title: The enantiomers of etodolac, a racemic anti-inflammatory agent, play different roles in efficacy and gastrointestinal safety.
abstract: 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.
authors.affiliation: Pharmacology Department, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd. Kisshoin, Minami-ku, Kyoto 601–8550, Japan. n.inoue@po.nippon-shinyaku.co.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Inoue
authors.forename: Masaki
authors.initials: M
authors.lastname: Nogawa
authors.forename: Sunao
authors.initials: S
authors.lastname: Ito
authors.forename: Koyuki
authors.initials: K
authors.lastname: Tajima
authors.forename: Sato
authors.initials: S
authors.lastname: Kume
authors.forename: Takashi
authors.initials: T
authors.lastname: Kyoi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D017308:Etodolac / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D041981:Gastrointestinal Tract / Q000187:drug effects*; D008297:Male; D051379:Mice; D051381:Rats; D013237:Stereoisomerism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017308:Etodolac