The purpose of the present study was to determine whether caffeine modifies the\npharmacokinetics and pharmacodynamics of (S)-ketoprofen following oral administration in a\ngout-type pain model. 3.2 mg/kg of (S)-ketoprofen alone and combined with 17.8 mg/kg of\ncaffeine were administered to Wistar rats and plasma levels were determined between 0.5 and\n24.0 h. Additionally, antinociception was evaluated based on the protocol of the PIFIR (pain-induced\nfunctional impairment in the rat) model before blood sampling between 0.5 and 4.0 h. Significant\ndifferences in Cmax, AUC0-24, and AUC0-âË?ž values were observed with caffeine administration\n(p < 0.05). Also, significant differences in Emax, Tmax, and AUC0-4 values were determined when\ncomparing the treatments with and without caffeine (p < 0.05). By relating the pharmacokinetic\nand pharmacodynamic data, a counter-clockwise hysteresis loop was observed regardless of the\nadministration of caffeine. When the relationship between AUCe and AUCp was fitted to the\nsigmoidal Emax model, a satisfactory correlation was found (R2 > 0.99) as well as significant differences\nin Emax and EC50 values (p < 0.05). With caffeine, Emax and EC50 values changed by 489.5% and\n695.4%, respectively. The combination studied represents a convenient alternative for the treatment\nof pain when considering the advantages offered by using drugs with different mechanisms of action.
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