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

被引:70
作者
LANDONI, MF [1 ]
LEES, P [1 ]
机构
[1] UNIV LONDON ROYAL VET COLL,DEPT VET BASIC SCI,HATFIELD AL9 7TA,HERTS,ENGLAND
关键词
HORSE; FLUNIXIN; KETOPROFEN; PK/PD MODELING;
D O I
10.1111/j.2042-3306.1995.tb03073.x
中图分类号
S85 [动物医学(兽医学)];
学科分类号
0906 ;
摘要
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 (T(1/2)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 (V-darea) 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, 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. CIB 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)B-2, exudate prostaglandin (PG)E(2), leukotriene (LT)B-4 and beta-glucuronidase (beta-glu) and intradermal bradykinin-induced swelling. Both drugs produced marked inhibition of serum TxB(2) synthesis for up to 24 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) 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 (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 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 modelling, it is possible to shed light on molecular mechanisms of drug action, and establish probable differences in mechanisms of action between structurally similar drugs. In future it should be possible to use PWPD modelling to provide a rational basis for selecting dosage schedules for clinical use.
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页码:247 / 256
页数:10
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