Pharmacokinetics of levofloxacin in male camels (Camelus dromedarius).

Levofloxacin (())-9-fluoro-3-methyl-10-(4-methyl-1-piprazinyl)7-oxo-2,3-dihydro-7Hpyrido [1,2,3-de]-[1,4]-benzoxazine-6carboxylic acid) is a third-generation fluoroquinolone (Martinez et al., 2006), effective new respiratory fluoroquinolone, is separated from the racemic compound ofloxacin, and is the pure S-(2) isomer. Levofloxacin possesses excellent activity against Gram-positive, Gram-negative and anaerobic bacteria (Davis & Bryson, 1994; North et al., 1998), as well as atypical pathogens such as Mycoplasma, Chlamydia and Legionella (Eliopoulos et al., 1996). Compared to other fluoroquinolones, ofloxacin and ciprofloxacin, it also has more pronounced bactericidal activity against organisms such as Pseudomonas, Enterobacteriaceae and Klebsiella (Klesel et al., 1995). The pharmacokinetics of levofloxacin has been investigated in rabbits (Destache et al., 2001) and calves (Dumka & Srivastava, 2006, 2007). However, there is no information available on the pharmacokinetics of levofloxacin in camel. Levofloxacin distributes well to target body tissues and fluids in the respiratory tract, skin, urinary tract, prostrate, other soft tissues and body fluids and its uptake by cells makes it suitable for use against intracellular pathogens. However, it penetrates poorly into the central nervous system (Langtry & Lamb, 1998). Several studies have presented levofloxacin as a safe and effective treatment for communityacquired pneumonia, and have indicated it to be at least equivalent to cephalosporins like ceftriaxone and cefuroxime (Shah & Members of the International Study Group, 1997; Norrby et al., 1998). The pharmacokinetic profile of levofloxacin supports oncedaily administration and, because of its high tissue distribution, levofloxacin may also be suitable in the treatment of bone diseases (Djabarouti et al., 2004). Based on its pharmacological profile, levofloxacin could be a promising therapeutic tool for several infections in camels. Consequently, the present study was undertaken to determine the pharmacokinetics, plasma protein binding of levofloxacin in camels following single intravenous and intramuscular administration and to investigate the bioavailability after the extravascular route. Tavanic (100 mL vial of solution of levofloxacin hemihydrate equivalent to 500 mg (5 mg ⁄ mL) levofloxacin) was purchased from Sanofi-Aventis, Frankfurt, Germany. This study was carried out on eight adult healthy male camels (Camelus dromedarius), weighing 380–500 kg and aged from 6 to 8 years old. Camels were determined to be clinically healthy before each study, based on history and physical examination. The camels were fed commercially-prepared concentrates beside alfalfa hay and wheat straw, with free access to food and water. The study was approved by the Bioethics Committee of the Faculty of Veterinary Medicine, Cairo University. A crossover design was used in two phases (4 · 4), with a washout period of two weeks. Four animals were given a single intravenous injection into the left jugular vein at dose of 4 mg ⁄ kg bodyweight levofloxacin, and the other four were injected intramuscularly into the semimembranous muscle with the drug at the same dose. Five ml venous whole blood samples were taken by jugular venepuncture into 10 mL heparinized Vacutainers (Becton Dickinson vacutainer Systems, Rutherford, NJ, USA). The sampling times were 0 (blank sample), 0.08, 0.166, 0.33, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 18, 24, 36 and 48 h after treatment. All the blood samples were centrifuged at 3000 g for 15 min to separate the plasma. The plasma samples were frozen at –20 C until analysed. After a washout period of 2 weeks, the animals that had been injected intravenously with the drug were injected intramuscularly and vice versa. Blood was collected and processed as above. Quantitation of levofloxacin in plasma samples was accomplished by a modified agar diffusion bioassay method previously reported by Bennett et al. (1966), using Escherichia Coli (ATCC 10536) as the reference organism. The microbiological assay does not distinguish the parent compound from the possible active metabolites. This approach seems to be justified by the fact that the metabolism of levofloxacin in camels is unknown, and hence all biologically active substances are detected in microbiological assay and this total activity which could be more useful for pharmacodynamic evaluations than a chemical method (McKellar et al., 1999). A linear relationship existed between the zone of inhibition and the logarithm of levofloxacin concentrations in plasma with a correlation rate of elimination of 0.995. The limit of quantification for the plasma was 0.04 lg ⁄ mL. The mean percentage recovery of levofloxacin (measured by comparing zone of inhibitions of the spiked samples with external standards in phosphate buffer saline) from plasma was 95%. The intra-assay variation coefficient was <4.3 and the inter-assay variation coefficient was <4.7 for plasma. The extent of protein binding was determined in vitro according to the method described previously by Craig and Suh (1991). This method is based on the diffusion of free antibiotic into the agar medium. The differences in the diameters of the inhibition zones between the solutions of the drugs in the buffer and plasma samples were then calculated. J. vet. Pharmacol. Therap. 32, 296–299, doi: 10.1111/j.1365-2885.2008. 01023.x. SHORT COMMUNICATION