Diaminopyrimidines Pyrimethamine, Trimethoprim

VI.a.2.4. Diaminopyrimidines. Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum... 

The recommendations for the treatment of EPM using pyrimethamine, trimethoprim and sulfadiazine were originally based on the use of these drugs for the treatment of malaria and toxoplasmosis in humans. Either pyrimethanune or trimethoprim in combination with sulfadiazine or sulfamethoxazole have been used with some success and have gained widespread acceptance as the treatment of choice for EPM. Pyrimethamine and trimethoprim are diaminopyrimidine antimicrobial agents that inhibit dihydrofolate reductase (DHFR see Ch. 2). These agents interfere with... 

The diaminopyrimidines trimethoprim and pyrimethamine are synthetic, antibacterial drags and inhibitors of dihydrofolate reductase that are used both independently as well as in combination with sulfanilamides, in particular, with sulfamethoxazole (cotrimoxazole, bactrim, biseptol, sulfatrim, and many others). 

Pyrimethamine (Daraprim) is the best of a number of 2,4-diaminopyrimidines that were synthesized as potential antimalarial and antibacterial compounds. Trimethoprim (Proloprim) is a closely related compound. 

Trimethoprim is a pyrimidine derivative (diaminopyrimidine) related to antimalarial drug pyrimethamine, which selectively inhibits bacterial dihydrofolate reductase, necessary for the conversion of dihydrofolate to tetrahydrofolic acid. Sulfonamides act by inhibiting the incorporation of PABA into dihydrofolate by bacteria. A combination of... 

Pyrimethamine does not belong to the group of known nephrotoxic agents [39]. Because pyrimethamine and trimethoprim have a similar 2, 4-diaminopyrimidine molecular structure, Opravil et d [197] reported a similar handling of tubular secretion of creatinine. In six healthy volunteers and nine patients with AIDS, pyrimethamine caused a reversible, small to moderate, similar between the two groups, but statistically significant increase (26%) in serum creatinine concentration with a concomitant... 

Diaminopyrimidines are weak bases. Peak plasma concentrations are reached early and diaminopyrimidines are soon found in high concentrations in tissues. In fact, the tissue concentrations are often higher than the concentrations in serum. When inflammation is present, trimethoprim levels in the CSF may reach 50% of the plasma concentrations. CSF concentrations of pyrimethamine are 25-50% of the plasma concentrations. The Vd for trimethoprim and pyrimethamine is 1.51/kg in horses. The protein binding of trimethoprim is moderate (50%). There is no protein-binding interaction between the sulfonamides and the diaminopyrimidines. 

Inhibitors of dihydrofolate reductase. Methotrexate, a structural analogue of dihydrofolate, is effective against intact mammalian cells but ineffective against protozoa and some bacteria owing to permeability barriers. Trimethoprim and pyrimethamine (2,4-diaminopyrimidines) are effective against microorganisms. The former is antibacterial and antimalarial the latter is primarily antimalarial. 

It is evident, therefore, that the 2,4-diaminopyrimidines, like pyrimethamine and trimethoprim, the dihydrotriazines like proguanil (in its active metabolite form), the 2,4-diaminopteridines, and methotrexate, inhibit dihydrofolate reductase. Their selective toxicity to plasmodia may be due to a combination of greater binding to the parasite enzyme and to their selective uptake by parasitised erythrocytes. However, a new antifolic mode of action has recently been proposed for compounds like tetrahydrohomopteroic acid [288], which may inhibit folate metabolism by an action on the feedback... 

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