PHARMACOKINETICS AND PHARMACODYNAMICS OF KETOPROFEN IN CALVES APPLYING PK/PD MODELING

The pharmacokinetics (PK) and pharmacodynamics (PD) of ketoprofen (KTP) were studied in calves following intravenous administration of the drug racemate at a dose rate of 3 mg/kg. To evaluate the anti-inflammatory properties of KTP, a model of acute inflammation, consisting of surgically implanted subcutaneous tissue cages stimulated by intracaveal injection of carrageenan, was used. No differences were observed between disposition curves of KTP enantiomers in plasma, exudate or transudate. This indicates that in calves KTP pharmacokinetics is not enantioselective. S(+)- and R(-)- KTP each had a short elimination half-life (t(1/2 beta)) of 0.42 +/- 0.08 h and 0.42 +/- 0.09 h, respectively. The volume of distribution (V-d) was low, values of 0.20 +/- 0.06 L/kg and 0.22 +/- 0.06 L/kg being obtained for R(-) and S(+)KTP, respectively. Body clearance (CIB) was high, correlating with the short elimination half-life, 0.33 +/- 0.03 L/kg/h [R(-)KTP] and 0.32 +/- 0.04 L/kg/h [S(+)-KTP]. KTP pharmacodynamics was evaluated by determining the effects on serum thromboxane (TxB(2)), exudate prostaglandin (PGE(2)), leukotriene (LTB(4)) and beta-glucuronidase (beta-glu) and bradykinin (BK)-induced oedematous swelling. Effect-concentration inter-relationships were analysed by PK/PD modelling, KTP did not affect exudate LTB(4), but inhibition of the other variables was statistically significant. The mean EC(50) values for inhibition of serum TxB(2), exudate PGE(2) and beta-glu and BK-induced swelling were 0.118, 0.086, 0.06 and 0.00029 mu g/mL, respectively. These data indicate that KTP exerted an inhibitory action, not only as expected, on eicosanoid (TxB(2) and PGE(2)) synthesis but also on exudate beta-glu and BK-induced oedema. The EC(50) values for these actions indicate that they are likely to contribute to the overall anti-inflammatory effects of KTP in calves. However, claims that KTP inhibits 5-lipoxygenase and thereby blocks the production of inflammatory mediators such as LTB(4) were not substantiated, PK/PD modelling has proved to be a useful tool for analysing the in vivo pharmacodynamics of KTP and for providing new approaches to elucidating its mechanism(s) of action.