus pneumoniae and Streptococcus pyogenes than that of other

fluoro-quinolones and exerts antibacterial effect by inhibiting topoisomerase II and IV enzymes, which are involved in the replication, transcription

and repair of bacterial DNA (Blondeau & Hansen, 2001; Miravitlles, 2005). Fluoroquinolones are recommended for the treatment of sev-eral diseases, including those of the central nervous, respiratory, and urinary systems, and soft and deep tissue infections in animals (Brown, 1996; Sarkozy, 2001). Although the pharmacokinetics of moxifloxacin has been assessed in a variety of species, it is not approved for use in sheep in the United States and several countries. Currently, moxi-floxacin is only approved for use in humans, but it can also be used in animals when other antibiotics are ineffective (Papich, 2016).

Received: 25 September 2019 

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  Revised: 27 December 2019 

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  Accepted: 13 January 2020 DOI: 10.1111/jvp.12841

P H A R M A C O K I N E T I C R E P O R T

Intravenous pharmacokinetics of moxifloxacin following

simultaneous administration with flunixin meglumine or

diclofenac in sheep

Feray Altan

1

 | Orhan Corum

2

 | Ramazan Yildiz

3

 | Hatice Eser Faki

4

 |

Merve Ider

5

 | Mahmut Ok

5

 | Kamil Uney

4

1Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Dicle, Diyarbakir, Turkey 2Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Kastamonu, Kastamonu, Turkey

3Department of Internal Medicine, Faculty of Veterinary Medicine, University of Mehmet Akif Ersoy, Burdur, Turkey 4Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Selcuk, Konya, Turkey 5Department of Internal Medicine, Faculty of Veterinary Medicine, University of Selcuk, Konya, Turkey

Correspondence

Feray Altan, Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Dicle, Diyarbakir, Turkey.

Email: feray.altan@dicle.edu.tr Funding information

The Coordination of Scientific Research Projects, University of Selcuk, Turkey, Grant/Award Number: 17401058

Abstract

In this study, the pharmacokinetics of moxifloxacin (5 mg/kg) was determined follow-ing a sfollow-ingle intravenous administration of moxifloxacin alone and co-administration with diclofenac (2.5 mg/kg) or flunixin meglumine (2.2 mg/kg) in sheep. Six healthy Akkaraman sheep (2 ± 0.3 years and 53.5 ± 5 kg of body weight) were used. A lon-gitudinal design with a 15-day washout period was used in three periods. In the first period, moxifloxacin was administered by an intravenous (IV) injection. In the sec-ond and third periods, moxifloxacin was co-administered with IV administration of diclofenac and flunixin meglumine, respectively. The plasma concentration of moxi-floxacin was assayed by high-performance liquid chromatography. The pharmacoki-netic parameters were calculated using a two-compartment open pharmacokipharmacoki-netic model. Following IV administration of moxifloxacin alone, the mean elimination half-life (t1/2β), total body clearance (ClT), volume of distribution at steady state (Vdss) and area under the curve (AUC) of moxifloxacin were 2.27 hr, 0.56 L h−1 kg−1, 1.66 L/ kg and 8.91 hr*µg/ml, respectively. While diclofenac and flunixin meglumine signifi-cantly increased the t1/2β and AUC of moxifloxacin, they significantly reduced the ClT and Vdss. These results suggest that anti-inflammatory drugs could increase the therapeutic efficacy of moxifloxacin by altering its pharmacokinetics.

K E Y W O R D S

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed drug groups in the veterinary field owing to their analgesic, antipyretic and anti-inflammatory effects (Lizarraga & Chambers, 2012). These drugs act by inhibiting cyclo-oxygenase (COX), which is responsible for prostaglandin synthesis from arachidonic acid (Curry, Cogar, & Cook, 2005). In addition, certain NSAIDs, such as diclofenac, indomethacin and ibupro-fen, reportedly exert antibacterial effects against organisms such as Escherichia coli, Listeria monocytogenes, Mycobacterium spp.,

