Proguanil

Proguanil and its triazine metabolite cycloguanil have the following structures: Proguanil has the widest margin of safety of a large series of antimalarial biguanide analogs examined. Dihalogen substitution in positions 3 and 4 of the benzene ring yields chlorproguanil ( lapudrine), a more potent prodrug that also is used clinically. Cycloguanil is structurally related to pyrimethamine.

ANTIMALARIAL ACTIONS In sensitive P. falciparum malaria, proguanil exerts activity against both the primary liver stages and the asexual red cell stages, thus adequately controlling the acute attack and usually eradicating the infection. Proguanil also is active against acute P. vivax malaria, but because the latent tissue stages of P. vivax are unaffected, relapses may occur after drug withdrawal. Proguanil treatment does not destroy gametocytes, but fertilized gametes in the gut of the mosquito fail to develop normally.

MECHANISMS OFANTIMALARIALACTION AND RESISTANCE The active triazine metabolite of proguanil selectively inhibits the bifunctional dihydrofolate reductase-thymidylate synthetase of sensitive plasmodia, inhibiting DNA synthesis and depleting folate cofactors. Certain amino acid changes near the dihydrofolate reductase-binding site are linked to resistance to either cycloguanil, pyrimethamine, or both. Resistance to cycloguanil (and chlorcycloguanil) can be linked to mutations in plasmodial dihydrofolate reductase. This pattern differs from that typically observed for pyrimethamine resistance, but overlapping resistance to cycloguanil and pyrimethamine indicates that resistance mechanisms may be quite complex.

The mechanism of the antimalarial activity of proguanil or chlorproguanil is unknown. Proguanil as the biguanide accentuates the mitochondrial membrane-potential-collapsing action of atovaquone against P. falciparum but displays no such activity by itself (see "Atovaquone," above). In contrast to cycloguanil, resistance to the intrinsic antimalarial activity of proguanil itself, either alone or in combination with atovaquone, has yet to be documented.

ABSORPTION, FATE, AND EXCRETION

Proguanil is slowly but adequately absorbed from the GI tract. After a single oral dose, peak plasma concentrations of the drug usually are attained within 5 hours. The mean plasma elimination t/2 is ~12—20 hours. Metabolism of proguanil cosegregates with CYP2C isoforms that control mephenytoin oxidation. Only ~3% of Caucasians are deficient in this oxidation versus 20% of Asians and Kenyans. Proguanil is oxidized to two major metabolites, cycloguanil and an inactive 4-chlorophenylbiguanide. On a 200-mg daily dosage regimen, extensive metabolizers develop plasma levels of cycloguanil that are above the therapeutic range, whereas poor metabolizers may not. Proguanil does not accumulate appreciably in tissues during long-term administration, except in erythrocytes, where its concentration is about three times that in plasma. The inactive 4-chlorophenyl-biguanide metabolite appears in increased quantities in the urine of poor proguanil metabolizers. In humans, from 40% to 60% of absorbed proguanil is excreted in urine either as the parent drug or as active metabolite.

THERAPEUTIC USES Proguanil as a single agent is not available in the U.S. but is prescribed in Europe for nonimmune travelers to malarious areas. Strains of P. falciparum resistant to proguanil emerge rapidly in areas where the drug is used exclusively, but breakthrough infections also may result from deficient conversion of this compound to its active antimalarial metabolite.

Proguanil is effective and well tolerated when given orally once daily for 3 days in combination with atovaquone for the treatment of malarial attacks owing to chloroquine- and multidrug-resistant strains of P. falciparum and P. vivax (see "Atovaquone," above). Indeed, this drug combination (malarone) has been successful in Southeast Asia, where highly drug-resistant strains of P. falci-parum prevail. P. falciparum readily develops clinical resistance to monotherapy with either proguanil or atovaquone, but resistance to the combination is uncommon unless the strain is initially resistant to atovaquone. In contrast, some strains resistant to proguanil do respond to proguanil plus atovaquone.

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