Effects of genetic variation at the CYP2C19/CYP2C9 locus on pharmacokinetics of chlorcycloguanil in adult Gambians.
;
Fatoumatta Sisay-Joof;
Majidah Hamid-Adiamoh;
Archibald Worwui;
Hannah L Chapman;
Hyginus Opara;
Sam Dunyo;
Paul Milligan ;
Kirk Rockett;
Peter Winstanley;
+4 more...
Munir Pirmohamed;
Ann K Miller;
David J Conway ;
Robert T Walton;
(2009)
Effects of genetic variation at the CYP2C19/CYP2C9 locus on pharmacokinetics of chlorcycloguanil in adult Gambians.
Pharmacogenomics, 10 (9).
pp. 1423-1431.
ISSN 1462-2416
DOI: 10.2217/pgs.09.72
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.