Streptococcus spp. and Bacillus spp. (Ahmed, El-Baky, Ahmed,

Waly, & Gad, 2017; Mazumdar, Dastidar, Park, & Dutta, 2009). Flunixin meglumine, an NSAID containing a nicotinic acid group, is approved for use in the United States and other countries for colic, endotoxemia, and pain and inflammation in the musculoskeletal system of horses; endotoxemia, peritonitis, endocarditis, mastitis, and respiratory system infections in cattle; and septic peritonitis and visceral and postoperative pains in dogs (CVMP, 2000; Smith, Davis, Tell, Webb, & Riviere, 2008). Diclofenac, an NSAID contain-ing an acetic acid group, is approved for use in cattle, horse and pig against inflammatory diseases in Turkey and some countries worldwide. It is recommended for use in rheumatic inflammation and degeneration, lameness (arthritis and tendinitis), postopera-tive pain, mastitis, and respiratory infections in horses and cattle (Anonymous, 2018a; CVMP, 2003). They are used in an extra-la-bel manner for pain and inflammation in sheep, as there is no ap-proved NSAID other than meloxicam (Anonymous, 2018b; Curry et al., 2005; Lizarraga & Chambers, 2012).

In the veterinary field, the simultaneous use of NSAIDs and antibiotics is recommended for bacterial diseases, such as mastitis, endotoxemia and pneumonia, which are accompanied with fever and inflammation (Deleforge, Thomas, Davot, & Boisrame, 1994; Neuman, 1987). The interactions occurring between NSAIDs and antibiotics when they are simultaneously used have been widely reported (Abo El-Sooud & Al-Anati 2011; Ogino & Arai, 2007; Ogino, Mizuno, Ogata, & Takahashi, 2005). However, with such simultaneous use, it is difficult to predict how their interactions affect the pharmacokinetics and therapeutic effects. Although the pharmacokinetics of enrofloxacin changed when it was simul-taneously used with flunixin meglumine in dogs and calves (Abo El-Sooud & Al-Anati 2011; Ogino et al., 2005), no change was observed in mice (Ogino & Arai, 2007). Thus, drug interactions should be determined based on the target species. The pharmaco-kinetics of moxifloxacin has been reported when simultaneously used with meloxicam and diclofenac in rats and with ketoprofen in sheep (Chen, Guo, Xu, Wu, & Zhang, 2014; Sadariya et al., 2010; Sadariya, Patel, Bhavsar, & Thaker, 2014).

The co-administration of moxifloxacin and diclofenac or flunixin meglumine can be an example of antimicrobial and anti-inflamma-tory drug combination used by veterinary clinicians against bacte-rial diseases in sheep. However, there are no studies on how the simultaneous use of diclofenac or flunixin meglumine affects the pharmacokinetics of moxifloxacin in sheep. In this study, we aimed to investigate the effect of diclofenac (2.5 mg/kg, IV) or flunixin

meglumine (2.2 mg/kg, IV) on the pharmacokinetics of a single intra-venous (IV) dose (5 mg/kg) of moxifloxacin in sheep.

2 | MATERIALS AND METHODS

2.1 | Chemicals

The moxifloxacin analytical standard (>98%) was collected from Sigma-Aldrich. Acetonitrile, triethylamine and orthophosphoric acid (Merk) were of analytical-reagent grade. For administration in ani-mals, the parenteral preparations of moxifloxacin (Avelox®, Bayer),

diclofenac (Diclovet®, Vetas Animal Health) and flunixin meglumine

(Finadyne®, Intervet Animal Health) were used.

2.2 | Animals

The study was performed with six Akkaraman breed sheep, which were found to be healthy on clinical examination. The sheep were all females aged 2 ± 0.3 years with the mean body weight of 53.5 ± 5 kg. One week before the study, the sheep were moved to a different compartment within the enterprise. They were maintained in this compartment throughout the study period. Before and during the study, the sheep were fed commercial feed and dry alfalfa grass twice a day (at 8:00 a.m. and 8:00 p.m.). Water was provided ad li-bitum. Before the study, all the procedures to be performed in the sheep were approved by the Ethics Committee of Selcuk University Faculty of Veterinary Medicine.

