Potentiated Embryotoxicity of Pyrimethamine by Folic Acid in Mice

Effects of folic acid (FA) and folinic acid (FNA) on the embryotoxicity of pyrimethamine (PYR), an antifolate drug, were examined in mice. PYR and FA were administered orally, and FNA was injected intraperitonially for 7 days from day 9 to 15 of pregnancy. The incidence of embryotoxicity including intrauterine deaths and malformations, was 33.5 % in the PYR 50 mg/kg/day group. However, all the fetuses were resorbed in the PYR 50 + FA 50 mg/kg/day group, and FA potentiated the embryotoxicity of PYR. On the contrary, FNA reduced the embryotoxicity of PYR (PYR 50 + FNA 10mg/kg/day; 8.5%). Plasma concentrations of PYR and 5-methyltetrahydrofolic acid (5MF), a principal form of folate in plasma, were determined after single oral administration of PYR 50 mg/kg with or without FA 50 mg/kg to non-pregnant mice. Plasma 5MF concentration decreased drastically in the group receiving PYR with FA, compared with the PYR alone group. The pharmacokinetics of PYR were not affected by co-administration of FA. Therefore, we consider that the potentiated embryotoxicity of PYR by oral FA results from a decrease of plasma 5MF concentration in dams.