Pharmacokinetics and pharmacodynamics of non-steroidal anti-inflammatory drugs in birds (2003)

The aims of this thesis were to investigate the pharmacokinetics and pharmacodynamics of non-steroidal anti-inflammatory drugs in birds. For decades, the inflammatory process and the properties of the NSAIDs have been extensively investigated in humans and other species. However, current knowledge on inflammation and anti-inflammatory drugs in birds is limited. Inflammation is a complex mechanism designed to protect the organism against different stimuli. NSAIDs act as inhibitors of the formation of certain mediators of inflammation, originating from the arachidonic acid cascade. In the general introduction, the literature is reviewed about the mechanism of action, the adverse reactions and the pharmacokinetics of non-steroidal anti-inflammatory drugs, and the possible indications for use of anti-inflammatory drugs in bird medicine. Due to the lack of information on NSAIDs in birds, most of the information about the mechanism of action and the adverse reactions are described based on the knowledge obtained in mammal species. In chapter 1.1., an overview about the main pharmacokinetic parameters and some bird specific anatomy and physiology is given. In chapter 2.1., the literature about the different aspects of inflammation in birds is reviewed: increased vascular permeability, leukocyte changes, acute phase proteins and inflammation mediators. On several occasions, a comparison with inflammation in mammals is made. Especially the acute phase of inflammation is described. Information on the pharmacokinetics of anti-inflammatory drugs in birds is scarce. Choice of drug and choice of dosage is usually empirical, since studies of antiinflammatory drugs are lacking. In chapter 1.2., the first experiments are described, three commonly used veterinary non-steroidal anti-inflammatory drugs (NSAIDs) were administered intravenously to five different bird species. Sodium salicylate, flunixin and meloxicam were selected as anti-inflammatory drugs. These NSAIDs were administered intravenously to chickens (Gallus gallus), ostriches (Struthio camelus), ducks (Cairina moshata), turkeys (Meleagris gallopavo) and pigeons (Columba livia). Plasma concentrations of the drugs were determined by validated high-performance liquid chromatography methods and pharmacokinetic parameters were calculated with compartment models. Also the plasma protein binding capacity of the different bird species for flunixin, meloxicam and salicylic acid at three different concentrations was studied. Most bird species exhibited a rapid elimination of these drugs. Ostriches had the fastest elimination rate for all three NSAIDs, but there were some interesting species differences. For salicylic acid, the half-life in pigeons was at least three to five times longer than the other bird species. Chickens had a half-life that was approximately ten times as long as the other bird species for flunixin and the half-life of meloxicam in chickens and pigeons was three times as long as for the other bird species. The plasma protein binding capacity for flunixin and meloxicam was moderate and showed a similar pattern for the different bird species. For salicylic acid more variation was seen between the species and pigeons exhibited a very low plasma protein binding capacity for salicylic acid. Several reasons for this difference in pharmacokinetic parameters are possible. Metabolism of these drugs can be species dependent. Therefore, the excretion pattern of sodium salicylate and its metabolites in chickens and pigeons was studied. This is described in chapter 1.3. An intravenous injection was made in these birds and the combined urinary and faecal droppings were collected at different time intervals. A marked difference was seen in the amino acid conjugation pattern of salicylic acid. Chickens used ornithine for conjugation and pigeons used glycine. Furthermore, the excretion of the glycine conjugate in pigeons was prolonged and in contrast to the ornithine conjugate in chickens, was not seen in the plasma. Based on preliminary information obtained in liver and kidney tissues of these species, it seems that the amino acid conjugation of salicylic acid with glycine in pigeons occurs only in the kidney and the amino acid conjugation of salicylic acid with ornithine in chickens occurs both in liver and in kidney. The pharmacodynamics of the NSAIDs in birds were studied in two inflammation models in chickens. In both models, sodium salicylate was used as NSAID, since this drug exhibited favourable pharmacokinetics in chickens and can be economically and practically interesting for use in poultry medicine. In chapter 2.2., an experiment where an acute inflammatory reaction was generated by implanting a carrageenan impregnated sponge strip in the subcutaneous tissue of broiler chickens is described. Half of the chickens received 50 mg/kg BW sodium salicylate orally and half received a placebo treatment. Blood and exudate samples were taken from these chickens at predetermined times. The pharmacokinetics of sodium salicylate were investigated in blood and exudate. Other parameters that were investigated were the volume of the exudate, the number of leukocytes in the exudate and the prostaglandin E2 concentration in the exudate. Also bradykinin was injected intradermally and the effects of sodium salicylate on bradykinin induced oedema were studied. Maximum salicylic acid plasma concentrations occurred within the hour after administration and maximum exudate levels were seen at the first exudate sampling point (4 h). Salicylic acid exudate concentrations exceeded plasma concentrations at the same time points and the exudate half-life was longer than the plasma half-life. No differences were found in the volume of the exudate and the leukocyte numbers between the treated and the untreated group. Sodium salicylate reduced the PGE2 concentration in the inflammatory exudate at the 4 hour time point, but at the later time points, no significant differences were found. The intradermally injected bradykinin did not produce significant effects in the chicken skin. Based on these findings, sodium salicylate may be used to suppress the inflammatory cascade in chickens, but further research is needed to characterise the inflammatory response in this chemical inflammation model and the actions of this non-steroidal antiinflammatory drug in chickens. In chapter 2.3., the last set of experiments are described. An acute phase reaction in broiler chickens was provoked through the intravenous injection of Escherichia coli lipopolysaccharide. Two experiments were set up with sodium salicylate to study the effects of this NSAID upon the LPS acute phase reaction. In the first experiment, different oral doses of sodium salicylate were given and the effect on body temperature was measured. Other inflammation indices, such as plasma corticosterone and ceruloplasmin levels, serum thromboxane B2 and zinc levels were also monitored during the experiment. In a separate experiment, food and water consumption and other behavioural parameters were studied. In the first experiment, a dose dependent attenuation of the fever response of the chickens in the salicylate treated groups was observed. Plasma corticosterone and ceruloplasmin levels rose and zinc and thromboxane B2 levels declined after an LPS injection. Except for thromboxane B2, no dose dependent differences after treatment with sodium salicylate were seen in these parameters. In the second experiment, the water intake, but not the food intake, was significantly higher in the salicylate treated group. No behavioural differences were seen between the positive control and the salicylate treated group. These data confirm that sodium salicylate is an effective antipyretic agent after injection of LPS in chickens, if used at an appropriate dosage. The general conclusions of this research after the pharmacokinetics and pharmacodynamics of NSAIDs in bird medicine are manifold : the investigated NSAIDs generally have a rapid half-life, but large species differences exist. The pharmacokinetics of other more practical administration routes need further research. The differences in metabolism may be a reason for the differences in pharmacokinetic parameters between the bird species. Salicylates have a clear antipyretic effect in chickens, but the mediation of avian inflammation and the influence of NSAIDs on disease and pain need further research.