2.3 | Experimental design

Before the study, two catheters were placed into the jugular veins, one in the right jugular for drug administration and a second one in the left jugular for blood sampling. The study was performed with a longitudinal pharmacokinetic design involving three periods with a 15-day washout period between administrations. In the first period, moxifloxacin (5 mg/kg) was administered to the sheep intravenously. In the second period, the same sheep were co-administered moxi-floxacin with diclofenac intravenously at a dose of 2.5 mg/kg. In the third period, moxifloxacin was co-administered with flunixin meglu-mine intravenously at a dose of 2.2 mg/kg to the same sheep. During simultaneous administration, moxifloxacin was administered approx-imately within 1 min following the administration of diclofenac and flunixin meglumine. The doses of moxifloxacin (5 mg/kg, Sadariya et al., 2014), diclofenac (2.5 mg/kg, Er, Dik, Corum, & Cetin, 2013) and flunixin meglumine (2.2 mg/kg, Welsh, McKellar, & Nolan, 1993) were determined from previous studies in sheep. No local or sys-temic adverse effects were observed in sheep after IV administra-tion of moxifloxacin alone and co-administraadministra-tion with diclofenac or flunixin meglumine. Blood samples were collected into 2-ml heparin-containing anticoagulant tubes at the following time points: before

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moxifloxacin administration (at 0 hr), at 5, 10, 15, 20, 25, 30 and 45 min, and at 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 18 hr following the administration. After centrifuging the blood at 4,000 g for 10 min blood, plasma was harvested and stored at −70°C until analysis.

2.4 | HPLC and chromatographic conditions

The plasma concentration of moxifloxacin was analysed using the high-performance liquid chromatography (HPLC)-UV system (Shimadzu) by modifying a previously reported method (Potter, Illambas, Pelligand, Rycroft, & Lees, 2013; Real et al., 2011). The HPLC system comprised a pump (LC-20AT controlled by CBM-20A), an autosampler (SIL 20A), a degasser (DGU-20A), a column oven (CTO-10A) and an SPD-20A UV-VIS detector. Data were analysed using PC-controlled LC solution software program (Shimadzu). Chromatographic separation was performed using Gemini™ C18 col-umn (250 mm × 4.6 mm; internal diameter, 5 µm; Phenomenex). The column and autosampler temperatures were maintained at 40°C and 23°C, respectively. The wavelength was set to 280 nm. The mobile phase comprising acetonitrile and 0.4% orthophosphoric acid (22:78 v/v) containing 0.04% triethylamine was pumped by the HPLC sys-tem at the flow rate of 1 ml/min.

The plasma samples, which were stocked in a deep freezer (at −70°C) until analysis, were thawed to room temperature. Thereafter, 400 μl of acetonitrile was mixed with 200 μl of plasma sample; the mixture was vortexed for 30 s and centrifuged at 10,000 g for 10 min. The clear supernatant layer of 100 μl was transferred into a polypropylene tube. Then, 100 μl of water was added and all tubes were vortexed for 10 s. The solution was transferred into auto sam-pler vials before being injected to the HPLC-UV system.

2.5 | Method validation

The moxifloxacin stock solution of concentration 1 mg/ml was pre-pared in pure water. Calibration standards (0.04–10 µg/ml) and qual-ity control samples were collected by adding the standard solutions

of moxifloxacin to blank sheep plasma. Standard curves were linear over the range of 0.04–10 µg/ml (r2 > .9997). The limit of detection,

the concentration with an S/G ratio of 3 on the chromatogram, was 0.02 µg/ml. The limit of quantification, the concentration with an S/G ratio of 6, was 0.04 µg/ml with CV of <15% and bias of ±15%. The quality control samples of moxifloxacin of concentrations 0.1, 1 and 10 µg/ml were prepared to determine the recovery, precision and accuracy of the HPLC method. The recovery of moxifloxacin from the plasma was 96%–103%. For intraday and interday precision and accuracy, analyses with six repeated measures within 6 days were performed for each level of quality control samples at 0.1, 1 and 10 µg/ml concentrations. The intraday and interday per cent coefficients of variation were ≤5.60% and ≤6.53%, respectively, whereas the intraday and interday per cent bias values were ±6.80% and ±4.70%, respectively.

2.6 | Pharmacokinetic calculations

WinNonlin 6.1.0.173 (Pharsight Corporation, Scientific Consulting Inc.) was used for plotting the plasma concentration–time curve of moxifloxacin and for calculating the pharmacokinetic parameters for each animal. The pharmacokinetic model selection was based on goodness-of-fit plots and the Akaike Information Criteria (Yamaoka, Nakagawa, & Uno, 1978). The pharmacokinetic parameters of moxi-floxacin in each animal were fitted to a two-compartment open model.

