Novartis Animal Health Inc., CH-4058, Basel, Switzerland.
Res Vet Sci. 2010 Jun;88(3):497-506. doi: 10.1016/j.rvsc.2009.11.002. Epub 2009 Dec 11.
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.
采用犬全血体外试验，定量检测新型非甾体类抗炎药（NSAID）罗非昔布对环氧化酶（COX）同工酶 COX-1 和 COX-2 的抑制作用，并与 NSAID 类的其它药物进行比较。COX-1 活性通过测定血液样本在 37°C 下凝血 1 小时后血清血栓素（Tx）B2 合成来确定。COX-2 活性通过测定血液样本在 37°C 下孵育 24 小时，在脂多糖存在下测定前列腺素（PG）E2 合成来确定。兽医用药物对 COX-2 与 COX-1 抑制的选择性（IC50 COX-1：IC50 COX-2）的排序，罗非昔布最高（128.8），其次是 deracoxib（48.5）、nimesulide（29.2）、S+ carprofen（17.6）、meloxicam（7.3）、etodolac（6.6）、R- carprofen（5.8）和 ketoprofen（0.88）。以临床相关比值 IC20 COX-1：IC80 COX-2 表示的选择性，罗非昔布最高（19.8），其次是 deracoxib（2.3）、S+ carprofen（2.5）、R- carprofen（2.1）、nimesulide（1.8）、etodolac（0.76）、meloxicam（0.46）和 ketoprofen（0.21）。犬体内药代动力学-体外药效动力学研究建立了罗非昔布单口服剂量 0.5-8.0mg/kg 时的剂量和浓度-效应关系。Cmax 和 AUC 值与测试范围内的剂量呈线性关系。罗非昔布在 0.5-4.0mg/kg 剂量下不抑制血清 TxB2 合成（COX-1），在 8mg/kg 剂量下仅产生短暂抑制（在 1h 和 2h 采样时间）。罗非昔布（0.5-8mg/kg）所有剂量均显著抑制前列腺素（PG）E2 合成（COX-2），呈剂量依赖性。数据表明，在犬中，罗非昔布是 COX-2 同工酶 COX 的高度选择性抑制剂，当口服剂量在 0.5-4.0mg/kg 范围内时，在体内显著抑制 COX-2 并保留 COX-1。
