Pharmacokinetics, urinary excretion and milk penetration of levofloxacin in lactating goats.

Levofloxacin, a recently introduced third-generation fluoroquinolone, is the L-isomer ofloxacin and possesses excellent activity against Gram-positive, Gram-negative and anaerobic bacteria (North et al., 1998). Compared with other fluoroquinolones (FQs), it also has more pronounced bactericidal activity against organisms such as Pseudomonas, Enterobacteriaceae and Klebsiella spp. (Klesel et al., 1995). Several species of staphylococci, streptococci including Streptococcus pneumoniae, bacteroides, clostridium, haemophilus, moraxella, legionella, mycoplasma and chlamydia are susceptible to levofloxacin (Langtry & Lamb, 1998). The bactericidal effect of levofloxacin is achieved through reversible binding to DNA gyrase and subsequent inhibition of bacterial DNA replication and transcription (Fu et al., 1992). Levofloxacin distributes well to target body tissues and fluids in the respiratory tract, skin, urine and prostrate, 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). FQs act by a concentration-dependent killing mechanism, whereby the optimal effect is attained by the administration of high doses over a short period of time (Drusano et al., 1993). This concentration-dependent killing profile is associated with a relatively prolonged postantibiotic effect (Aliabadi & Lees, 2001). The drug undergoes a limited metabolism in rats and human (Langtry & Lamb, 1998) and is primarily excreted by kidney mainly as active drug. Inactive metabolites (N-oxide and demethyl metabolites) represent <5% of the total dose (Hurst et al., 2002). The pharmacokinetics of levofloxacin has been fully investigated in humans (Chulavatnatol et al., 1999), rabbits (Destache et al., 2001), cats (Albarellos et al., 2005) and calves (Dumka & Srivastava, 2006, 2007). However, there is no information available on the pharmacokinetics of levofloxacin in goats. In view of the marked species variation in the kinetic data of antimicrobial drugs, the present study was undertaken to determine the pharmacokinetics, urinary excretion and milk penetration of levofloxacin following single intravenous (i.v.) and intramuscular (i.m.) administration in lactating goats. Tavanic [100 mL vial of solution of levofloxacin hemihydrate equivalent to 500 mg (5 mg ⁄mL) levofloxacin] was purchased from Aventis, Frankfurt, Germany and Mueller– Hinton agar from Mast Group Ltd., Merseyside, UK. Six adult lactating goats weighing 27–35 kg and aged from 3 to 5 years were determined to be clinically healthy before the study based on physical examination. The goats were fed on barley, alfalfa hay and wheat straw with free access to food and water. The animals did not receive any drug treatment before the study. The study was approved by the Bioethics Committee of the Faculty of Veterinary Medicine, Cairo University. The study was performed in two phases, following a crossover design (2 · 2) with a 15-day washout period between the two phases. Three animals were given a single i.v. injection into the left jugular vein at a dose of 4 mg ⁄kg bodyweight (b.w.) levofloxacin, and the other three were injected i.m. into the semimembranous muscle with the drug at the same dose. Five millilitre 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, 48 and 72 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 analysis. After a washout period of 2 weeks, the animals that had been injected i.v. with the drug were injected i.m. and vice versa. Blood was collected and processed as above. Urine and milk samples were also collected simultaneously from the same animals at various predetermined time intervals of 0.5, 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48 and 72 h postadministration. The urine samples were collected via a rubber balloon catheter (Folatex No.12; Sewoon Medical Co., Ltd, Seoul, Korea) previously inserted in the bladder and their volumes were measured. Milk samples were collected by hand stripping both halves of the udder. Complete evacuation of the udder was carried out after each sampling. The concentration of levofloxacin in plasma, urine and milk samples was estimated by a standard microbiological assay (Bennett et al., 1966) using Escherichia coli ATCC 10536 as test micro-organism. This method estimated the level of drug having antibacterial activity, without differentiating between the parent drug and its active metabolites. The reasons why we selected the bioassay are: (i) bioassay measures the total activity which could be more practical for pharmacodynamic evaluations than HPLC (McKellar et al., 1999); (ii) the bioassay method is precise, reproducible and does not require neither J. vet. Pharmacol. Therap. 32, 101–104, doi: 10.1111/j.1365-2885.2008. 01001.x. SHORT COMMUNICATION