2.7 | Statistical analyses

All pharmacokinetic values are presented as geometric mean ± stand-ard deviation. Harmonic mean was calculated for distribution half-life (t1/2α), elimination half-life (t1/2β) and mean residence time (MRT), which analysed using Wilcoxon's rank-sum test. The statistical differences among other pharmacokinetic parameters determined in sheep were analysed using the one-way analysis of variance and post hoc Duncan's test. SPSS 22.0 (IBM Corp.) statistical program was used for statistical analysis, and p < .05 was considered statistically significant.

F I G U R E 1   Semi-logarithmic

plasma concentration–time curves after intravenous administration of moxifloxacin (MXF, 5 mg/kg) alone and co-administered with diclofenac (DIC, 2.5 mg/kg) or flunixin meglumine (FM, 2.2 mg/kg) in sheep (n = 6)

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3 | RESULTS

Semi-logarithmic plasma concentration–time profiles and pharma-cokinetic parameters in sheep after IV administration of moxifloxacin alone and co-administration with diclofenac, and flunixin meglumine are presented in Figure 1 and Table 1, respectively. Diclofenac and flu-nixin meglumine had no effect on the transfer rate constant of moxi-floxacin from the central to the peripheral compartment (k12), transfer

rate constant of moxifloxacin from the peripheral to the central com-partment (k21) and distribution rate constant (p > .05). Only flunixin

meglumine administration shortened the t1/2α of moxifloxacin (p < .05). The mean Vdss and ClT of moxifloxacin reduced from approximately

1.66–1.20 L/kg and from 0.56 to 0.32 L h−1 kg−1, respectively,

follow-ing co-administration of diclofenac with moxifloxacin. Similarly, flun-ixin meglumine co-administered with moxifloxacin reduced the mean Vdss of moxifloxacin from 1.66 to 1.19 L/kg and the mean ClT from 0.56

to 0.30 L h−1 kg−1. Diclofenac and flunixin meglumine prolonged the

t1/2β and MRT of moxifloxacin and increased the AUC.

4 | DISCUSSION

Plasma concentration–time curves following a single IV adminis-tration of moxifloxacin and co-adminisadminis-tration of moxifloxacin with diclofenac or flunixin meglumine in sheep best fit the two-compart-ment open model. Previously, studies conducted on calves (Goudah & Hasabelnaby, 2010), rabbits (Fernández-Varón et al., 2005), broil-ers (Goudah, 2009) and quails (Goudah & Hasabelnaby, 2014) also

revealed that the plasma concentration–time curve of moxifloxacin best fits the two-compartment open model.

In the present study, the doses were intravenously administered to eliminate the effect of bioavailability on the pharmacokinetics of moxi-floxacin. Similarly, no adverse effects have been reported following the simultaneous administration of NSAIDs and fluoroquinolone antibiot-ics in buffalo calves (Baroni et al., 2011) and dogs (Ogino et al., 2005).

Moxifloxacin has a wide distribution volume owing to its lipo-philic structure. Its tissue concentration in the lungs, liver and kidneys is higher than its plasma concentration (Goudah, 2009; Schubert, Dalhoff, Stass, & Ullmann, 2005). Moxifloxacin is a P-glycoprotein (P-gp) substrate, and the induction or inhibition of this efflux protein might alter its pharmacokinetics (Brillault et al., 2009). Nonsteroidal an-ti-inflammatory drugs, such as diclofenac, indomethacin, fenbufen and nimesulide, reportedly induce P-gp expression (Sanchez-Covarrubias et al., 2014; Takara et al., 2009). P-gp induced in some tissues might cause changes in the passage of pharmacotherapeutic agents into tis-sues; this condition leads to an increase or decrease in the plasma con-centrations of these drugs (Takara et al., 2009). In the present study, diclofenac and flunixin meglumine caused a statistically insignificant increase in the passage of moxifloxacin between compartments.

