Influence of prolonged exposure of a short half life non-steroidal anti-inflammatory drugs on gastrointestinal safety.
OBJECTIVE
To test the influence of frequent concentration peaking, as occurs in multiple-dosing of non-steroidal anti-inflammatory drugs (NSAIDs) with short t (1/2), and duration of therapy of NSAIDs on gastrointestinal permeability.


METHODS
2.5 mg/(kg 12 h) flurbiprofen was administered as repeated oral and interperitoneal (i.p) doses or as i.p. osmotic pump (once implanted to mimic long t(1/2)) for 7 days to healthy rats. Urinary excretion of (51)Cr-EDTA (days 0, 1, 4 and 7 during all regimens) and sucrose (days 0, 1 and 7 for i.p. doses) were measured as markers of gastroduodenal and intestinal permeability, respectively.


RESULTS
Both i.p. regimens elevated (51)Cr-EDTA permeability suggestive of a systemic effect. There was no significant difference between the i.p regimens in (51)Cr-EDTA permeability. The first day (51)Cr-EDTA permeability was significantly higher for the oral than for the i.p. doses suggestive of a topcal effect. The effect became less potent with time despite continuous dosing indicating adaptation for both topical and systemic effects. None of the i.p. regimen altered sucrose permeability.


CONCLUSIONS
NSAID's potency to increase permeability reduces with time despite continuous dosing. Topical effect following oral dosing, and not the frequent peaking differentiates regimens from each other in elevating (51)Cr-EDTA permeability. The repeated dosing rather than the magnitude of t(1/2) may influence the gut safety profile of NSAIDs.
Campanella
Corinne
C
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2N8, Canada.
Jamali
Fakhreddin
F
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002860:Chromium Radioisotopes; D004334:Drug Administration Schedule; D004492:Edetic Acid / Q000378:metabolism; D005480:Flurbiprofen / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D006207:Half-Life; D015918:Infusion Pumps, Implantable; D007263:Infusions, Parenteral; D007274:Injections, Intraperitoneal; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D013395:Sucrose / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002860:Chromium Radioisotopes; D013395:Sucrose; D005480:Flurbiprofen; D004492:Edetic Acid