Comparative study of anti-inflammatory, ulcerogenic and cytotoxic activities of racemate and S-ibuprofen

Ibuprofen is widely commercialized in racemic form. Although metabolic chiral inversion occurs through the conversion of R(-)-ibuprofen to S(+)-ibuprofen and the latter enantiomer is considered the active form, clinical trials involving the administration of a racemate to S-enantiomer dosage ratio of 1:0.5 have demonstrated that S(+)-ibuprofen is as efficacious as the racemic formulation. Moreover, the R(-)-enantiomer has been implicated in adverse gastrointestinal effects found with the racemic form, but the mechanisms involved in this process are not yet fully understood. The aim of the present study was to evaluate the anti-inflammatory activity of a racemate to S(+)-ibuprofen dosage ratio of 1:0.5 using the carrageenan air pouch model of inflammation and determine both ulcerogenic activity and the chiral conversion rate in rats. An in vitrostudy of the cytotoxicity of racemate and S(+)-ibuprofen in gastric cells was also performed. Although the plasma level of S(+)-ibuprofen was raised after racemate administration, no significant difference was found in anti-inflammatory activity, as assessed by exudate formation, PGE2production and leukocyte migration to the air pouches. Fewer gastric lesions were found after S(+)-ibuprofen administration, despite the low gastric PGE2content. In the in vitro study, the racemic compound proved more cytotoxic than S(+)-ibuprofen. The present findings suggest that the S-enantiomer of ibuprofen could be considered a therapeutic alternative to minimize gastrointestinal side effects, since the chiral inversion of R(-)-ibuprofen to S(+)-ibuprofen did not result in an improved anti-inflammatory response. Keywords: Ibuprofen. Enantiomers. Air pouch model. PGE2. Gastric ulcers. RESUMO Estudo comparativo da atividade antiinflamatoria, ulcerogenica e citotoxica do S-ibuprofeno e ibuprofeno racemico O Ibuprofeno e normalmente comercializado na forma racemica. Embora ocorra inversao quiral convertendo a forma R(-)- em S(+)-ibuprofeno e, a ultima seja considerada a forma ativa, a administracao da proporcao 1:0,5 (racemato:S-enantiomero) demonstrou que o S(+)-ibuprofeno e mais eficaz que a formulacao racemica. Adicionalmente, o R(-)-enantiomero esta envolvido nos efeitos adversos gastrintestinais descritos para a formulacao racemica, embora os mecanismos nao sejam complemente compreendidos. O objetivo deste estudo foi avaliar a atividade antiinflamatoria da proporcao 1:0,5 (racemato:S-ibuprofeno) utilizando o modelo experimental de bolsa de ar, a atividade ulcerogenica e a taxa de conversao quiral em ratos. Tambem estudamos in vitro,a citotoxicidade provocada pelo racemato e S(+)-ibuprofeno em celulas gastricas. Embora os niveis plasmaticos de S(+)-ibuprofeno tenham aumentado apos a administracao do racemato, a atividade antiinflamatoria avaliada pela formacao de exsudato, producao de PGE2e migracao de leucocitos para a bolsa de ar nao foram diferentes. As lesoes gastricas foram reduzidas apos a administracao de S(+)-ibuprofeno, apesar da inibicao de PGE2gastrica. In vitro, o composto racemico foi mais citotoxico que o S(+)-ibuprofeno. Nossos resultados sugerem que o S-enantiomero do ibuprofeno pode ser considerado uma alternativa terapeutica visando a reducao dos efeitos colaterais gastrintestinais, visto que a inversao quiral do R(-)- para o S(+)-ibuprofeno nao resultou em melhora do efeito antiinflamatorio observado. Palavras-chave: Ibuprofeno. Enantiomeros. Modelo experimental de bolsa de ar. PGE2. Ulceras gastricas.