Comparative teratogenicity of pyrimethamine in rats and hamsters

Abstract

Pyrimethamine, a drug used in the treatment of toxoplasmosis, was much less teratogenic in golden hamsters than in Wistar rats. About 70% of rat fetuses were killed or malformed by administration of single oral doses of 5 mg to pregnant females. Less than 10% of hamster fetuses died or were malformed following single doses to the mother of 20 mg, which on a mg/kg basis was eight to nine times greater than that given to rats. In the rats repeated daily doses of 0.5 mg per female were severely teratogenic. The incidence of dead and abnormal fetuses in rats treated with 5 mg pyrimethamine was markedly reduced, from about 70 to lo%, by single intraperitoneal injections of 6 mg folinic acid; this result suggests that folinic acid might be potentially of value in lessening the teratogenic risk that may exist when pyrimethamine is employed in toxoplasmosis therapy during early pregnancy.Pyrimethamine ( 2,4-diamino-5-p-chlor-

Effect of intramuscular sulfadoxine-pyrimethamine on pregnant Wistar rats

“…Folic acid defiency has been reported by Nelson et al (1952) to be teratogenic in rats, whereas pyrimethamine has been shown by Sullivan and Takacs (1971), Dyban et al (1976), and Golinski and Baranou (1976) to cause multiple congenital malformations in rats, mice, and hamsters. Nelson et al (1952) and Nelson (1960) had reported that when Wistar rats were commenced on folic acid deficient diet from the 5 th day of gestation, the rats produced no litters.…”

“…According to Laurence and Bennet (1995), folic acid is reduced to 7,8 dihydrofolic acid (TH 2 ) by folic acid reductase, while dihydrofolic acid is reduced to 5,6,7,8 tetrahydrofolic acid (TH 4 ). Sulfonamides and sulphones, according to Sullivan and Takacs (1971) and Mayers et al (1980), inhibit folic acid reductase, whereas pyrimethamine (2,4 diamino-5-p-chlorophenyl 6 ethyl primidine) inhibits dihydrofolic acid reductase. The teratogenicity of pyrimethamine alone has been reported in rats, mice, and hamsters by Dyban et al (1972) and Golinski et al (1972).…”

“…The teratogenicity of pyrimethamine alone has been reported in rats, mice, and hamsters by Dyban et al (1972) and Golinski et al (1972). Sulfadoxine-pyrimethamine preparations have been reported (Sullivan and Takacs, 1971) to contain 500 mg of sulfadoxine and 25 mg of pyrimethamine. This preparation has been reported by Laurence and Bennet (1995) to inhibit the activities of folic acid reductases necessary for the production of tetrahyrofolic acid.…”

Effects of Folic Acid and Pyrimethamine, a Dihydrofolate Reductase Inhibitor, on Intestinal Absorption of Folates in Rats

“…Pyrimethamine (PYR), an antiprotozoan drug, is a dihydrofolate reductase (DHFR) inhibitor, and it has a teratogenic property in animals (5,6). Our previous studies demonstrated that oral co-administration of folic acid (pteroylglutamic acid, PteGlu) markedly potentiated the teratogenicity of PYR in rats (7) and mice (8).…”

Effect of oral administration of folate sources on plasma folate levels in pigs: Comparison between reduced and oxidized forms of folate

“…Suboptimal folate nutrition during pregnancy is known to cause abortion or fetus malformation in many animals including humans (Scott et al 1995). Several groups of investigators reported that an antifolate agent, pyrimethamine, produces malformed fetuses in the rat, hamster, and pig (Sullivan and Takacs 1971;Misawa et al 1982;Kudo et al 1988;Ohnishi et al 1989). Miller et al (1989) reported that rat embryos cultured using serum devoid of folate showed striking abnormalities using a technique of whole-body embryo culture.…”