Doyle M J, Eichhold T H, Loomans M E, Farmer R W, Kelm G R
Procter & Gamble Company, Miami Valley Laboratories, Cincinnati, OH 45239-8707.
J Pharm Sci. 1993 Aug;82(8):847-50. doi: 10.1002/jps.2600820819.
It is recognized that some acidic nonsteroidal antiinflammatory drugs (NSAIDs) accumulate in the synovial fluids of inflamed joints. The distribution of tebufelone, a member of the di-tert-butylphenol class of NSAIDs, between rat plasma and paw tissues (inflamed and noninflamed) was determined. Tebufelone was administered (doses providing 80% maximal effectiveness) perorally (po, 10 mg/kg) or intravenously (i.v., 0.5 mg/kg) to Sprague-Dawley rats just prior to injection of an inflammatory adjuvant (carrageenan) into one of the hind paws. Levels of the drug were measured in plasma, inflamed paws, and noninflamed paws at prescribed times postdosing by capillary gas chromatography/stable isotope dilution mass spectrometry. Tebufelone levels, as determined from areas under the curves of concentration versus time were sevenfold (po) and 11-fold (i.v.) higher in paw tissue than in plasma. Inflamed and noninflamed tissues have equal affinity for the drug. Calculated terminal-phase half-lives of tebufelone in paw tissue were similar following i.v. and po dosing (approximately 14 h) and equivalent to the plasma half-life of the drug after po dosing (approximately 10 h). The plasma half-life determined following i.v. dosing was considerably lower (2.8 h). The anti-inflammatory activity of tebufelone appears to correlate more closely with tissue distribution profiles than plasma drug levels at the dose levels examined.
人们认识到，一些酸性非甾体抗炎药（NSAIDs）会在发炎关节的滑液中蓄积。测定了NSAIDs中二-叔丁基苯酚类成员替布非隆在大鼠血浆与爪组织（发炎和未发炎）之间的分布。在向一只后爪注射炎性佐剂（角叉菜胶）之前，将替布非隆（提供80%最大效力的剂量）经口（po，10mg/kg）或静脉内（i.v.，0.5mg/kg）给予Sprague-Dawley大鼠。在给药后规定时间，通过毛细管气相色谱/稳定同位素稀释质谱法测定血浆、发炎爪和未发炎爪中的药物水平。根据浓度-时间曲线下面积确定的替布非隆水平，爪组织中的水平比血浆中高7倍（经口）和11倍（静脉内）。发炎和未发炎组织对该药物具有相同的亲和力。静脉内和经口给药后，爪组织中替布非隆的计算终末相半衰期相似（约14小时），且与经口给药后药物的血浆半衰期相当（约10小时）。静脉内给药后测定的血浆半衰期显著更低（2.8小时）。在所研究的剂量水平下，替布非隆的抗炎活性似乎与组织分布情况的相关性比与血浆药物水平的相关性更密切。
