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In vitro effects and in vivo efficacy of a novel cyclooxygenase-2 inhibitor in cats with lipopolysaccharide-induced pyrexia

Margaret E. McCannDepartment of Animal Health Research, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065.
Present address is Department of Pharmacology, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065.

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Eric L. RickesDepartment of Animal Health Research, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065.

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Donald F. HoraDepartment of Comparative Medicine, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065.

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Paul K. CunninghamDepartment of Comparative Medicine, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065.

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Donghui ZhangDepartment of Biometrics Research, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065.

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Christine BrideauDepartment of Biochemistry & Molecular Biology, Merck Frosst Centre for Therapeutic Research, Kirkland, QC H9R4P8, Canada.

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W. Cameron BlackDepartment of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Kirkland, QC H9R4P8, Canada.

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Gerard J. HickeyDepartment of Animal Health Research, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065.

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Abstract

Objective—To determine cyclooxygenase (COX)-2 selectivity, pharmacokinetic properties, and in vivo efficacy of firocoxib (ML-1,785,713) in cats.

Animals—5 healthy male and 14 healthy female domestic shorthair cats.

Procedure—Selectivity of firocoxib for inhibiting COX-2 was determined by comparing the potency for inhibiting COX-1 with that of COX-2 in feline blood. Pharmacokinetic properties were determined after IV (2 mg/kg) and oral (3 mg/kg) administration in male cats. In vivo efficacy was evaluated in female cats with lipopolysaccharide (LPS)-induced pyrexia with administration of firocoxib 1 or 14 hours before LPS challenge.

Results—Blood concentrations resulting in 50% inhibition of COX-1 and COX-2 activity in vitro were 7.5 ± 2µM and 0.13 ± 0.03µM, respectively, and selectivity for inhibiting COX-2 relative to COX-1 was 58. Firocoxib had moderate to high oral bioavailability (54% to 70%), low plasma clearance (4.7 to 5.8 mL/min/kg), and an elimination half-life of 8.7 to 12.2 hours. Firocoxib at doses from 0.75 to 3 mg/kg was efficacious in attenuating fever when administered to cats 1 or 14 hours before LPS challenge.

Conclusions and Clinical Relevance—Firocoxib is a potent COX-2 inhibitor and is the only selective COX-2 inhibitor described for use in cats to date. It is effective in attenuating febrile responses in cats when administered 14 hours before LPS challenge, suggesting it would be suitable for once-a-day dosing. Because selective COX-2 inhibitors have an improved therapeutic index relative to nonselective nonsteroidal antiinflammatory drugs in humans, firocoxib has the potential to be a safe, effective anti-inflammatory agent for cats. (Am J Vet Res 2005;66:1278–1284)

Abstract

Objective—To determine cyclooxygenase (COX)-2 selectivity, pharmacokinetic properties, and in vivo efficacy of firocoxib (ML-1,785,713) in cats.

Animals—5 healthy male and 14 healthy female domestic shorthair cats.

Procedure—Selectivity of firocoxib for inhibiting COX-2 was determined by comparing the potency for inhibiting COX-1 with that of COX-2 in feline blood. Pharmacokinetic properties were determined after IV (2 mg/kg) and oral (3 mg/kg) administration in male cats. In vivo efficacy was evaluated in female cats with lipopolysaccharide (LPS)-induced pyrexia with administration of firocoxib 1 or 14 hours before LPS challenge.

Results—Blood concentrations resulting in 50% inhibition of COX-1 and COX-2 activity in vitro were 7.5 ± 2µM and 0.13 ± 0.03µM, respectively, and selectivity for inhibiting COX-2 relative to COX-1 was 58. Firocoxib had moderate to high oral bioavailability (54% to 70%), low plasma clearance (4.7 to 5.8 mL/min/kg), and an elimination half-life of 8.7 to 12.2 hours. Firocoxib at doses from 0.75 to 3 mg/kg was efficacious in attenuating fever when administered to cats 1 or 14 hours before LPS challenge.

Conclusions and Clinical Relevance—Firocoxib is a potent COX-2 inhibitor and is the only selective COX-2 inhibitor described for use in cats to date. It is effective in attenuating febrile responses in cats when administered 14 hours before LPS challenge, suggesting it would be suitable for once-a-day dosing. Because selective COX-2 inhibitors have an improved therapeutic index relative to nonselective nonsteroidal antiinflammatory drugs in humans, firocoxib has the potential to be a safe, effective anti-inflammatory agent for cats. (Am J Vet Res 2005;66:1278–1284)