Effects of genetic variation at the CYP2C19/CYP2C9 locus on pharmacokinetics of chlorcycloguanil in adult Gambians.
OBJECTIVE
Antimalarial biguanides are metabolized by CYP2C19, thus genetic variation at the CYP2C locus might affect pharmacokinetics and so treatment outcome for malaria.


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).


CONCLUSIONS
CYP2C19*17 determines antimalarial biguanide metabolic profile at the CYP2C19/CYP2C9 locus.
Janha
Ramatoulie E
RE
Medical Research Council Laboratories, Fajara, Banjul, The Gambia, West Africa. rjanha@mrc.gm
Sisay-Joof
Fatoumatta
F
Hamid-Adiamoh
Majidah
M
Worwui
Archibald
A
Chapman
Hannah L
HL
Opara
Hyginus
H
Dunyo
Sam
S
Milligan
Paul
P
Rockett
Kirk
K
Winstanley
Peter
P
Pirmohamed
Munir
M
Miller
Ann K
AK
Conway
David J
DJ
Walton
Robert T
RT
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000962:Antimalarials / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001711:Biotransformation / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004247:DNA / Q000235:genetics; D005260:Female; D005714:Gambia / Q000453:epidemiology; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D002727:Proguanil / Q000493:pharmacokinetics*; D014227:Triazines / Q000493:pharmacokinetics*; D055815:Young Adult
D000962:Antimalarials; D014227:Triazines; C026009:cycloguanil; D004247:DNA; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D002727:Proguanil