Abstract
Doxycycline is a well-tolerated tetracycline antibiotic, registered for use in rabbits and administered for treatment of bacterial infections in this animal species. Nevertheless, the available pharmacokinetic data are limited and this study aimed to investigate the pharmacokinetics of orally administered doxycycline in mature and immature rabbits by application of the population approach. The rabbits were treated orally with doxycycline hyclate (5 mg/kg bw) in the form of a solid gelatin capsules. Free plasma concentrations were determined with HPLC analysis with Photodiode array detection. The estimated typical value of volume of distribution (tvV), total body clearance, and absorption rate constant were 4.429 L/kg, 1.473 L/kg/h, and 0.257 h−1, respectively. The highest between-subject variability (BSV) of 69.30% was observed for tvV. Co-variates such as body weight, age, and biochemical parameters did not improve the tested model and did not contribute to explanation of the BSV. The population pharmacokinetic model of the orally administered doxycycline in rabbits should be further developed by addition of data from more animals treated with higher doses. An oral dose of 5 mg/kg could ensure percentage of the time from the dosing interval during which the concentration is above minimum inhibitory concentration (MIC) %fT > MIC of 35% if MIC of 0.18 μg·mL−1 and a dosing interval of 12 h is assumed which does not cover criteria for rational use of antibiotics.
Highlights
The importance of rabbits in veterinary medicine is increasing due to the high nutritional value of rabbit meat and their breeding as pets [1,2]. This animal species often suffers from infections caused by pathogenic bacteria such as Pasteurella multocida, Staphylococcus aureus, Bordetella bronchiseptica, Salmonella spp., Escherichia coli, Clostridium spp., and Pseudomonas spp. [3,4]
Administration of antimicrobials is not well tolerated by rabbits and treatment with penicillins, cephalosporins, macrolides, and lincosamides is associated with enteritis [11] as they destroy normal gastrointestinal microbiota allowing overpopulation of pathogenic bacteria such as E.coli and Clostridium spiroforme [12]
The maximum plasma concentrations (Cmax) and the time of Cmax (Tmax) in mature rabbits read from the observed data, were 0.58 ± 0.15 μg·mL−1 and 3.40 ± 0.96 h, respectively
Summary
The importance of rabbits in veterinary medicine is increasing due to the high nutritional value of rabbit meat and their breeding as pets [1,2] This animal species often suffers from infections caused by pathogenic bacteria such as Pasteurella multocida, Staphylococcus aureus, Bordetella bronchiseptica, Salmonella spp., Escherichia coli, Clostridium spp., and Pseudomonas spp. Different values of Cmax between 1.10 ± 0.00 μg·mL−1 and 2.06 ± 2.96 μg·mL−1 were reported for the drug in studies conducted with various dosage forms and doses These concentrations were achieved at Tmax between 0.55 ± 0.33 and 0.70 ± 0.48 h for suppositories, 3.00 h for the solution and 12.00 h for chitosan microcapsulated suspension [17,18]. No data are published about the pharmacokinetics of doxycycline in young animals, which often suffer from infections caused by the above-mentioned pathogens
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