Feasibility of the Ussing chamber technique for the determination of in vitro jejunal permeability of passively absorbed compounds in different animal species.

The aim of this study was to assess the feasibility of the Ussing chamber technique for the determination of the jejunal permeability of passively absorbed, high permeability model compounds (acetaminophen and ketoprofen) in different animal species. Additionally, electrophysiological measurements and histological examination of pre- and post-incubation tissue specimens were performed. Apparent permeability coefficients of turkey and dog jejunum were low and highly variable due to tissue fragility caused by differences in thickness of the remaining intestinal layers after stripping and resulting in severe damage. Pig and horse jejunum were markedly more suitable for permeability determinations and mild signs of deterioration were noticed after 120 min of incubation. Transepithelial electrical resistance and potential difference did not correlate well with the observed tissue damage. From these data, the Ussing chamber technique appears to allow for permeability measurements within a species, but seems unsuitable for interspecies permeability comparison. However, further validation of the method with low permeability compounds and actively transported compounds is needed.

Species comparison of enantioselective oral bioavailability and pharmacokinetics of ketoprofen.

As a part of ongoing research to further elucidate frequent and species-specific causes of differences in oral bioavailability, a 3mg/kg dose of racemic ketoprofen, a high permeability/low solubility compound in the human biopharmaceutics classification system, was administered intravenously and orally to different species. Due to possible enantioselective disposition kinetics and inversion, enantiomers were quantitated separately using a stereospecific HPLC assay. The absolute bioavailability of R(-) and S(+) ketoprofen in chickens, turkeys, dogs and pigs was 31.5% and 52.6%, 42.6% and 32.5%, 33.6% and 89.1%, and 85.9% and 83.5% respectively. Incomplete bioavailability in poultry is probably due to incomplete absorption in addition to first-pass elimination. Low bioavailability of R(-) ketoprofen in dogs, strongly indicates first-pass metabolism. High bioavailability of S(+) ketoprofen in dogs and both enantiomers in pigs confirms that absorption of these substances is complete and controlled by gastric emptying rather than dissolution.

Pharmacodynamics of tepoxalin, sodium-salicylate and ketoprofen in an intravenous lipopolysaccharide inflammation model in broiler chickens.

The pharmacodynamic properties of tepoxalin, Na-salicylate and ketoprofen were determined in an intravenous lipopolysaccharide (LPS) inflammation model in broiler chickens. The drugs were administered orally at a dose of 30, 50 and 3 mg/kg, respectively. LPS administration induces an increase in the intracellular expression of interleukin (IL)-1ß and IL-6 and the secreted IL-6 plasma concentration. Furthermore, an elevation in body temperature is noted. Despite pretreatment with a single dose of the drugs and LPS administration on the T(max) of the drug after a second dose, no decrease was seen in systemic IL-6 levels. The intracellular expression of IL-1ß in the heterophils was slightly decreased if LPS was administered in combination with each of the three drugs. Tepoxalin and Na-salicylate administration had no significant effect on the LPS-induced increase in prostaglandin E(2) plasma concentration, in contrast to ketoprofen. None of the three drugs were able to influence the elevation in body temperature after LPS administration. The pharmacokinetic properties of Na-salicylate and ketoprofen were not altered in combination with LPS administration. However, LPS significantly decreased the AUC(0→6 h) of the active metabolite of tepoxalin, RWJ-20142, indicating a perfusion-limited elimination for this molecule.

Species comparison of oral bioavailability, first-pass metabolism and pharmacokinetics of acetaminophen.

Species differences in oral bioavailability, first-pass metabolism and pharmacokinetics of biopharmaceutics classification system (BCS) class I compound acetaminophen were studied. The absolute bioavailability was 42.2%, 39.0%, 44.5%, 75.5% and 91.0% in chickens, turkeys, dogs, pigs and horses, respectively. After hydrolysis of metabolites by beta-glucuronidase/sulfatase, apparent bioavailability increased significantly in all species (turkeys: 72.4%, dogs: 100.5%, pigs: 102.2%), except horses (91.6%). Mean metabolic ratios of [acetaminophen glucuronide]/[acetaminophen] between 0 and 1h were significantly higher after oral dosing in turkeys, dogs and pigs, revealing the role of first-pass metabolism in incomplete bioavailability. Evidence of species differences in acetaminophen metabolism is provided by differences in plasma clearance, which was inversely proportional to bioavailability. In conclusion, differences in BA appeared to originate predominantly from differences in first-pass metabolism, demonstrating that the BCS high permeability classification of acetaminophen is consistent across the mammalian species studied. In turkeys, however, incomplete absorption additionally seemed to contribute to the low BA.