COMPARISON OF THE ANTIINFLAMMATORY ACTIONS OF FLUNIXIN AND KETOPROFENIN HORSES APPLYING PK PD MODELING/

A comparative study in horses of the pharmacokinetics (PK) and pharmac odynamics (PD) of 2 extensively used nonsteroidal anti-inflammatory dr ugs (NSAIDs), flunixin (FXN) and ketoprofen (KTP), was carried out app lying PK/PD modelling. To evaluate the anti-inflammatory properties of these drugs a model of acute inflammation, comprising surgically impl anted subcutaneous tissue cages stimulated by intracaveal injection of carrageenan, was used. FXN elimination half-life (T(1/2)beta) in plas ma was 3.37 +/- 1.09 h. However, in exudate a much longer T1/2 beta wa s obtained (15.99 +/- 3.80 h). Apparent volume of distribution (V-dare a) for FXN was 0.317 +/- 0.126 I/kg and body clearance (CIB) was 0.058 +/- 0.004 l/kg/h. KTP displayed enantioselective pharmacokinetics, th e S(+) enantiomer being predominant in plasma, exudate and transudate. T1/2 beta values for R(-) and S(+)KTP were, respectively, 1.09 +/- 0. 19 h and 1.51 +/- 0.45 h (plasma) and 19.73 +/- 2.72 h and 22.64 +/- 4 .34 h (exudate), respectively. R(-)KTP was cleared more rapidly than t he S(+) enantiomer. CIB values were 0.277 +/- 0.035 l/kg/h and 0.202 /- 0.022 l/kg/h, respectively. FXN and KTP pharmacodynamics was evalua ted by determining their inhibitory effects on serum thromboxane (Tx)B -2, exudate prostaglandin (PG)E(2), leukotriene (LT)B-4 and beta-glucu ronidase (beta-glu) and intradermal bradykinin-induced swelling. Both drugs produced marked inhibition of serum TxB(2) synthesis for up to 2 4 h, with no significant differences between the drugs. FXN was a more potent inhibitor of exudate PGE(2), the EC50 for FXN being lower (P<0 .01) than that for KTP (0.019 +/- 0.010 mu g/ml and 0.057 +/- 0.009 mu g/ml, respectively). Neither drug had any effect on exudate LTB(4) co ncentration. Differences between the 2 drugs were observed for the inh ibition of beta-glu, the Emax for KTP being higher (P<0.01) than for F XN. However, no differences were observed in other PD parameters. Both FXN and KTP inhibited bradykinin-induced swelling. Differences betwee n the drugs were obtained for Emax, which was greater for FXN (P<0.01) than for KTP. Equilibration half-life (T-1/2KeO) also differed, being much longer (P<0.01) for FXN than for KTP. PK/PD modelling proved to be a useful and novel analytical technique for studying the pharmacody namics of NSAIDs, with the advantage over classical in vitro methods t hat it provides data in the whole animal. By quantifying action-concen tration interrelationships through PK-PD modelling, it is possible to shed light on molecular mechanisms of drug action, and establish proba ble differences in mechanisms of action between structurally similar d rugs. In future it should be possible to use PWPD modelling to provide a rational basis for selecting dosage schedules for clinical use.