Potentiation of methotrexate-induced gastrointestinal toxicity by non-steroidal anti-inflammatory drugs (NSAIDs) and vincristine.
Inhibition of intestinal nutrient absorption by the folate antagonist methotrexate (MTX) and the effects of several organic acid drugs and vincristine on MTX-induced gastrointestinal toxicity were investigated. Male Swiss-Webster mice received MTX, 25 mg/kg, i.p. once daily for 4 successive days. Using the everted sac technique, the rates of D-glucose and L-tyrosine transport were decreased by MTX to 10.9 and 6.3 mumol/g/h from control values of 35.0 and 10.0 mumol/g/h, respectively. Probenecid, sodium salicylate, phenylbutazone, or vincristine administered simultaneously with MTX, further decreased the rates of D-glucose transport to 3.6, 2.0, 0.8, and 2.6 mumol/g/h, respectively, and the rates of L-tyrosine transport to 1.2, 1.9, 0.6 and 0.9 mumol/g/h, respectively. When intestinal sacs from untreated animals were exposed to MTX (10(-3) M) on the serosal side only, the drug had no significant effect on the rate of transport of D-glucose or L-tyrosine. The rate of lactate production in everted intestinal sacs from MTX treated animals decreased to 11.8 from a control value of 30.3 mumol/g/h. Co-administration of phenylbutazone with MTX further decreased the rate of lactate production to 8.2 mumol/g/h. Body weight loss caused by MTX treatment (15.0%) was potentiated by the concurrent administration of probenecid (19.4%), salicylate (22.4%), phenylbutazone (23.0%) or vincristine (22.8%). These results demonstrate that vincristine and several commonly used organic acid drugs can potentiate the inhibitory effect of MTX on intestinal nutrient absorption. Thus, MTX dosage adjustment may be required in patients receiving such drugs.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004357:Drug Synergism; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D008727:Methotrexate / Q000633:toxicity*; D051379:Mice; D014443:Tyrosine / Q000378:metabolism; D014750:Vincristine / Q000633:toxicity*
D000893:Anti-Inflammatory Agents; D014443:Tyrosine; D014750:Vincristine; D005947:Glucose; D008727:Methotrexate