Pharmacokinetics and Pharmacodynamics of (S)-Ketoprofen Co-Administered with Caffeine: A Preclinical Study in Arthritic Rats

Abstract

The purpose of the present study was to determine whether caffeine modifies the pharmacokinetics and pharmacodynamics of (S)-ketoprofen following oral administration in a gout-type pain model. 3.2 mg/kg of (S)-ketoprofen alone and combined with 17.8 mg/kg of caffeine were administered to Wistar rats and plasma levels were determined between 0.5 and 24.0 h. Additionally, antinociception was evaluated based on the protocol of the PIFIR (pain-induced functional impairment in the rat) model before blood sampling between 0.5 and 4.0 h. Significant differences in Cmax, AUC0-24, and AUC0-∞ values were observed with caffeine administration (p < 0.05). Also, significant differences in Emax, Tmax, and AUC0-4 values were determined when comparing the treatments with and without caffeine (p < 0.05). By relating the pharmacokinetic and pharmacodynamic data, a counter-clockwise hysteresis loop was observed regardless of the administration of caffeine. When the relationship between AUCe and AUCp was fitted to the sigmoidal Emax model, a satisfactory correlation was found (R2 > 0.99) as well as significant differences in Emax and EC50 values (p < 0.05). With caffeine, Emax and EC50 values changed by 489.5% and 695.4%, respectively. The combination studied represents a convenient alternative for the treatment of pain when considering the advantages offered by using drugs with different mechanisms of action.

The Effect of Coffee on Pharmacokinetic Properties of Drugs : A Review

“…When ketoprofen is administered with caffeine, the values of C max and AUC were increased by 90.1% and 82.7%, respectively. The ketoprofen plasma concentrations were determined by HPLC analysis with ultraviolet (UV) detection [27].…”

“…The most probable reason, according to the authors, is due to decreasing gastric pH, reducing gastric emptying, and increasing blood flow of the gastric mucosa effects of caffeine. In addition, coffee decreases the metabolic clearance of ketoprofen by decreasing the liver blood flow [27]. A study done on voluntary humans in Malaysia showed that there was an increase in the paracetamol rate and extent of absorption with coffee containing 65 and 195 mg of caffeine.…”

“…The most probable reason, according to the authors, is due to decreasing gastric pH, reducing gastric emptying, and increasing blood flow of the gastric mucosa effects of caffeine. In addition, coffee decreases the metabolic clearance of ketoprofen by decreasing the liver blood flow [ 27 ].…”

“… Variation of the pharmacokinetic profile when orally administered with ketoprofen alone (3.2 mg/kg) and ketoprofen administered with caffeine (17.8 mg/kg) in rats (redrawn from published paper [ 27 ]). …”

“…Levodopa plasma concentration profile after administration of a single oral dose of levodopa 250 mg alone and with caffeine 200 mg in human volunteers (Redrawn from published paper[25]). alone (3.2 mg/kg) Ketoprofen (3.2 mg/kg) with caffeine (17.8 mg/kg) Variation of the pharmacokinetic profile when orally administered with ketoprofen alone (3.2 mg/kg) and ketoprofen administered with caffeine (17.8 mg/kg) in rats (redrawn from published paper[27]). …”