Estimation of acute flurbiprofen and ketoprofen toxicity in rat gastric mucosa at therapy-relevant doses.
OBJECTIVE
Since assessment of the acute gastrotoxicity of nonsteroidal antiinflammatory drugs (NSAIDs) in rats requires high doses of the drugs, we sought to establish an experimental model with which this adverse NSAID effect can be estimated at therapy-relevant doses.


METHODS
The study was performed with racemic flurbiprofen-trometamol (R/S-FBP), its pure enantiomers S-FBP and R-FBP, and racemic ketoprofen-trometamol (R/S-KP). Two hours after administration of FBP or KP to Sprague-Dawley rats, HCl (0.5 M, 10 ml/kg) was given intragastrically (IG), and the haemorrhagic lesion area in the gastric mucosa quantified 1 h post-HCI.


RESULTS
FBP amplified gastric acid injury in a dose-related manner, the rank order of potency being S-FBP > R/S-FBP >> R-FBP. While less than 1 micromol/kg S-FBP and R/S-FBP aggravated acid injury, doses up to 50 micromol/kg failed to cause appreciable damage without subsequent HCl challenge. Similar observations were made with R/S-KP which at doses of > or = 1 micromol/kg aggravated gastric acid injury. There was no significant difference in the gastrotoxicity of FBP when the drug was administered subcutaneously or IG, whereas subcutaneously injected R/S-KP was slightly more toxic than IG R/S-KP.


CONCLUSIONS
These data show that FBP- and KP-induced amplification of acid injury in the rat gastric mucosa is a sensitive assay whereby, with single drug dosing, the gastrotoxic potential of these and other NSAIDs may be estimated at therapy-relevant doses that in humans threaten mucosal integrity only following chronic use.
Holzer
P
P
Department of Experimental and Clinical Pharmacology, University of Graz, Austria. peter.holzer@kfunigraz.ac.at
Jocic
M
M
Cabré
F
F
Mauléon
D
D
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000633:toxicity*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D005480:Flurbiprofen / Q000008:administration & dosage / Q000633:toxicity*; D005753:Gastric Mucosa / Q000473:pathology*; D007279:Injections, Subcutaneous; D007441:Intubation, Gastrointestinal; D007527:Isoenzymes / Q000187:drug effects; D007660:Ketoprofen / Q000008:administration & dosage / Q000633:toxicity*; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D005480:Flurbiprofen; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat