Pharmacokinetic Criteria of Ketoprofen and its Cyclooxygenase-2 Inhibition in Mice: Influence of Xylazine Administration

Abstract

The objective of this study was to examine the effect of ketoprofen with or without combination with xylazine on the level of cyclooxygenase-2 in mice. The intraperitoneal (i.p.) dose of ketoprofen and xylazine that caused an analgesic response in half of the mouse population was 1.26 mg/kg and 6.63 mg/kg, respectively. Serum cyclooxygenase-2 concentration (activity) in the control mice was 16.94 ng/ml. The ketoprofen-treated group (2.52 mg/kg, i.p.) decreased the cyclooxygenase-2 concentration by 58% (7.16 ng/ml). The combined ketoprofen and xylazine treatment (13.26 mg/kg, i.p.) decreased the cyclooxygenase-2 by 94% (0.98 ng/ml). The ketoprofen plasma concentration in the combined treatment group was significantly higher compared to the ketoprofen treatment group. Ketoprofen plasma concentrations measured at 0.25, 0.5, 1, 2, 4, and 24 hours were 19.07, 18.94, 14.66, 6.53, 5.44, and 5.54 µg/ml, respectively. Plasma concentrations of ketoprofen and xylazine were raised to 28.74, 29.74, 15.32, 13.04, 14.64, and 11.95 µg/ml or by 51%, 56%, 5%, 100%, 169%, and 116%, respectively. Ketoprofen pharmacokinetic variables were increased (AUC0-∞ (515%), AUMC0-∞ (2389%), MRT (305%), t1/2β (375%), Tmax (100%), and Cmax (55%)), while other values were decreased (Kel (79%), Vss (25%), and Cl (88%)). Our findings suggested a synergistic interaction between ketoprofen and xylazine on the level of cyclooxygenase-2 (pharmacodynamic interaction) which was exerted by modification of the ketoprofen pharmacokinetic properties in mice.

Effect of Xylazine on Pharmacokinetics and Physiological Efficacy of Intravenous Carprofen in Castrated Goats Kids

“…Xylazine administration increased the C 0.083 h (from 60.14 to 69.82 µg/mL) and AUC 0-∞ (from 1925.48 to 2361.32 h*µg/mL) of carprofen in castrated goat kids. Xylazine raised the AUC 0-∞ and peak concentration values of meloxicam in castrated goats and ketoprofen in mice, which was similar to our findings [7,42]. In this study, xylazine was administered 10 min before carprofen.…”

“…Xylazine administration reduced the Cl T of carprofen from 2.08 to 1.69 mL/h/kg in castrated male goats. Xylazine also reduced the Cl T of meloxicam in castrated goats and ketoprofen in mice [7,42]. E body of carprofen after alone and co-administered with xylazine in castrated goat kids was 0.0087 and 0.0081, respectively.…”

“…In castrated male goat, xylazine administration decreased the V dss of carprofen from 116.49 to 99.45 mL/kg. Similarly, xylazine decreased the V dss of meloxicam in castrated goats and ketoprofen in mice [7,42]. The volume of distribution is influenced by body composition, ionization state, and binding of drugs to plasma proteins [43].…”

Comparison of the Analgesic, Antipyretic, and Anti-inflammatory Efficiency Between Nimesulide and Aspirin in Mice

“…At the level of visceral pain, nimesulide and aspirin decreased the contractions of the abdomen (writhing reflex) which were induced by acetic acid. The ED100 of nimesulide was superior to that of aspirin in reduction of the number of writhing reflexes in the percentage of nimesulide (66%) in comparison to aspirin (46%) which following the previous study proved that nimesulide outperformed the diclofenac (nonselective COX2 inhibitors) in analgesic effect at assayed writhing test in mice [28][29][30][31]. Other previous studies confirmed that NSAIDs had various anti-hyperalgesic actions than nimesulide which appears to be specially more efficient and rapid acting against inflammatory nociceptive in comparison to diclofenac, celecoxib, and rofecoxib [13] which was proven in the present study that nimesulide (preferential COX2 inhibitor) having more analgesic effect than aspirin (non-selective COX inhibitor).…”