Effects of genetic variation at the CYP2C19/CYP2C9 locus on pharmacokinetics of chlorcycloguanil in adult Gambians.

Abstract

AIMS:

Antimalarial biguanides are metabolized by CYP2C19, thus genetic variation at the CYP2C locus might affect pharmacokinetics and so treatment outcome for malaria.

MATERIALS & METHODS:

Polymorphisms in CYP2C19 and CYP2C9 in 43 adult Gambians treated with chlorproguanil/dapsone for uncomplicated malaria were assessed. Chlorcycloguanil pharmacokinetics were measured and associations with CYP2C19 and CYP2C9 alleles and CYP2C19 metabolizer groups investigated.

RESULTS:

All CYP2C19/CYP2C9 alleles obeyed Hardy-Weinberg equilibrium. There were 15 CYP2C19/2C9 haplotypes with a common haplotype frequency of 0.23. Participants with the CYP2C19*17 allele had higher chlorcycloguanil area under the concentration versus curve at 24 h (AUC(0-24)) than those without (geometric means: 317 vs 216 ng.h/ml; ratio of geometric means: 1.46; 95% CI: 1.03 to 2.09; p = 0.0363) and higher C(max) (geometric mean ratio: 1.52; 95% CI: 1.13 to 2.05; p = 0.0071).

CONCLUSION:

CYP2C19*17 determines antimalarial biguanide metabolic profile at the CYP2C19/CYP2C9 locus.

• Authors: Ramatoulie E Janha, Fatoumatta Sisay-Joof, Majidah Hamid-Adiamoh, Archibald Worwui, Hannah L Chapman, Hyginus Opara, Sam Dunyo, Paul Milligan, Kirk Rockett, Peter Winstanley, Munir Pirmohamed, Ann K Miller, David J Conway, Robert T Walton
• Journal: Pharmacogenomics (Pharmacogenomics) Vol. 10 Issue 9 Pg. 1423-31 (Sep 2009) ISSN: 1744-8042 [Electronic] England
• PMID: 19761366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Triazines
• cycloguanil
• DNA
• CYP2C9 protein, human
• Cytochrome P-450 CYP2C9
• Aryl Hydrocarbon Hydroxylases
• CYP2C19 protein, human
• Cytochrome P-450 CYP2C19
• Proguanil

Topics

• Adolescent
• Adult
• Alleles
• Antimalarials (pharmacokinetics)
• Area Under Curve
• Aryl Hydrocarbon Hydroxylases (genetics)
• Biotransformation (genetics)
• Cytochrome P-450 CYP2C19
• Cytochrome P-450 CYP2C9
• DNA (genetics)
• Female
• Gambia (epidemiology)
• Gene Frequency
• Genetic Variation
• Genotype
• Haplotypes
• Humans
• Male
• Middle Aged
• Proguanil (pharmacokinetics)
• Triazines (pharmacokinetics)
• Young Adult