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Original Scientific Article PHARMACOKINETICS of CIPROFLOXACIN in BROILER CHICKENS AFTER SINGLE INTRAVENOUS and INTRAINGLUVIAL ADMINISTRATION

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Original Scientific Article PHARMACOKINETICS of CIPROFLOXACIN in BROILER CHICKENS AFTER SINGLE INTRAVENOUS and INTRAINGLUVIAL ADMINISTRATION Macedonian Veterinary Review Mac Vet Rev 2017; 40 (1): 67-72 Available online at www.macvetrev.mk Original Scientific Article PHARMACOKINETICS OF CIPROFLOXACIN IN BROILER CHICKENS AFTER SINGLE INTRAVENOUS AND INTRAINGLUVIAL ADMINISTRATION Sofiya Ivanova1, Dimitrichka Dimitrova2, Metodi Petrichev1 1Non-infectious Diseases Unit, National Diagnostic and Research Veterinary Medical Institute, Sofia, Bulgaria 2Department of Internal Non-infectious Diseases, Pathology and Pharmacology, Faculty of Veterinary Medicine of the University of Forestry, Sofia, Bulgaria Received 9 June 2016; Received in revised form 12 December 2016; Accepted 12 January 2017 ABSTRACT The trial was performed on 10 clinically healthy Ross hybrid chickens, 5 from each gender, weighing 2.75-2.84 kg. The tested quinolone was applied at the same dose for both routes of application - 10 mg/kg of body weight. Ciprofloxacin hydrochloridum 5% solution for i.v. and 1% solution for intraingluvial treatment were prepared. In a crossover study design, ciprofloxacin hydrochloridum was administered as 5 % solution for i.v. bolus injection to broiler chickens and after 14 days as 1 % solution for intraingluvial administration into a crop to the same birds. Serum ciprofloxacin concentrations were assayed by HPLC with UV detection at a wavelength of 279 nm. After intravenous injection the following pharmacokinetic m parameters were determined: t1/2b = 9.07 h; t1/2a= 0.36 h; MRT = 10.20 h and MRT = 10.75 h; AUC0→∞ = 19.560 g.h/mL and m AUC0→∞ = 19.843 g.h/mL. After intraingluvial application parameters determined by the two pharmacokinetic models were m as: t1/2a= 0.86 h; t1/2b = 7,20 h and t1/2b = 7.89 h; MRT = 12.67 h and MRT = 12.93 h; AUC0→∞ = 11.340 g.h/mL and AUC0→24 h = m m m 11.973 g.h/mL; Cmax = 2.841 g/mL and Cmax = 2.638 g/mL; Tmax = 0.48 h and Tmax = 0.39 h; t1/2abs. = 0.146 h; MAT = 2.47 h and MAT = 2.18 h; F = 57.91% and F = 63.89%. These results suggested that a dose of 10 mg/kg of body weight provides maximum plasma concentration ater intraingluvial administration and is effective in the control of many infectious diseases of poultry. Key words: ciprofloxacin, pharmacokinetics, chickens INTRODUCTION that it is most efficient against Gram-negative microorganisms and mycoplasmae (1, 2). The Ciprofloxacin is a fluorinated quinolone with a pyperazine ring to position 7 of the ciprofloxacin broad antimicrobial spectrum and high bactericidal molecule is responsible for its activity against activity. It is highly effective against a variety of Pseudomonas, while the fluorine atom at position bacteria – Gram-negative, including Pseudomonas 6 confers activity against some Gram-positive and Enterobacteriaceae, as well as some Gram- bacteria (3, 4). positive organisms and many anaerobes and The bactericide activity of ciprofloxacin, facultative anaerobes. In-vitro tests of the effects similarly to other fluoroquinolones, is due to of different quinolones against some bacterial the effect on bacterial DNA gyrase (5). The drug pathogens in veterinary practice demonstrated suppresses DNA gyrase through interaction with microbial DNA (2). Corresponding author: Prof. Dimitrichka J. Dimitrova, PhD Ciprofloxacin is well tolerated by animals after E-mail address: [email protected] parenteral application (6-13). In the organism, it Present address: Department of Internal Non-infectious Diseases, Pathology and Pharmacology, Faculty of Veterinary Medicine of the is metabolised in the liver. In humans, there are University of Forestry, Sofia, Bulgaria Phone: +359 02 819 2951 fiur ciprofloxacin metabolites (sulfociprofloxacin, Copyright: © 2017 Ivanova S. This is an open-access article published oxociprofloxacin, desethylenciprofloxacin and under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, formyl-ciprofloxacin), which are excreted with provided the original author and source are credited. the bile. In animals, it is converted only to two Competing Interests: The authors have declared that no competing interests exist. metabolites - desethyl-eneciprofloxacin and Available Online First: 1 February 2017 oxociprofloxacin, detected in the urine of calves Published on: 15 March 2017 http://dx.doi.org/10.1515/macvetrev-2017-0013 and monkeys (6, 14). Ivanova S. et al. The possible use of ciprofloxacin for treatment the drug. Water was withheld for 4 h (1 h before of infections, provoked by Mycoplasma and ciprofloxacin application and 3 h after that). A secondary infections (respiratory colibacillosis and 2-week wash-out period was allowed between the