Proguanil (DB01131): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Proguanil is a synthetic biguanide derivative classified as an antimalarial agent. Historically, its mechanism of action was understood primarily through its role as a prodrug. Following administration, proguanil is metabolized in the liver to its active metabolite, cycloguanil, a potent inhibitor of the parasitic enzyme dihydrofolate reductase (DHFR). This inhibition disrupts the folate synthesis pathway, which is essential for the production of nucleic acids, thereby arresting parasite replication. However, this classical mechanism does not fully account for the drug's contemporary clinical success.

The modern therapeutic value of proguanil is realized almost exclusively through its use in a fixed-dose combination with atovaquone. In this combination, a second, distinct mechanism of action emerges, mediated by the parent proguanil molecule itself. Proguanil acts synergistically with atovaquone, a mitochondrial electron transport chain inhibitor, by lowering the effective concentration at which atovaquone collapses the parasite's mitochondrial membrane potential. This action is independent of proguanil's metabolism to cycloguanil and is crucial for the combination's high efficacy against multi-drug resistant strains of Plasmodium falciparum. This dual-action pharmacology explains the combination's robust performance even in regions where resistance to DHFR inhibitors is prevalent and in individuals who are genetically poor metabolizers of proguanil.