Local effect of adenosine 5'-triphosphate on indomethacin-induced permeability changes in the human small intestine.
BACKGROUND
Nonsteroidal anti-inflammatory drug (NSAID) use is associated with an elevated risk of gastrointestinal damage. As adenosine 5'-triphosphate (ATP) may play a protective role in the small intestine, our objective was to determine the local effect of ATP on small intestinal permeability changes induced by short-term challenge of the NSAID indomethacin in healthy humans.


METHODS
Mucosal permeability of the small intestine was assessed by the lactulose/rhamnose permeability test, that is, ingestion of a test drink containing 5 g lactulose and 0.5 g L-rhamnose followed by total urine collection for 5 h. Urinary excretion of lactulose and L-rhamnose was determined by fluorescent detection high-pressure liquid chromatography (HPLC). Basal small intestinal permeability was assessed as a control condition. As a model of increased small intestinal permeability, two doses of indomethacin were ingested before ingestion of the test drink (75 mg and 50 mg at 10 h and 1 h before the test drink, respectively). Concomitantly with indomethacin ingestion, placebo or 30 mg/kg ATP was administered through a naso-intestinal tube.


RESULTS
Median urinary lactulose/rhamnose ratio (g/g) in the control condition was 0.023 (interquartile range: 0.013-0.041). Compared with the control condition, urinary lactulose/rhamnose ratio after ingestion of indomethacin and administration of placebo was significantly increased [0.042 (0.028-0.076); P<0.01]. In contrast, urinary lactulose/rhamnose ratio after indomethacin ingestion plus ATP administration [0.027 (0.020-0.046)] was significantly lower than the lactulose/rhamnose ratio in the placebo condition (P<0.01).


CONCLUSIONS
Topical ATP administration into the small intestine during short-term challenge of the NSAID indomethacin attenuates the NSAID-induced increase in small intestinal permeability in healthy humans.
Bours
Martijn J
MJ
Department of Epidemiology, Maastricht University, Nutrition and Toxicology Research Institute Maastricht, Maastricht, The Netherlands. M.Bours@EPID.unimaas.nl
Troost
Freddy J
FJ
Brummer
Robert-Jan M
RJ
Bast
Aalt
A
Dagnelie
Pieter C
PC
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D007792:Lactulose / Q000652:urine; D008297:Male; D010539:Permeability / Q000187:drug effects; D012210:Rhamnose / Q000652:urine
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007792:Lactulose; D000255:Adenosine Triphosphate; D012210:Rhamnose; D007213:Indomethacin