Effects of Nabumetone, A New Non-Steroidal Anti-Inflammatory Drug, on Urinary Prostaglandin Excretion in Man

Abstract

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 6MNA 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)E 2 and 6-keto-PGF 1α, as a reflection of the renal production of PGE 2 and PGI 2, 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-PGF 1α and PGE 2 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-PGF 1α 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-PGF 1α from 12.3±6.0 to 12.1± 8.7ng h -1, mean±S.D.; for PGE 2 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.