Mechanism of Action of Pyrimethamine
Primary Mechanism
Pyrimethamine is a folic acid antagonist that selectively inhibits dihydrofolate reductase (DHFR) in parasites, blocking the synthesis of nucleic acid precursors required for parasite growth and replication. 1
Detailed Pharmacologic Action
Pyrimethamine acts as a competitive inhibitor of the DHFR enzyme, which is part of the bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) enzyme complex in parasites like Toxoplasma gondii and Plasmodium species. 1, 2
The drug's therapeutic selectivity is based on differential requirements between host and parasite for nucleic acid precursors involved in growth, with highly selective activity against Toxoplasma gondii. 1
By inhibiting DHFR, pyrimethamine prevents the reduction of dihydrofolate to tetrahydrofolate, which is essential for one-carbon transfer reactions necessary for purine and pyrimidine synthesis. 2
Synergistic Effects
The action of pyrimethamine against Toxoplasma gondii is greatly enhanced when used in conjunction with sulfonamides, which block an earlier step in the folate synthesis pathway. 1
This synergistic combination effectively prevents severe disease in experimental models, as demonstrated in toxoplasmic uveitis studies where the dual therapy prevented development of severe ocular disease. 1
Clinical Pharmacology
Pyrimethamine is well absorbed orally with peak plasma levels occurring between 2 to 6 hours following administration. 1
The drug has a prolonged plasma half-life of approximately 96 hours and is 87% bound to human plasma proteins, which explains why leucovorin must be continued for at least 1 week after the last pyrimethamine dose in poisoning cases. 1, 3
Resistance Mechanisms
Resistance to pyrimethamine occurs through point mutations in the DHFR domain, most commonly at residue 108 (S108N), with additional mutations at positions C59R, N51I, and I164L conferring progressively greater resistance. 4, 5
These mutations cause structural changes that reduce pyrimethamine binding affinity while maintaining enzyme function, leading to Ki values increasing from 1.5 nM in wild-type to 859 nM in quadruple-mutant forms. 4