Antinociceptive effects of a novel dual cyclooxygenase/5‐lipoxygenase inhibitor (tepoxalin) and its primary (carboxylic acid) metabolite (RWJ 20142) in acute tests in mice and rats

Abstract

AbstractTepoxalin is a novel dual inhibitor of cyclooxygenase (CO) and lipoxygenase (LO) pathways of arachidonic acid metabolism with a relative lack of gastrointestinal side effects within its preclinical therapeutic dose range. The present study investigated the antinociceptive action of tepoxalin and its primary (carboxylic acid) metabolite (RWJ 20142) in several acute tests in mice and rats. Tepoxalin produced dose‐related, non‐opioid (i.e., naloxone‐insensitive) antinociception in the mouse acetylcholine (ACh) induced abdominal irritant test (AIT) with an onset within 15 min and an exceptional duration (about 12 h). The oral ED50 value at peak effect (30 min) was 0.3 mg/kg (0.8 μmol/kg), compared to 0.9, 38.0, and 164 mg/kg (2.5, 160.8, and 1, 085 μmol/kg), respectively, for indomethacin, zileuton, and acetaminophen. Tepoxalin was inactive via intracerebroventricular (i.c.v.) administration (up to 200μg) or (up to 100mg/kg [259 μg/kg] p.o. or s.c.) in the endothelin‐1 (ET‐1) AIT and mouse 48°C hot‐plate tests. RWJ 20142 (a CO inhibitor), produced dose‐related, non‐opioid antinociception in the ACh test following oral (ED50 = 0.3 mg/kg [0.8 μmol/kg] at 30 min) or i.c.v. administration (ED50 = 3.3 μg [0.1 μmol] at 15 min) and was active p.o. in the phenyl‐p ‐quinone (PpQ) (ED50 = 0.2 mg/kg [0.6 μmol/kg] at 30 min) and ET‐1 tests (ED50 = 19.6 mg/kg [54.9 μmol/kg] at 30 min). It was the only compound active p.o. in the 48°C hot‐plate test and was significantly more potent than tepoxalin in the rat air‐induced AIT. Measurement of plasma levels suggests RWJ 20142 might be a major contributor to tepoxalin‐induced antinociception. The inactivity of tepoxalin in the ET‐1 test suggests a separate antinociceptive action of the parent compound. In summary, it appears that both tepoxalin and its primary metabolite contribute to tepoxalin‐induced antinociception in rodents, possibly by different mechanisms or at different sites, i.e., peripheral vs. central. © 1995 Wiley‐Liss, Inc.