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Proguanil


ACCESSION NB: DB01131 (APRD00188)


TYPE: small molecule


GROUP: approved


DESCRIPTION:
Proguanil is a prophylactic antimalarial drug, which works by stopping the malaria parasite, Plasmodium falciparum and Plasmodium vivax, from reproducing once it is in the red blood cells. It does this by inhibiting the enzyme, dihydrofolate reductase, which is involved in the reproduction of the parasite.

VOLUME OF DISTRIBUTION: Not Available

CATEGORIES:
Antimetabolites Antimalarials

ABSORPTION: Rapidly and well absorbed in humans following oral doses ranging from 50 to 500 mg.

INDICATION:
For the causal prevention and suppression of malaria caused by susceptible strains of P. falciparum and other species of Plasmodium found in some geographical areas of the world.

PHARMACODYNAMICS:
Proguanil is a biguanide derivative that is converted to an active metabolite called cycloguanil. It exerts its antimalarial action by inhibiting parasitic dihydrofolate reductase enzyme. It has causal prophylactic and suppressive activity against P. falciparum and cures the acute infection. It is also effective in suppressing the clinical attacks of vivax malaria. However it is slower compared to 4-aminoquinolines.

MECHANISM OF ACTION:
Proguanil inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver.

PROTEIN BINDING:
Approximately 75%

METABOLISM:
Variably metabolized in the liver by cytochrome P450 isoenzymes to the active triazine metabolite, cycloguanil. This variable metabolism of proguanil may have profound clinical importance in poor metabolizers such as the Asian and African populations at risk for malaria infection. Prophylaxis with proguanil may not be effective in these persons because they may not achieve adequate therapeutic levels of the active compound, cycloguanil, even after multiple doses. Enzyme Metabolite Reaction Km Vmax Cytochrome P450 2C19 cycloguanil cyclisation 82 0.008

TOXICITY:
Not Available

AFECTED ORGANISMS:
Plasmodium