A major portion of moxifloxacin is transformed into inactive acyl-glucuronide (14%) and N-sulphonate (38%) conjugates by phase II re-actions and excreted from the body via urine and bile (Stass & Kubitza, 1999; Stass, Kubitza, Halabi, & Delesen, 2002). Moxifloxacin and its conjugates are transported by the multi-drug resistance protein (MRP)-2 into the bile (Ahmed et al., 2008) and excreted via glomer-ular filtration (Stass et al., 2002). Diclofenac or flunixin meglumine are transformed into acyl glucuronide metabolites by phase II reac-tions and excreted from the body via the urine and bile (Brady, Kind, Hyde, Favrow, & Hill, 1998; Davies & Anderson, 1997; Horii, Ikenaga, Shimoda, & Kokue, 2004). Nonsteroidal anti-inflammatory drugs can reduce the glomerular filtration rate by inhibiting prostaglandin syn-thesis (Hörl, 2010). Diclofenac and some NSAIDs reportedly exhibit an inhibitory effect on MRP-2 (Nozaki et al., 2007). It has also been reported that diclofenac inhibits the glucuronidation reaction of tes-tosterone (Sten, Finel, Ask, Rane, & Ekström, 2009), decreases Vdss and ClT of morphine, and increases Cmax and AUC of morphine by inhibiting

the glucuronidation reactions (Kimura, Muryoi, Shibata, Ozaki, & Arai, 2016). Also, diclofenac may decrease the elimination of moxifloxacin by inhibiting phase II reactions and MRP-2. However, the possible ef-fect of flunixin meglumine on P-gp, MRP-2 and glucuronidation reac-tions has not been explored, and it might be similar to that of other NSAIDs. Diclofenac and flunixin meglumine may decrease the excre-tion of moxifloxacin by reducing glomerular filtraexcre-tion rate.

Moxifloxacin binds to the plasma proteins at a low degree (30%–50%) (Goudah, 2009; Schubert et al., 2005). Diclofenac and flunixin meglumine have a high plasma protein binding with the ratio of 99.7% and 84%–100%, respectively (Anonymous, 2019; CVMP, 2003). In the present study, the high binding ratio of di-clofenac and flunixin meglumine to plasma proteins could result by decreasing protein binding of moxifloxacin. The decrease in bind-ing of moxifloxacin to plasma proteins can be expected to increase

TA B L E 1   Pharmacokinetic parameters (GM ± SD) collected after

intravenous administration moxifloxacin (MXF, 5 mg/kg) alone and co-administered with diclofenac (DIC, 2.5 mg/kg) or flunixin meglumine (FM, 2.2 mg/kg) in sheep (n = 6) Parameter MXF MXF + DIC MXF + FM k12 (1/hr) 2.20 ± 0.17 2.38 ± 0.86 2.87 ± 0.35 k21 (1/hr) 1.89 ± 0.28 2.21 ± 0.55 2.41 ± 0.41 α (1/hr) 4.52 ± 0.37 4.92 ± 1.41 5.61 ± 0.67 β (1/hr) 0.31 ± 0.00c 0.25 ± 0.01b 0.23 ± 0.01a t1/2α (hr) (HM) 0.15 ± 0.01b 0.14 ± 0.05b 0.12 ± 0.01a t1/2β (hr) (HM) 2.27 ± 0.03c 2.74 ± 0.12b 2.95 ± 0.13a MRT (hr) (HM) 2.96 ± 0.07c 3.70 ± 0.13b 4.02 ± 0.14a AUC (h*µg/mL) 8.91 ± 0.20c 15.49 ± 0.33b 16.94 ± 0.19a ClT (L/h/kg) 0.56 ± 0.01c 0.32 ± 0.01b 0.30 ± 0.00a Vdss (L/kg) 1.66 ± 0.07b 1.20 ± 0.04a 1.19 ± 0.05a

Note: Varied superscript characters in the same row are statistically different (p < .05).

Abbreviations: AUC, area under the plasma concentration–time curve;

ClT, total clearance; GM, geometric mean; HM, harmonic mean; k12,

transfer rate from central to peripheral compartment; k21, transfer rate

from peripheral to central compartment; MRT, mean residence time; t1/2α, distribution half-life; t1/2β, elimination half-life; Vdss, volume of

distribution at steady state; α, distribution rate constant; β, elimination rate constant.

