Correlation of Active Folate Availability with Effects of Folic Acid on Pyrimethamine Teratogenesis in Rats

Oral administration of pyrimethamine (PYR) 3.6 mg/kgBW/day to the pregnant rats from day 11 to day 15 of gestation caused malformations in all the fetuses, but concomitant intraperitoneal administration of folic acid (ip FA) 50 mg/kg/day inhibited the incidence of malformations by 25%. On the other hand, the same dose of oral FA (in feed) had an opposite effect on PYR teratogenesis; the incidences of malformed fetuses were 0% in the PYR 1.6 group, but 100% in the PYR with oral FA group. The plasma levels of 5-methyltetrahydrofolic acid (5MF), a principal transfer form of folate, were measured after single oral administration of PYR with or without FA (ip or oral) in non-pregnant female rats. The area under the plasma concentration-time curve (AUC) after the concomitant administration of PYR with ip FA was larger than that after PYR alone. This result indicated that the available 5MF for the peripheral tissues was increased by the concomitant administration of ip FA. The AUC after the concomitant administration of PYR with oral FA was smaller than that after PYR alone. These results suggested that ip FA increased the available 5MF to ameliorate, but oral FA decreased the availability to aggravate the PYR teratogenesis.