Inter-individual variation in the metabolic activation of the antimalarial biguanides

The aryl-biguanides proguanil and chlorproguonil were developed as part of a collaborative programme between ICI and the Liverpool School of Tropical Medicine during the 1940s. The compounds were characterized by their absence of host toxicity. However, the rapid development of parasite resistance to the actions of these drugs and the development of the 4-aminoquinoline, chloroquine, severely limited their use. The subsequent widespread development of parasite resistance to chloroquine, together with the observations that the magnitude of dihydrofolate reductose inhibitor resistance (the site of action of the biguanides) developed to pyrimethamine is not directly correlated with biguanide resistance1,2. has resulted in renewed interest in these drugs. In particular, proguanil is now the drug of choice for malaria prophylaxis, in combination with chloroquine; used in combination with a suitable sulphonamide, it may be of value in malaria therapy.