Pharmacodynamics of tolfenamic acid in dogs. Evaluation of dose response relationships

Q.A. McKellar, P. Lees, G. Gettinby

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Tolfenamic acid was administered to beagle dogs at 2, 4 and 8 mg/kg bodyweight i.m. and the concentration of drug in plasma and in inflamed (administered carrageenan) and non-inflamed subcutaneous tissue cage fluid was measured. The concentration of thromboxane B2 in serum from blood allowed to clot under standardized conditions was determined and the concentrations of prostaglandin E2, 12-hydroxyeicosatetraenoic acid (12-HETE) and leucocyte numbers were measured in fluid from the carrageenan administered tissue cages. Skin temperature was also measured over each tissue cage following administration of drug. Tolfenamic acid displayed linear pharmacokinetics since the area under the plasma concentration time curve (AUC) values were 13.74 ± 1.88, 29.82 ± 6.53 and 50.52 ± 5.73 μg/ml.h following administration of 2, 4 and 8 mg/kg, respectively. Tolfenamic acid proved to be a potent inhibitor of ex vivo thromboxane B2 generation in clotting blood. Maximal inhibition was greater than 80% at all dose rates and 97% at the 8 mg/kg dose rate 1 h after drug administration. It also proved to be a potent inhibitor of prostaglandin E2 production in inflammatory exudate, and significantly (P < 0.05) decreased prostaglandin E2 production at all dose levels. Tolfenamic acid did not significantly alter 12-HETE generation or white blood cell accumulation in inflammatory exudate. Tolfenamic acid significantly reduced the elevated skin temperature over carrageenan administered cages at all dose levels.
LanguageEnglish
Pages191-200
Number of pages9
JournalEuropean Journal of Pharmacology
Volume253
Issue number3
DOIs
Publication statusPublished - 3 Mar 1994

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Culture Diffusion Chambers
Dogs
Carrageenan
Dinoprostone
Hydroxyeicosatetraenoic Acids
Thromboxane B2
Skin Temperature
Exudates and Transudates
Pharmaceutical Preparations
Subcutaneous Tissue
Blood Coagulation
Leukocyte Count
Area Under Curve
Leukocytes
Pharmacokinetics
tolfenamic acid
Serum

Keywords

  • tolfenamic acid
  • thromboxane B2
  • prostaglandin E2
  • 12-hydroxyeicosatetraenoic acid
  • dog

Cite this

McKellar, Q.A. ; Lees, P. ; Gettinby, G. / Pharmacodynamics of tolfenamic acid in dogs. Evaluation of dose response relationships. In: European Journal of Pharmacology. 1994 ; Vol. 253, No. 3. pp. 191-200.
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Pharmacodynamics of tolfenamic acid in dogs. Evaluation of dose response relationships. / McKellar, Q.A.; Lees, P.; Gettinby, G.

In: European Journal of Pharmacology, Vol. 253, No. 3, 03.03.1994, p. 191-200.

Research output: Contribution to journalArticle

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AB - Tolfenamic acid was administered to beagle dogs at 2, 4 and 8 mg/kg bodyweight i.m. and the concentration of drug in plasma and in inflamed (administered carrageenan) and non-inflamed subcutaneous tissue cage fluid was measured. The concentration of thromboxane B2 in serum from blood allowed to clot under standardized conditions was determined and the concentrations of prostaglandin E2, 12-hydroxyeicosatetraenoic acid (12-HETE) and leucocyte numbers were measured in fluid from the carrageenan administered tissue cages. Skin temperature was also measured over each tissue cage following administration of drug. Tolfenamic acid displayed linear pharmacokinetics since the area under the plasma concentration time curve (AUC) values were 13.74 ± 1.88, 29.82 ± 6.53 and 50.52 ± 5.73 μg/ml.h following administration of 2, 4 and 8 mg/kg, respectively. Tolfenamic acid proved to be a potent inhibitor of ex vivo thromboxane B2 generation in clotting blood. Maximal inhibition was greater than 80% at all dose rates and 97% at the 8 mg/kg dose rate 1 h after drug administration. It also proved to be a potent inhibitor of prostaglandin E2 production in inflammatory exudate, and significantly (P < 0.05) decreased prostaglandin E2 production at all dose levels. Tolfenamic acid did not significantly alter 12-HETE generation or white blood cell accumulation in inflammatory exudate. Tolfenamic acid significantly reduced the elevated skin temperature over carrageenan administered cages at all dose levels.

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