pasteurellosis) in birds and pigs requires detailed two routes of application of the quinolone. information about the pharmacokinetic behaviour Care and handling of animals were performed – distribution, metabolism, elimination and in accordance with the provisions for welfare of bioavailability of ciprofloxacin in food-producing Regulation (EC) No 882/2004 of the European animal species. Therefore, the purpose of the present Parliament and of the Council of 29 April 2004 experiment was to follow up the pharmacokinetics adopted by the Government of the Republic of of this fluoroquinolone in broiler chickens after Bulgaria with Ordinance No 20 from 01.11.2012. intravenous and intraingluvial application. Blood sampling Blood samples of 1 mL were collected from the MATERIAL AND METHODS left wing’s v. brachialis before drug application and at post treatment hours 0.085, 0.17, 0.33, 0.50, 1, 2, Animals and housing 3, 4, 5, 9, 12 and 24. The serum was separated by The present pharmacokinetic experiment centrifugation at 1500×g for 10 min. Blood serum was conducted with 10 sexually mature Ross samples was stored frozen at –25° С over 3 days broiler chickens from both sexes, 60 days of age, until analysis. weighing 2.75 to 2.840 kg. They were reared in compliance with the standards for the species and Analysis of samples fed a compound feed for stock layers. The ambient For assays, ciprofloxacin hydrochloridum temperature in the premise was 22-23°C, with substance purchased from Actavis Ltd – Sofia was continuous ventilation and mixed lighting regimen: used, as well as acetonitrile HPLC grade (Merck); 12-hour light period between 8.00 AM and 8.00 triethylamine (TEA; Merck); tetrabutyl ammonium PM. The birds were floor reared, and food and water hydrochloride 40% (TBA, Merck); phosphoric acid were provided аd libitum. Before the beginning of 85% (Merck) and perchloric acid for analysis 70% the pharmacokinetic trial, the birds were neither (Merck). The water used in the analyses was treated vaccinated nor treated with other drugs. through a Millipore purifying system. Drugs Chromatography system In this study, the substance ciprofloxacin Serum ciprofloxacin concentrations were hydrochloridum was used (Actavis Ltd, Sofia, assayed by HPLC with UV detection according to Bulgaria), dissolved ex tempore in sterile distilled the slightly modified method of Imre et al. (15). The water to obtain 5% solution for intravenous and 1% difference consisted in substituting blood serum for solution for oral (intraingluvial) application. plasma. The chromatography was run on HPLC system Waters equipped with quaternary pump, Experimental design HPLC with UV detector, protected and analytical The tested fluoroquinolone was applied once, columns Lichrospher (Beckman). intravenously or intraingluvially at a dose of 10 mg/ The mobile phase consisted of acetonitrile kg of body weight after preliminary dissolution in and water (1:1), supplemented with 3% potassium sterile distilled water. Intravenous solutions were phosphate buffer, 2% ТЕА and 2% ТВА. Mobile warmed to 37° С, whereas the solution for oral use phase pumping rate was 1.2 ml/min. Chromatograms was at room temperature. were integrated with a computer program. For intravenous application, solutions were The reference standard of ciprofloxacin was injected in the wing vein (v. brachialis) of the right used to prepare a stock solution, which was used wing of chickens, and those for oral application to fortify serum from untreated chikens (control were introduced in the crop by means of an elastic serum). silicone probe and a syringe. The intraingluvial The calibration curve for ciprofloxacin consisted application was performed after a 16-hour fasting of 7 standard solutions that ranged from 0.05 to period (from 4.00 PM the day before to 8.00 AM 10 mg/mL and included a blank (0 mg/mL) sample. on the test day). Food deprivation continued for The calibration curve was accepted if the linear another 6 hours after the crop administration of coefficient of determination (R2) was ≥ 0.99 and if 68 Pharmacokinetics of ciprofloxacin after intravenous and intraingluvial administration the calibration curve concentrations could be back- concentration time curves after single intravenous calculated to within < 15% of the true concentration or intraingluvial application (16). For description of of the standard. All serum, calibration, quality- drug behaviour, two pharmacokinetic models were control, and blank serum samples were prepared in used –compartmental and non-compartmental an identical manner. analysis (17). The pharmacokinetic modelling was done according to Akaike’s criterion (18). Preparation of samples Pharmacokinetic parameters were presented as Blood proteins were precipitated by consecutive means (Means) ± standard error (SE). The absolute addition of two acids – 85% phosphoric acid and 70% bioavailability (F) after
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