Pharmacokinetics Of S)-Ketoprofen Case Study

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2.3. Pharmacokinetics of (S)-ketoprofen
2.3.1. Blood sampling
On the day of the study, rats were cannulated approximately 30 min before uric acid injection and 3 h before the drugs were administered. The animals were anesthetized and the caudal artery was cannulated with a PE-10 cannula (Clay Adams, Parsippany, NJ, USA) connected to a PE-50 cannula. The cannula was kept patent with heparinized saline solution and stopped with a needle. Rats were allowed to recover from anesthesia and (S)-ketoprofen alone or combined with caffeine was orally administered. Blood samples were withdrawn from the caudal artery at 0 h (before the administration of the drug) and at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 8.0, and 24.0 h after drug administration.
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From the time courses obtained, the following pharmacokinetic parameters were determined: maximum plasma concentration (Cmax), time to achieve this value (Tmax), area under the curve from zero time until 24.0 h after drug administration (AUC0-24), area under the curve from zero time to infinity (AUC0-∞), rate constant of the terminal phase of elimination (λz), half-life of elimination (t½) and mean residence time (MRT). Non-compartmental analysis was performed using the Excel add-in PKSolver [32]. Treatment effect on pharmacokinetic parameters was tested using unpaired Student’s t-test after logarithmic transformation. Differences were considered statistically significant if p < 0.05. Antinociceptive temporal courses for (S)-ketoprofen alone and combined with caffeine were plotted for each treatment. Mean Emax, Tmax were calculated directly from the observed data. Area under the effect–time curve (AUC0-4) values were calculated by the trapezoidal rule [33]. Treatment effect on Emax, Tmax and AUC0-4 was tested using unpaired Student’s t-test. Differences were considered statistically significant if p < 0.05. In order to investigate the relationship between the antinociceptive effect observed and (S)-ketoprofen plasma concentrations under different experimental conditions, mean FI% was plotted against mean plasma concentrations at each sampling time during the first 4.0 h. If the resulting curve exhibited a counterclockwise hysteresis loop, then a distribution delay between the systemic drug concentration and the time to reach the effect site was suggested. Finally, as a previously reported technique [34], the cumulative area under the effect–time curve (AUCe %h) vs. cumulative AUC plasma concentrations-time curve (AUCp µgh/mL) of (S)-ketoprofen alone and combined with caffeine, were plotted and fitted to the sigmoidal Emax model according to the

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