The Enantiomers of Etodolac, a Racemic Anti-inflammatory Agent, Play Different Roles in Efficacy and Gastrointestinal Safety

• Published in: Biological & Pharmaceutical Bulletin 2011/05/01, Vol.34(5), pp.655-659
• Main Authors: Inoue, Naoki, Nogawa, Masaki, Ito, Sunao, Tajima, Koyuki, Kume, Sato, Kyoi, Takashi
• Format: Article
• Language: English
• Subjects: adjuvant arthritis; Animals; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; enantiomer; etodolac; Etodolac - adverse effects; Etodolac - chemistry; Etodolac - pharmacology; Gastrointestinal Tract - drug effects; Male; Mice; neuropathic pain; Rats; Stereoisomerism; ulcerogenic activity
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.34.655

The anti-inflammatory agent etodolac is used worldwide and it has a good gastrointestinal safety profile. Etodolac consists of two enantiomers, S- and R-etodolac. Here, we investigated the beneficial activities of racemic etodolac and its enantiomers. First, we compared S- and R-etodolac in terms of their inhibition of cyclooxygenase (COX) activity in vitro and their suppression of paw swelling in adjuvant-induced arthritic rats. The COX-2 inhibitory and anti-inflammatory effects of etodolac were found to be due to the S-enantiomer. We previously reported that etodolac attenuates allodynia in a mouse model of neuropathic pain by a COX-2-independent mechanism [N. Inoue et al., J. Pharmacol. Sci., 109, 600—605 (2009)]. In the present study, we showed that the anti-allodynic effects of etodolac in mice were also due to the S-enantiomer. In addition, we investigated the ulcerogenic activity of racemic etodolac and its enantiomers. At high doses, racemic etodolac showed a lower gastric lesion index in rats than the equivalent dose of S-etodolac. In contrast, R-etodolac showed no ulcerogenic activity and even showed protection against HCl/ethanol-induced gastric damage in rats. In conclusion, S-etodolac exhibited anti-inflammatory effects mediated by COX-2 inhibition and anti-allodynic effects that were independent of COX-2 inhibition, while R-etodolac showed gastroprotective effects that may contribute to the low gastrointestinal toxicity of racemic etodolac. Our results show that each enantiomer plays a different role in the efficacy and gastrointestinal safety of etodolac.