title: In vitro and ex vivo inhibition of canine cyclooxygenase isoforms by robenacoxib: a comparative study.
abstract: In vitro whole blood canine assays were used to quantify the inhibitory actions of the novel non-steroidal anti-inflammatory drug (NSAID) robenacoxib on the cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, in comparison with other drugs of the NSAID class. COX-1 activity was determined by measuring serum thromboxane (Tx)B(2) synthesis in blood samples allowed to clot at 37 degrees C for 1h. COX-2 activity was determined by measuring prostaglandin (PG)E(2) synthesis in blood samples incubated at 37 degrees C for 24h in the presence of lipopolysaccharide. The rank order of selectivity for inhibition of COX-2 versus COX-1 (IC(50) COX-1:IC(50) COX-2) for veterinary drugs was highest with robenacoxib (128.8) compared to deracoxib (48.5), nimesulide (29.2), S+ carprofen (17.6), meloxicam (7.3), etodolac (6.6), R- carprofen (5.8) and ketoprofen (0.88). Selectivity expressed as the clinically relevant ratio IC(20) COX-1:IC(80) COX-2 was highest for robenacoxib (19.8) compared to deracoxib (2.3), S+ carprofen (2.5), R- carprofen (2.1), nimesulide (1.8), etodolac (0.76), meloxicam (0.46) and ketoprofen (0.21). An in vivo pharmacokinetic ex vivo pharmacodynamic study in the dog established dosage and concentration-effect relationships for single oral doses of robenacoxib over the dosage range 0.5-8.0mg/kg. Values of C(max) and AUC were linearly related to dosage over the tested range. Robenacoxib did not inhibit serum TxB(2) synthesis (COX-1) ex vivo at dosages of 0.5-4.0mg/kg and produced only transient inhibition (at the 1h and 2h sampling times) at the 8mg/kg dosage. All dosages of robenacoxib (0.5-8mg/kg) produced marked, significant and dose related inhibition of PGE(2) synthesis (COX-2) ex vivo. The data demonstrate that in the dog robenacoxib is a highly selective inhibitor of the COX-2 isoform of COX, and significantly inhibits COX-2 and spares COX-1 in vivo when administered orally over the dosage range 0.5-4.0mg/kg.
authors.affiliation: Novartis Animal Health Inc., CH-4058, Basel, Switzerland. jonathan.king@novartis.com
authors.forename: J N
authors.initials: JN
authors.lastname: King
authors.forename: C
authors.initials: C
authors.lastname: Rudaz
authors.forename: L
authors.initials: L
authors.lastname: Borer
authors.forename: M
authors.initials: M
authors.lastname: Jung
authors.forename: W
authors.initials: W
authors.lastname: Seewald
authors.forename: P
authors.initials: P
authors.lastname: Lees
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000097:blood; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000097:blood; D004285:Dogs; D017308:Etodolac / Q000494:pharmacology; D007527:Isoenzymes / Q000097:blood / Q000187:drug effects; D007660:Ketoprofen / Q000494:pharmacology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D000077239:Meloxicam; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood*; D013449:Sulfonamides / Q000494:pharmacology; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013929:Thromboxane B2 / Q000097:blood; D000096926:Benzenesulfonamides
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D017308:Etodolac; D007527:Isoenzymes; D007660:Ketoprofen; D008070:Lipopolysaccharides; D000077239:Meloxicam; D011451:Prostaglandin-Endoperoxide Synthases; D013449:Sulfonamides; D013843:Thiazines; D013844:Thiazoles; D013929:Thromboxane B2; C471996:deracoxib; D000096926:Benzenesulfonamides