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  • Author or Editor: Maria F. Landoni x
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SUMMARY

Pharmacokinetic and pharmacodynamic variables of flunixin were studied in calves after IV administration of the drug at a dose rate of 2.2 mg/kg of body weight. The anti-inflammatory properties of flunixin were investigated, using a model of acute inflammation; this involved surgically implanting tissue cages at subcutaneous sites and stimulating the tissue cage granulation tissue by intracavitary injection of carrageenan. The actions of flunixin on exudate concentrations of several substances related to the inflammatory process, including proteases (metalloprotease [active and total] and cysteine and serine proteases), enzymes (lactate dehydrogenase, acid phosphatase, and β-glucuronidase [β-glu]), eicosanoid (prostaglandin E2 [pge 2], leukotriene B4, and serum thromboxane B2 [txb 2]) concentrations, and bradykinin (BK)-induced edema, were investigated.

Flunixin had a long elimination half-life—6.87 ± 0.49 hours—and volume of distribution was 2.11 ± 0.37 L/kg, indicating extensive distribution of the drug in the body. Body clearance was 0.20 ± 0.03 L/ kg/h.

Flunixin exerted inhibitory effects on serum txb 2 and exudate pge 2 concentrations, β-glu activity, and BK-induced swelling. Other enzymes and inflammatory mediators were not significantly affected. Pharmacokinetic/pharmacodynamic modeling of the data revealed similar mean concentration producing 50% of the maximal effect values for inhibition of exudate pge 2 and p-glu and of BK-induced swelling (0.070 ± 0.006, 0.064 ± 0.040, and 0.061 ± 0.030 μg/ml, respectively). A lower concentration producing 50% of the maximal effect value was obtained for inhibition of serum txb 2 concentration (0.023 ± 0.004 μg/ml). Differences also were observed in equilibration halflife for these actions, suggesting the existence of 3 distribution compartments correlating with 3 sites of action—a central compartment and shallow and deep peripheral compartments. Pharmacokinetic/pharma- codynamic modeling proved to be a useful analytical method, providing a quantitative description of in vivo drug pharmacodynamics and indicating possible mechanisms of action.

Free access
in American Journal of Veterinary Research

Abstract

Objective—To establish pharmacokinetic and pharmacodynamic properties of a racemic mixture and individual R(–) and S(+) enantiomeric forms of ketoprofen (KTP) in sheep and determine pharmacodynamic variables of KTP by pharmacokinetic-pharmacodynamic modeling.

Animals—8 female Dorset crossbred sheep.

Procedure—A tissue cage model of inflammation was used. Carrageenan was administered into tissue cages. Time course of cyclooxygenase (COX)-2 inhibition was determined in vivo by measurement of exudate prostaglandin E2 (PGE2) concentrations. Time course of COX-1 inhibition was determined ex vivo by measurement of serum thromboxane B2 (TXB2) concentrations. In addition, plasma concentration-time course and penetration of KTP enantiomers into inflammatory exudate and transudate (noninflamed tissue cage fluid) were investigated. Four treatments were compared: placebo, racemic mixture (rac-KTP [3 mg/kg of body weight, IV]), S(+) KTP (1.5 mg/kg, IV),and R(–) KTP (1.5 mg/kg, IV).

Results—Both KTP enantiomers had elimination halflife and mean residence time measurements that were short and volume of the central compartment and steady state volume of distribution that were low. Clearance was rapid, particularly for R(–) KTP. Elimination of both enantiomers from exudate was > 10 times slower than from plasma. Both rac-KTP and the individual enantiomers significantly inhibited serum TXB2 concentrations for 12 hours. Rac-KTP and S(+) KTP, but not R(–) KTP, also significantly inhibited PGE2 synthesis in exudate for 12 hours.

Conclusions and Clinical Relevance—Inhibition of serum TXB2 concentration and exudate PGE2 synthesis for similar time courses after S(+) KTP administration indicates that it is a nonselective inhibitor of COX in sheep. ( Am J Vet Res 2001;62:77–86)

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in American Journal of Veterinary Research