The increasing resistance of
falciparum malaria to common
antimalarial drugs has renewed interest in the compound
proguanil normally metabolized to
cycloguanil, a strong
dihydrofolate reductase inhibitor, via the
cytochrome P450 isozyme CYP2C19. The relationship between
CYP2C19 genotypes and
proguanil metabolism was therefore studied in 100 uncomplicated
malaria patients on Malakula island in Vanuatu, where a CYP2C19-related poor metabolizer genotype status was known to be frequent. The patients (median age, 7 years) with Plasmodium falciparum or P. vivax
infections, received
proguanil treatment for 3 days in daily doses corresponding to adult doses of 300-500 mg. Capillary blood samples were collected on filter paper for determining both human
CYP2C19 mutations by polymerase chain reaction and mutation-specific restriction
enzyme digestion and blood concentrations of
proguanil and its metabolites by high-performance liquid chromatography. The frequencies of the defective alleles,
CYP2C19*2 and
CYP2C19*3, were 0.57 and 0.25, respectively. The patients were genotyped as 68 CYP2C19-related poor metabolizers and 32 extensive metabolizers.
Proguanil concentrations were higher and
cycloguanil and
4-chlorophenylbiguanide concentrations were lower in poor compared to extensive metabolizers. Among the extensive metabolizers, 27 were heterozygous and five were homozygous for unmutated alleles. The tendency of an intermediate degree of
proguanil metabolism in heterozygous extensive metabolizers as compared to homozygous extensive metabolizers and poor metabolizers suggests the trend towards the existence of a gene dose effect. Mild adverse events (mainly gastro-intestinal symptoms) were often reported and positively correlated with
proguanil concentrations. The incidence was, however, similar in poor and extensive metabolizers. In conclusion, our data demonstrate an association between
CYP2C19 mutations and
poor metabolism of proguanil.