leukotriene-b4 and flunixin

A comparative study in horses of the pharmacokinetics (PK) and pharmacodynamics (PD) of 2 extensively used nonsteroidal anti-inflammatory drugs (NSAIDs), flunixin (FXN) and ketoprofen (KTP), was carried out applying PK/PD modelling. To evaluate the anti-inflammatory properties of these drugs a model of acute inflammation, comprising surgically implanted subcutaneous tissue cages stimulated by intracaveal injection of carrageenan, was used. FXN elimination half-life (T1/2 beta) in plasma was 3.37 +/- 1.09 h. However, in exudate a much longer T1/2 beta was obtained (15.99 +/- 3.80 h). Apparent volume of distribution (Vdarea) for FXN was 0.317 +/- 0.126 l/kg and body clearance (ClB) was 0.058 +/- 0.004 l/kg/h. KTP displayed enantioselective pharmacokinetics, the 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 the S(+) enantiomer. ClB values were 0.277 +/- 0.035 l/kg/h and 0.202 +/- 0.022 l/kg/h, respectively. FXN and KTP pharmacodynamics was evaluated by determining their inhibitory effects on serum thromboxane (Tx)B2, exudate prostaglandin (PG)E2, leukotriene (LT)B4 and beta-glucuronidase (beta-glu) and intradermal bradykinin-induced swelling. Both drugs produced marked inhibition of serum TxB2 synthesis for up to 24 h, with no significant differences between the drugs. FXN was a more potent inhibitor of exudate PGE2, the EC50 for FXN being lower (P < 0.01) than that for KTP (0.019 +/- 0.010 microgram/ml and 0.057 +/- 0.009 microgram/ml, respectively). Neither drug had any effect on exudate LTB4 concentration. Differences between the 2 drugs were observed for the inhibition of beta-glu, the Emax for KTP being higher (P < 0.01) than for FXN. However, no differences were observed in other PD parameters. Both FXN and KTP inhibited bradykinin-induced swelling. Differences between the drugs were obtained for Emax, which was greater for FXN (P < 0.01) than for KTP. Equilibration half-life (T1/2Ke0) 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 pharmacodynamics of NSAIDs, with the advantage over classical in vitro methods that it provides data in the whole animal. By quantifying action-concentration interrelationships through PK-PD mod

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Clonixin; Cross-Over Studies; Dinoprostone; Exudates and Transudates; Glucuronidase; Half-Life; Horses; Inflammation; Ketoprofen; Leukotriene B4; Male; Models, Biological; Thromboxane B2

A study was made to compare the effects of two nonsteroidal antiinflammatory drugs (NSAIDs), flunixin and tolfenamic acid, on the leukotriene B4 (LTB4) production and migration of human polymorphonuclear leukocytes (PMNs) as well as on platelet aggregation and thromboxane B2 (TxB2) production during blood clotting. Tolfenamic acid inhibited LTB4 production in PMNs as well as FMLP- and LTB4-induced PMN migration (IC50 values 23 +/- 3, 39 +/- 11, and 68 +/- 13 microM, respectively), whereas flunixin inhibited these cell functions only with the highest concentration tested (100 microM). On the other hand, flunixin was clearly a more potent inhibitor of TxB2 production and adrenaline-induced platelet aggregation than tolfenamic acid, the IC50 values in TxB2 production being 0.28 +/- 0.02 microM and 2.6 +/- 0.3 microM for flunixin and tolfenamic acid, respectively. We suggest that inhibition of PMN functions may be an additional mechanism in the antiinflammatory action of tolfenamic acid. At least in human PMNs and platelets, flunixin seems to be only an inhibitor of cyclooxygenase.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Blood Coagulation; Blood Platelets; Cell Movement; Clonixin; Humans; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; ortho-Aminobenzoates; Platelet Aggregation; Thromboxane B2