Ketoprofen-induced intestinal permeability changes studied in side-by-side diffusion cells.
It is known that non-steroidal anti-inflammatory drugs (NSAIDs) increase intestinal permeability. Increased intestinal permeability is believed to result from the opening of tight junctions because of NSAID-induced reduction of prostaglandin synthesis and/or energy-depletion. In this study, ketoprofen-induced changes in intestinal permeability were evaluated by measuring tissue electrical parameters, namely tissue electrical resistance (TER), short circuit current (I(sc)) and transepithelial potential difference (PD), and the transport of a paracellular marker, fluorescein, across rat jejunum in-vitro. Ketoprofen, added to the mucosal side of the tissue, decreased TER and increased fluorescein transport in a concentration-dependent manner. I(sc) values and the active transport of D-glucose were not affected at ketoprofen concentrations of less than 5 mM. Higher ketoprofen concentrations decreased I(sc) values and diminished active transport of D-glucose, while transport of fluorescein increased markedly. Similar effects on intestinal properties were observed when the metabolic inhibitor sodium azide was added to the incubation medium. The results of this study suggest that the increased intestinal permeability observed at lower ketoprofen concentrations (< 5 mM) is most probably a consequence of reduced prostaglandin tight junction control, whereas at higher concentrations, ATP depletion caused by ketoprofen seems to be the major mechanism for increased intestinal permeability.
Legen
Igor
I
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
Kristl
Albin
A
D000465:Algorithms; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015194:Diffusion Chambers, Culture; D004553:Electric Conductivity; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019793:Fluorescein / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D007422:Intestines / Q000187:drug effects / Q000502:physiology; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D007660:Ketoprofen / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D019810:Sodium Azide / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D007660:Ketoprofen; D019810:Sodium Azide; D019793:Fluorescein