Proguanil

Proguanil (Paludrine®) and chlorproguanil (Lapudrine®)

These are biguanides which are converted in the body to the active product cycloguanil. The enzyme which catalyses this oxidative activation is probably mephenytoin hydroxylase. Absorption is delayed by simultaneous ingestion of magnesium trisilicate (e.g. stomach powders). The concentration of proguanil in red blood cells is 6 times higher than that in plasma. There is genetic polymorphism for the conversion of the prodrug to the active product. Persons are "extensive metabolisers" or "poor metabolisers". One way to determine this is by measuring the proguanil/cycloguanil ratio in the plasma. Poor metabolisers have a lower plasma level of the active form (= higher P/C ratio) and theoretically are more at risk that the drug will fail. Nevertheless, the importance of phenotype status is not really known. There is also a lack of clarity concerning the various metabolites of the product. Approximately 20% of the population of Southeast Asia are said to convert proguanil to cycloguanil scarcely if at all. In Kenya this is 35%. This does not, however, appear to diminish the efficacy of Malarone®. Chlorproguanil has chlorcycloguanil as its active metabolite. The combination of chlorproguanil with dapsone is also known as Lapdap®. It is used as a cheap, short-half-life antifolate. It may be combined with artesunate (combination known as "CDA"). Proguanil is excreted via the kidneys.

Note: Proguanil

Proguanil is a biguanide. The term “pro” refers to the fact that this is a “prodrug”. The term biguanide refers to the part of the lateral chains where the five nitrogen atoms are found. During metabolism the side chains are converted to a triazine ring, from which the name ‘cycloguanil’ comes.

Cycloguanil is a powerful inhibitor of dihydrofolic acid reductase in the parasite. That is how the synthesis of nucleic acids in the parasite is disturbed. It has a slow action, and therefore cannot be used in monotherapy as a curative agent in an acute attack. There is swift development of resistance if proguanil is taken as the only prophylaxis. The therapeutic role of proguanil has changed recently, since the confirmation that atovaquone has fulfilled its initial promise (synergistic effect). As a prophylactic proguanil is given as one dose of 100-200 mg per day and chlorguanil as 20 mg per week.

Category: Medicine Notes