K. Abo-EL-Sooud

Influence of Pasteurella multocida infection on the pharmacokinetic behavior of marbofloxacin after intravenous and intramuscular administrations in rabbits

The pharmacokinetic behavior of marbofloxacin was studied in healthy (n = 12) and Pasteurella multocida infected rabbits (n = 12) after single intravenous (i.v.) and intramuscular (i.m.) administrations. Six rabbits in each group (control and diseased) were given a single dose of 2 mg/kg body weight (bw) of marbofloxacin intravenously. The other six rabbits in each group were given the same dose of the drug intramuscularly. The concentration of marbofloxacin in plasma was determined using high-performance liquid chromatography. The plasma concentrations were higher in diseased rabbits than in healthy rabbits following both routes of injections. Following i.v. administration, the values of the elimination half-life (t(1/2beta)), and area under the curve were significantly higher, whereas total body clearance was significantly lower in diseased rabbits. After i.m. administration, the elimination half-life (t(1/2el)), mean residence time, and maximum plasma concentration (C(max)) were higher in diseased rabbits (5.33 h, 7.35 h and 2.24 microg/mL) than in healthy rabbits (4.33 h, 6.81 h and 1.81 microg/mL, respectively). Marbofloxacin was bound to the extent of 26 +/- 1.3% and 23 +/- 1.6% to plasma protein of healthy and diseased rabbits, respectively. The C(max)/MIC (minimum inhibitory concentration) and AUC/MIC ratios were significantly higher in diseased rabbits (28 and 189 h) than in healthy rabbits (23 and 157 h), indicating the favorable pharmacodynamic characteristics of the drug in diseased rabbits.

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

Pharmacokinetics and intramuscular bioavailability of difloxacin in dromedary camels (Camelus dromedarius).

Single-dose disposition kinetics of difloxacin (5mg/kg bodyweight) were determined in clinically normal male dromedary camels (n=6) following intravenous (IV) and intramuscular (IM) administration. Difloxacin concentrations were determined by high performance liquid chromatography with fluorescence detection. The concentration-time data were analysed by compartmental and non-compartmental kinetic methods. Following a single IV injection, the plasma difloxacin concentration-time curve was best described by a two-compartment open model, with a distribution half-life (t(1/2alpha)) of 0.22+/-0.02h and an elimination half-life (t(1/2beta)) of 2.97+/-0.31h. Steady-state volume of distribution (V(dss)) and total body clearance (Cl(tot)) were 1.02+/-0.21L/kg and 0.24+/-0.07L/kg/h, respectively. Following IM administration, the absorption half-life (t(1)(/)(2ab)) and the mean absorption time (MAT) were 0.44+/-0.03h and 1.53+/-0.22h, respectively. The peak plasma concentration (C(max)) of 2.84+/-0.34microg/mL was achieved at 1.42+/-0.21h. The elimination half-life (t(1/2el)) and the mean residence time (MRT) was 3.46+/-0.42h and 5.61+/-0.23h, respectively. The in vitro plasma protein binding of difloxacin ranged from 28-43% and the absolute bioavailability following IM administration was 93.51+/-11.63%. Difloxacin could be useful for the treatment of bacterial infections in camels that are sensitive to this drug.

Effect of Paracetamol on the Pharmacokinetics of Cephalexin in Dogs

The pharmacokinetics of single oral dose (20 mg kg b.wt.) of cephalexin alone and concomitantly with paracetamol was studied in normal healthy dogs. Moreover, the effect of simultaneous co-administration during five continuous days of treatment on hepato-renal functions was also evaluated. Cephalexin was rapidly absorbed from the gastrointestinal tract and the calculated peak serum concentration of cephalexin Cmax was 16.47 μg ml -1 attained at 1.96 h (tmax). Paracetamol treatment significantly decreased the cephalexin concentrations from 30 minutes till 4 hours post administration. Paracetamol significantly lowered the peak serum concentration and the area under the concentration curve AUC of cephalexin. The relative bioavailability (Fr) of cephalexin with paracetamol was 76.65%. The percents of cephalexin protein binding in normal dogs serum either alone or in combination with paracetamol were 15.60, and 14.24 % respectively, indicating that the co-administration were significantly decreased the binding tendency. Following multiple doses of cephalexin alone, AP, ALT and AST activities, urea and creatinine were significantly increased till the fifth day then returning to the normal level. While concomitant administration of cephalexin with paracetamol induced transient significantly increases in the concentrations of urea and creatinine during the treatment period. Therefore, concomitant use of paracetamol with cephalexin may require close monitoring for clinical consequence of potential drug interaction.