Document Detail


Pharmacokinetics and pharmacodynamics of ketoprofen in calves applying PK/PD modelling.
MedLine Citation:
PMID:  8587147     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 (t1/2 beta) of 0.42 +/- 0.08 h and 0.42 +/- 0.09 h, respectively. The volume of distribution (Vd) 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 (ClB) 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 (TxB2), exudate prostaglandin (PGE2), leukotriene (LTB4) 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 LTB4, but inhibition of the other variables was statistically significant. The mean EC50 values for inhibition of serum TxB2, exudate PGE2 and beta-glu and BK-induced swelling were 0.118, 0.086, 0.06 and 0.00029 microgram/mL, respectively. These data indicate that KTP exerted an inhibitory action, not only as expected, on eicosanoid (TxB2 and PGE2) synthesis but also on exudate beta-glu and BK-induced oedema. The EC50 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 LTB4 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.
Authors:
M F Landoni; F M Cunningham; P Lees
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Publication Detail:
Type:  Clinical Trial; Controlled Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of veterinary pharmacology and therapeutics     Volume:  18     ISSN:  0140-7783     ISO Abbreviation:  J. Vet. Pharmacol. Ther.     Publication Date:  1995 Oct 
Date Detail:
Created Date:  1996-03-25     Completed Date:  1996-03-25     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7910920     Medline TA:  J Vet Pharmacol Ther     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  315-24     Citation Subset:  IM    
Affiliation:
Department of Veterinary Basic Sciences, Royal Veterinary College, Hatfield, UK.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics*,  pharmacology,  therapeutic use
Bradykinin / toxicity
Carrageenan / administration & dosage,  toxicity
Cattle / metabolism*
Cattle Diseases / chemically induced,  drug therapy*
Cross-Over Studies
Diffusion Chambers, Culture
Dinoprostone / metabolism
Dose-Response Relationship, Drug
Edema / chemically induced,  drug therapy,  veterinary
Glucuronidase / toxicity
Half-Life
Inflammation / chemically induced,  drug therapy,  veterinary*
Injections, Intravenous / veterinary
Ketoprofen / pharmacokinetics*,  pharmacology,  therapeutic use
Leukotriene B4 / metabolism
Male
Stereoisomerism
Thromboxane B2 / blood
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 22071-15-4/Ketoprofen; 363-24-6/Dinoprostone; 54397-85-2/Thromboxane B2; 58-82-2/Bradykinin; 71160-24-2/Leukotriene B4; 9000-07-1/Carrageenan; EC 3.2.1.31/Glucuronidase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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