title: In vitro effects and in vivo efficacy of a novel cyclooxygenase-2 inhibitor in cats with lipopolysaccharide-induced pyrexia.
abstract: OBJECTIVE
  To determine cyclooxygenase (COX)-2 selectivity, pharmacokinetic properties, and in vivo efficacy of firocoxib (ML-1,785,713) in cats.
  
  
  METHODS
  5 healthy male and 14 healthy female domestic shorthair cats.
  
  
  METHODS
  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 i.v. (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 75 +/- 2 microM and 0.13 +/- 0.03 microM, 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
  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 anti-inflammatory drugs in humans, firocoxib has the potential to be a safe, effective anti-inflammatory agent for cats.
authors.affiliation: Department of Animal Health Research, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065, USA.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McCann
authors.forename: Eric L
authors.initials: EL
authors.lastname: Rickes
authors.forename: Donald F
authors.initials: DF
authors.lastname: Hora
authors.forename: Paul K
authors.initials: PK
authors.lastname: Cunningham
authors.forename: Donghui
authors.initials: D
authors.lastname: Zhang
authors.forename: Christine
authors.initials: C
authors.lastname: Brideau
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Hickey
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D002371:Cat Diseases / Q000139:chemically induced / Q000188:drug therapy*; D002415:Cats; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy*; D066298:In Vitro Techniques; D007275:Injections, Intravenous / Q000662:veterinary; D007660:Ketoprofen / Q000627:therapeutic use; D008070:Lipopolysaccharides; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D013450:Sulfones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D013450:Sulfones; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015107:4-Butyrolactone; C487384:firocoxib