Browsing by Subject "kidney"

Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) widely used for the treatment of pain in sheep and swine. Information of correct ketoprofen doses in different animal species is limited. The correct dose cannot be reliably extrapolated based on other species or human. The problem in cases of suspected overdose is knowing whether the given dose was toxic. The objective of the study with sheep was to figure out if the kinetics of ketoprofen is altered by a tenfold overdose, study the effect of the overdose to kidneys and find out a way to diagnose overdose by a simple urine test. The objective of the study with swine was to figure out the bioavailability and pharmacokinetics of ketoprofen after oral, intramuscular and intravenous administration. The most important variables were AUC0-_, Cmax and Tmax. Bioavailability was calculated based on intravascular administration. 30 mg/kg ketoprofen was administered intravenously to six sheep. The concentration of ketoprofen in sheep plasma was followed for 24 hours. Pharmacokinetic parameters were calculated afterwards. Blood and urine samples were analysed to detect enzyme markers indicating possible renal failure. The sheep were finished off 24 hours after the administration and the possible damage to kidneys was evaluated from histological samples. Ketoprofen was also administered to eight swine. The doses were 3 mg/kg of oral, intramuscular and intravascular, and 6 mg/kg of oral ketoprofen. The study was performed as a randomized, cross-over study. The concentration of ketoprofen in swine plasma was followed for 48 hours after administration. Pharmacokinetic parameters were calculated and bioequivalence evaluated afterwards. The in vivo -studies of both of the studies as well as the histological study of the kidneys, and the urine and blood analysis except for the analysis of ketoprofen concentration, were carried out by the researchers of the Faculty of Veterinary Medicine. Plasma ketoprofen concentrations were measured by high-performance liquid chromatography (HPLC). Drug concentration and pharmacokinetic analysis were carried out in the Faculty of Pharmacy. The tenfold dose of ketoprofen was toxic in sheep. Serum concentrations of urea and creatinine increased. Histological samples revealed acute tubular damage. Many urine enzyme concentrations increased. The rise of urine lactate dehydrogenase (LD) concentration was most significant and earliest. LD appears to be a potential marker of a toxic ketoprofen dose. Compared with the therapeutic dose, overdose did not affect ketoprofen elimination rate from plasma, so the kinetics of ketoprofen was not altered. AUC- and Cmax -values were over tenfold compared to the therapeutic dose, so the values did not rise linearly as the dose reached a toxic level. Bioequivalence of ketoprofen in swine was not observed between different routes of administration. The bioavailability was excellent in all routes of administration. Tmax was slightly over one hour after administration. Cmax and AUC were 5,1 mg/l and 32 mg l-1 h after oral 3 mg/kg dose and 7,6 mg/l and 37 mg l-1 h after intramuscular dose. The increases in AUC and Cmax were linear between the different dosages of oral ketoprofen. The difference of the elimination rates between oral and intravascular administration was statistically significant. Ketoprofen distribution volume and clearance did not differ significantly between different routes of administration.