Effects of non-steroidal anti-inflammatory drugs on the methotrexate transport in rat small intestine.
BACKGROUND
Methotrexate (MTX) is used in the treatment of rheumatic disease, sometimes along with non-steroidal anti-inflammatory drugs (NSAIDs), and is actively co-transported with H+ in the small intestine, mediated by a reduced folate carrier (RFC). The co-administration of NSAIDs with MTX might cause a decrease in MTX absorption through the small intestine, since some NSAIDs are uncouplers of oxidative phosphorylation. The present study investigates whether flufenamic acid, diclofenac and indomethacin, NSAIDs, decrease the ATP content of small intestinal epithelial cells and affect MTX transport (the secondary active transport) in the small intestine.


METHODS
MTX transport was examined in the presence and absence of the NSAIDs, using the everted intestine technique and brush border membrane vesicles (BBMVs) from the rat small intestine. The change in physical properties of the membrane was studied in BBMVs using the fluorescence techniques.


RESULTS
MTX absorption in the small intestine with H+ gradient (mucosal side, pH 6.0; serosal side, pH 7.4) decreased in the presence of the NSAIDs, but absorption without H+ gradient (both sides, pH 7.4) was unaffected. The intestinal mucosal ATP content decreased in the presence of the NSAIDs. The uptake of MTX in BBMVs was unaffected by the NSAIDs. The activity of intestinal Na+-K+-ATPase was enhanced in the presence of the NSAIDs. The fluorescence measurements showed that membrane fluidity, membrane potential and membrane hydrophobicity of BBMVs were unaffected by the NSAIDs.


CONCLUSIONS
NSAIDs decreased the H+/MTX absorption in the small intestine, but not the passive transport. The uncoupling effect of the NSAIDs decreased the ATP content in the small intestine, resulting in inhibition of the secondary active transport.
Sosogi
A
A
Dept. of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
Gao
F
F
Tomimatsu
T
T
Hirata
K
K
Horie
T
T
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D004008:Diclofenac / Q000494:pharmacology; D005439:Flufenamic Acid / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics*; D007213:Indomethacin / Q000494:pharmacology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005493:Folic Acid Antagonists; D004008:Diclofenac; D005439:Flufenamic Acid; D000254:Sodium-Potassium-Exchanging ATPase; D007213:Indomethacin; D008727:Methotrexate