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Vdss. However, an increase in plasma concentration of moxifloxacin due to reduced elimination by diclofenac and flunixin meglumine may caused the small Vdss calculation. In the present study, the decrease in Vdss and ClT of moxifloxacin following the

simultane-ous administration might be caused by the effects of diclofenac or flunixin meglumine on binding to plasma protein, transporter pro-teins, glucuronidation reactions and renal blood flow. In addition, this study was performed according to longitudinal design in three ways. Therefore, the inter-occasion variability occurring with time in animals could contribute to the pharmacokinetic differences ob-served between treatment groups.

Escherichia coli, Klebsiella pneumoniae, Pasteurella multocida, S. pneumonia, Staphylococcus aureus and Bacteroides fragilis in sheep

cause diseases such as pneumonia, abscess and diarrhoea (Bell, 2008; Musa, Babiker, Eltom, Rodwan, & El Sanousi, 2012; Myers, Firehammer, Shoop, & Border, 1984). Although the MIC values of moxifloxacin for these pathogens in sheep have not been deter-mined, they have been determined in humans (Edmiston et al., 2004; Odenholt & Cars, 2006; Schubert et al., 2005). For the above-men-tioned susceptible pathogens, the MIC value of moxifloxacin was ≤0.03–2 μg/ml (Edmiston et al., 2004; Katechakis et al., 2019; Odenholt & Cars, 2006) and the breakpoint for susceptible patho-gens is reportedly 8 μg/mL (USCAST, 2015). When pharmacokinetic and pharmacodynamic parameters are evaluated together, they pro-vide information about the efficacy of antibacterial drugs against infectious agents (Theuretzbacher, 2012).

The antibacterial effect of moxifloxacin is concentration depen-dent, and the Cmax/MIC and AUC/MIC values are used to evaluate

its antibacterial activity (Kuti, 2016; Odenholt & Cars, 2006; Rybak, 2006). The AUC/MIC ratio recommended to achieve maximum effi-cacy and to prevent the development of resistance in moxifloxacin treatment is recommended as >100 for Gram-negative bacteria and >50 for Gram-positive bacteria such as S. pneumoniae (Odenholt & Cars, 2006). In the present study, the AUC/MIC ratio of the moxi-floxacin-, moxifloxacin + diclofenac- and moxifloxacin + flunixin me-glumine-treated groups was >100 for bacteria with the MIC values of <0.09, <0.16 and <0.17 µg/ml, respectively, and >50 for bacteria with MIC values of <0.18, <0.31 and <0.34 µg/ml, respectively.

In conclusion, the administration of diclofenac or flunixin meglu-mine led to significant changes in the pharmacokinetics of moxiflox-acin. This in turn led to an increase in the therapeutic efficacy of moxifloxacin administered simultaneously with diclofenac or flunixin meglumine in sheep. However, further studies are warranted to de-termine the interactions and alterations in the therapeutic effect of moxifloxacin in case of repeated administrations. In addition, fluo-roquinolones are considered as critically important for both human and animal health (EMA, 2019). Therefore, the use of moxifloxacin in sheep should be based on current prudent-use guidelines.

ACKNOWLEDGMENTS

This study was supported by The Coordination of Scientific Research Projects, University of Selcuk, Turkey (project no. 17401058). The study was presented in the form of abstract as oral presentation in

the 5th International Symposium on Multidisciplinary Studies (ISMS), Ankara, Turkey, November 16–17, 2018.

CONFLIC T OF INTEREST

All authors declare that they have no conflicts of interest.

AUTHOR CONTRIBUTION

FA drafted the manuscript, critically revised the manuscript, provided final approval, and agreed to be accountable for all aspects of work en-suring integrity and accuracy. OC and KU contributed to conception, design, analysis, data acquisition and experimental design. RY, MI, MO and HEF contributed to experimental design. All authors agreed to be accountable for all aspects of work ensuring integrity and accuracy. All authors have read and approved the final manuscript.

ORCID

Feray Altan https://orcid.org/0000-0002-9017-763X

Orhan Corum https://orcid.org/0000-0003-3168-2510

Kamil Uney https://orcid.org/0000-0002-8674-4873

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How to cite this article: Altan F, Corum O, Yildiz R, et al.

Intravenous pharmacokinetics of moxifloxacin following simultaneous administration with flunixin meglumine or diclofenac in sheep. J vet Pharmacol Therap. 2020;43:108– 114. https ://doi.org/10.1111/jvp.12841

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