Effects of folic acid and pyrimethamine, a dihydrofolate reductase inhibitor, on intestinal absorption of folates in rats.
Oral co-administration of folic acid (pteroylglutamic acid, PteGlu) potentiates the decrease of plasma 5-methyltetrahydrofolic acid (5-CH3-H4PteGlu) concentration induced by pyrimethamine (PYR) in rats. To clarify the mechanisms of this potentiated decrease, we examined the effects of PteGlu and PYR on intestinal absorption of folates in rat jejunum loops, because plasma 5-CH3-H4PteGlu concentration is maintained by enterohepatic circulation of folates. The intestinal absorption of 5-[14C]CH3-H4PteGlu was inhibited by PteGlu, but not by PYR. The absorption of [3H]PteGlu was inhibited by reduced folates that exist in bile. These findings indicate that PteGlu competes with the bile reduced folates for the intestinal transport system. The bile secretion of reduced folates was also examined to observe the conversion of absorbed PteGlu to reduced folates in the liver in the presence of PYR. The bile secretion of reduced folates increased drastically after the administration of PteGlu alone, but not after the administration of PteGlu with PYR. These facts suggest that the absorbed PteGlu was not converted to reduced folates in the liver due to PYR. In conclusion, the potentiated decrease of plasma 5-CH3-H4PteGlu concentration must have resulted from a combination of the following two factors: the inhibition of reabsorption of bile reduced folates by PteGlu and the inhibition of PteGlu conversion to reduced folates in the liver by PYR.
Kudo
G
G
Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Japan.
Ohgushi
N
N
Shimoda
M
M
Kokue
E
E
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005492:Folic Acid / Q000378:metabolism* / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects*; D011739:Pyrimethamine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D005492:Folic Acid; D011739:Pyrimethamine