title: Proguanil disposition and toxicity in malaria patients from Vanuatu with high frequencies of CYP2C19 mutations.
abstract: 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.
authors.affiliation: Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University School of Medicine, Japan. akirak@research.twmc.ac.jp
authors.forename: A
authors.initials: A
authors.lastname: Kaneko
authors.forename: Y
authors.initials: Y
authors.lastname: Bergqvist
authors.forename: G
authors.initials: G
authors.lastname: Taleo
authors.forename: T
authors.initials: T
authors.lastname: Kobayakawa
authors.forename: T
authors.initials: T
authors.lastname: Ishizaki
authors.forename: A
authors.initials: A
authors.lastname: Björkman
mesh_terms: D000962:Antimalarials / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005787:Gene Frequency; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008288:Malaria / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006899:Mixed Function Oxygenases / Q000235:genetics*; D002727:Proguanil / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000962:Antimalarials; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D002727:Proguanil