Competitive inhibition of folate absorption by dihydrofolate reductase inhibitors, trimethoprim and pyrimethamine.

Trimethoprim and pyrimethamine, inhibitors of dihydrofolate reductase (DHFR), cause folate deficiency in some patients. We investigated impairment of intestinal folate absorption by these drugs. By use of the in vivo intestinal-loop methods in rats, absorption of [3H] folic acid was significantly decreased in the presence of either drug. Kinetic studies using the influx chamber method demonstrated a pattern of competitive inhibition of folate transport. [3H] folic acid absorption from jejunal loops was determined 3-16 h after IV administration of methotrexate; this treatment abolished DHFR activity in the small intestine. In rats pretreated with methotrexate, luminal disappearance and systemic absorption of folic acid were significantly enhanced with respect to controls. Trimethoprim and pyrimethamine are weak competitive inhibitors of intestinal folate transport and folate absorption inhibition occurs at the site of membrane transport and appears to be unrelated to concurrent inhibition of DHFR activity in enterocytes.