Influence of prolonged exposure of a short half life non-steroidal anti-inflammatory drugs on gastrointestinal safety

Aims: 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. Methodology: 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 51Cr-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 51Cr-EDTA permeability suggestive of a systemic effect. There was no significant difference between the i.p regimens in 51Cr-EDTA permeability. The first day 51Cr-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. Conclusion: 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 51Cr-EDTA permeability. The repeated dosing rather than the magnitude of t 1/2 may influence the gut safety profile of NSAIDs. © 2009 Birkhäuser Verlag.