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 Blood samples were withdrawn from the caudal artery at 0 h (before the administration of the drug) and at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 8.0, and 24.0 h after drug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. …show more content…
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
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. …show more content…
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