Giannessi D, Lazzerini G, Filipponi P, Mannarelli C, Vaiani G, Grossi E, De Caterina R
CNR Institute of Clinical Physiology, Pisa, Italy.
Pharmacol Res. 1993 Oct-Nov;28(3):229-41. doi: 10.1006/phrs.1993.1126.
Nabumetone is a non-acidic pro-drug which, after absorption, is transformed by the liver into 6-methoxy-2-naphthylacetic acid (6-MNA), the active metabolite responsible for its anti-inflammatory activity. The urinary concentrations of 6-MNA are very low and its urinary metabolites are weak inhibitors of cyclo-oxygenase. For these reasons we hypothesized that nabumetone could spare renal cyclo-oxygenase products and, consequently, better preserve renal function unlike most other non-steroidal anti-inflammatory drugs (NSAIDs) which are known to cause an impairment of renal function, mostly related to inhibition of renal prostaglandin synthesis. We measured serum creatinine, creatinine clearance and the urinary excretion of stable prostaglandins (PG)E2 and 6-keto-PGF1 alpha, as a reflection of the renal production of PGE2 and PGI2, respectively, in 12 arthritic patients (5 males, 7 females) with normal creatinine clearance. Measurements were performed before and after a 2-week treatment with nabumetone (1 g day-1). 6-keto-PGF1 alpha and PGE2 were measured by specific radioimmunoassays (RIA) after organic solvent extraction and silicic acid column chromatography. The assay sensitivity to detect renal cyclo-oxygenase inhibition was independently verified by measuring urinary 6-keto-PGF1 alpha in normal subjects before and after aspirin and ibuprofen, known inhibitors of renal prostaglandins. At the end of treatment, serum levels of 6-MNA ranged between 24.5 and 122.4 mg 1-1, within the described therapeutic range for the drug. After nabumetone, no significant differences in the urinary excretion of the two prostaglandins with respect to baseline values were observed (for 6-keto-PGF1 alpha from 12.3 +/- 6.0 to 12.1 +/- 8.7 ng h-1, mean +/- S.D.; for PGE2 from 12.3 +/- 13.6 to 11.3 +/- 15.3 ng h-1). Also no changes in serum creatinine or creatinine clearance were observed. These results suggest that nabumetone does not significantly impair renal prostaglandin synthesis in patients with osteoarthritis.
萘丁美酮是一种非酸性前体药物，吸收后在肝脏转化为6-甲氧基-2-萘乙酸（6-MNA），即具有抗炎活性的活性代谢产物。6-MNA的尿浓度非常低，其尿代谢产物是环氧化酶的弱抑制剂。基于这些原因，我们推测萘丁美酮可能不会影响肾脏环氧化酶产物，因此，与大多数其他已知会导致肾功能损害（主要与抑制肾前列腺素合成有关）的非甾体抗炎药（NSAIDs）不同，它能更好地保护肾功能。我们测量了12名肌酐清除率正常的关节炎患者（5名男性，7名女性）的血清肌酐、肌酐清除率以及稳定前列腺素（PG）E2和6-酮-PGF1α的尿排泄量，分别反映肾脏PGE2和PGI2的生成情况。在萘丁美酮（1克/天）治疗2周前后进行测量。在有机溶剂萃取和硅酸柱色谱分离后，通过特异性放射免疫分析（RIA）测定6-酮-PGF1α和PGE2。通过测量正常受试者在服用已知的肾前列腺素抑制剂阿司匹林和布洛芬前后的尿6-酮-PGF1α，独立验证了检测肾脏环氧化酶抑制作用的测定灵敏度。治疗结束时，6-MNA的血清水平在24.5至122.4毫克/升之间，处于该药物规定的治疗范围内。服用萘丁美酮后，未观察到两种前列腺素的尿排泄量相对于基线值有显著差异（6-酮-PGF1α从12.3±6.0降至12.1±8.7纳克/小时，平均值±标准差；PGE2从12.3±13.6降至11.3±15.3纳克/小时）。血清肌酐或肌酐清除率也未观察到变化。这些结果表明，萘丁美酮不会显著损害骨关节炎患者的肾前列腺素合成。
