Pyrimethamine was one of the first of many 2,4-diaminopyrimidines to be synthesized and tested for antimicrobial activity.The main value of pyrimethamine has been its antiprotozoal activity, especially against malaria and toxoplasma. The main clinical use of pyrimethamine has been in combination with sulfadoxine, known as S/P, as an antimalarial. However, the development of widespread resistance in Plasmodium falciparum has led to a decline in its use for treatment of falciparum malaria. It remains useful for intermittent preventive therapy for malaria in pregnancy (IPTp) and intermittent preventive therapy for malaria in infancy (IPTi). It also remains a key drug for treatment of toxoplasmosis, Pneumocystis jirovecii pneumonia, and diarrhea due to Cystoisospora belli, often in combination with non-sulfa compounds such as clindamycin.

Mechanism of action

Pyrimethamine is a folic acid antagonist with a similar mechanism of action as trimethoprim. Pyrimethamine, a class II antifolate, binds to DHFR in malaria parasites and mammalian cells, but there is a large differential in the drug’s affinity for malaria DHFR over mammalian DHFR, such that it inhibits DHFR of plasmodia at concentrations significantly below those required to produce inhibition of mammalian enzymes (1400-fold in the rat). DHFR provides reduced folate for the thymidylate cycle vital for the successful biosynthesis of purines, pyrimidines, and ultimately DNA. Pyrimethamine inhibition of DHFR in malaria parasites is manifested by failure of nuclear division at the time of schizont formation in erythrocytes and liver. Similarly, pyrimethamine inhibits DHFR in T. gondii and P. jirovecii, although the DHFR enzymes of these two organisms have rather different molecular characteristics.

Drug interactions 

Concomitant administration of lorazepam and pyrimethamine has been reported to cause mild hepatic toxicity. In vitro studies suggest that pyrimethamine may inhibit tolbutamide metabolism, although the in vivo relevance of these data is less clear. Phenobarbital therapy appears to be associated with a shortening of the pyrimethamine half-life and reduction in serum pyrimethamine concentrations when the two agents are administered concomitantly to children, compared with children treated solely with pyrimethamine. 

Such an effect may be predicted since phenobarbital induces hepatic enzymes which degrade pyrimethamine. In vitro and animal studies suggest that zidovudine may reduce the efficacy of pyrimethamine in the treatment of toxoplasma encephalitis, but this has yet to be confirmed in clinical studies. 

Co-administration with zidovudine enhances hematological toxicity when used for toxoplasmic encephalitis in HIV-infected patients. An in vitro assessment found no interaction between nine antiretroviral drugs and the antitoxoplasma effect of pyrimethamine and sulfadiazine. Artesunate does not appear to have any influence on the pharmacokinetics of pyrimethamine, whereas co-administration of artemether with pyrimethamine resulted in a significantly increased Cmax and reduced the volume of distribution of pyrimethamine.