The effect of oral methotrexate on the rat intestine

The effects of the administration of methotrexate to rats at different oral doses has been studied. The administration of a single dose of 6 mg kg provokes little response from the intestine; no morphological alterations could be detected, and only marginal changes in absorptive capacity were perceived. However, the ingestion of a sub-lethal dose (40 mg kg ) induces serious lesions of the intestinal mucosa by arresting cellular regeneration in the crypts. In spite of the morphological damage, the active absorption of amino-acid persists, albeit at a reduced level, until nearly all the mucosal surface has been desquamated. However, when a certain level of destruction has been sustained, the function falls suddenly to zero. The metabolic activity of the mucosa, as witnessed by respiration, glucose consumption, and lactic acid production, reflects the changes in absorptive capacity. Successive daily administrations of the drug at the lower level eventually induce the same changes that occur after a single high dose. The ingestion of this drug has provided an excellent model by which the functional activity of the intestinal mucosa can be correlated with the histological findings. Two cases are presented where the morphological pattern would not predict the state of functional viability of the tissue. After 48 and 96 hr, following the administration of a single high dose of methotrexate, there is extensive and severe mucosal derangement, but sometimes a considerable though depressed transport capacity is maintained. On the other hand, rats surviving the high dose of methotrexate have a normal histological pattern after 8 days, though their functional activity is still depressed. These findings suggest that clinical studies on intestinal biopsy samples should include functional tests as well as histological examinations whenever possible.