title: Gastric toxicity of racemic ketoprofen and its enantiomers in rat: oxygen radical generation and COX-expression.
abstract: OBJECTIVE
  The gastric toxicity of racemic-ketoprofen and its enantiomers (S(+)- and R(-)-ketoprofen), oxygen free radical generation and neutrophil infiltration in response to damage were evaluated in rats. Changes in prostaglandin synthesis, cyclooxygenase expression and glutathione metabolism were also studied.
  
  
  METHODS
  Studies were performed in Wistar rats. Drugs were given by oral administration: racemic-ketoprofen (100, 50 and 25 mg/kg body weight); S(+) and R(-)-ketoprofen (50, 25 and 12.5 mg/kg body weight). Determinations were made of gastric mucosal injury, lipid peroxidation, xanthine oxidase, myeloperoxidase and superoxide dismutase activities, glutathione levels, glutathione peroxidase and glutathione reductase activities, gastric prostaglandin synthesis (PGE2 levels) and COX-expression.
  
  
  RESULTS
  Racemic-ketoprofen dose-dependently exhibited the highest toxicity. In contrast, S(+)-ketoprofen at half the dose of the racemic compound proved to be less ulcerogenic. R(-)-ketoprofen was also less ulcerogenic, but when administered as the racemate exacerbated gastric ulceration caused by S(+)-ketoprofen. Drug administration produced significant increases in lipid peroxidation levels and xanthine-oxidase and a decrease in superoxide dismutase activity. Nevertheless the racemate induced the highest disturbances in oxidative metabolism. No changes in myeloperoxidase values and glutathione metabolism were found. Cyclooxygenase-1 immunoreactivity was observed and did not differ from that in control rats. Cyclooxygenase-2 could also be expressed after treatments.
  
  
  CONCLUSIONS
  R(-)-ketoprofen and S(+)-ketoprofen have a comparable gastric toxicity and they both have a better gastric toxicity profile as compared to the racemate. In addition to inhibition of prostaglandin synthesis, damage resulted in an increase of cyclooxygenase-2 protein expression. Oxygen radicals, including superoxide anions, could also be implicated.
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Sevilla, Spain. alarcon@fafar.us.es
authors.forename: C
authors.initials: C
authors.lastname: Alarcón de la Lastra
authors.forename: A
authors.initials: A
authors.lastname: Nieto
authors.forename: M J
authors.initials: MJ
authors.lastname: Martín
authors.forename: F
authors.initials: F
authors.lastname: Cabré
authors.forename: J M
authors.initials: JM
authors.lastname: Herrerías
authors.forename: V
authors.initials: V
authors.lastname: Motilva
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007527:Isoenzymes / Q000032:analysis; D007660:Ketoprofen / Q000009:adverse effects* / Q000737:chemistry; D008297:Male; D008565:Membrane Proteins; D009504:Neutrophils / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013237:Stereoisomerism; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000473:pathology; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D005978:Glutathione; D015232:Dinoprostone