Proguanil

Proguanil is an antimalarial drug and dihydrofolate reductase inhibitor. It acts like the other antifolate antimalarials by interfering with the folic-folinic acid systems and thus exerts its effect mainly at the time the nucleus is dividing. Since its activity is dependent on its metabolism, proguanil has a slow schizonticidal effect in the blood. It also has some schizonticidal activity in the tissues.

Proguanil is effective against the exoerythrocytic forms of some strains of plasmodium falciparum but it has little or no activity against the exoerythrocytic forms of P. Vivax. It has a marked sporonticidal effect against some strains of P. falciparum; it does not kill the gametocytes, but renders them non-infective for the mosquito while the drug is present in the blood. Malaria parasites in the red blood cells are killed more rapidly by chloroquine or quinine than by proguanil, which is therefore not the best drug to use for the treatment of acute malaria.

Soon after proguanil was introduced, it was observed that the drug was inactive as an inhibitor of the in vitro growth of P. Gallinaceum and P. Cynomolgi, but that sera from dosed monkeys were active against P. Cynomolgi in vitro. These findings suggested that proguanil was activated in vivo.

Since that time it has been accepted by most investigators in this field that cycloguanil is the active metabolite of proguanil and that parent compound is inactive per se.

Cycloguanil acts by binding to the enzyme dihydrofolate reductase in the malaria parasite. The effect of this action is to prevent the completion of schizogony. This is seen in the asexual blood stages as an arrest of maturation of the developing schizonts and an accumulation of large, abnormal looking trophozoites.

Proguanil is highly active against the primary exoerythocytic forms of P. Falciparum and it has a fleeting inhibiting action on those of P. Vivax. Proguanil is therefore a valuable drug for causal prophylaxis in falciparum malaria.

Absorption

Rapid, reaching a peak at 3 to 4 hours. The active metabolite (cycloguanil) peaks somewhat later (4 to 9 hours).

Half-life

The half-life of proguanil is 14 to 20 hours, whilst cycloguanil has a half-life of the order of 20 hours. Accumulation during repeated dosing is therefore limited, steady-state being reached within approximately 3 days.

Metabolism

Transformation of proguanil into cycloguanil is associated with cytochrome P450, CYP 2C19, activity. A smaller part of the transformation of proguanil into cycloguanil is probably catalysed by CYP 3A4.

Elimination

Elimination occurs both in the faeces and, principally, in the urine.

In the event of a daily dose being missed, the blood levels fall rapidly but total disappearance of the drug only occurs 3 to 5 days after stopping treatment.

Proguanil is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in the summary.