Relationship between proguanil metabolic ratio and CYP2C19 genotype in a Caucasian population.
OBJECTIVE
To investigate the relationship between proguanil metabolic ratio (MR, proguanil/cycloguanil) and CYP2C19 genotype in a Caucasian population.


METHODS
Ninety-nine Caucasians (age range: 18-55 years, 54 female, 45 male) were genotyped for CYP2C19 and phenotyped for proguanil oxidation by collecting urine for 8 h after taking 100 mg proguanil hydrochloride. Proguanil and cycloguanil concentrations were measured by h.p.l.c. PCR was employed for CYP2C19 genotyping.


RESULTS
The three (3%) individuals who were homozygous for CYP2C19*2 (*2/*2) had the highest proguanil MRs (range: 8.0-134.6). Seventy-three (74%) individuals were homozygous for the wild-type allele (*1/*1) and 23 (23%) were heterozygous (*1/*2). The *1/*1 individuals had lower MRs (median=1.4, range: 0.23-5.9, P=0.003, Mann-Whitney U-test) than the *1/*2 subjects (median=2.5, range: 0.88-7.3).


CONCLUSIONS
A CYP2C19 gene-dose effect for proguanil oxidation to cycloguanil was observed, confirming a role for CYP2C19 in cycloguanil formation in vivo. However, there was substantial overlap of proguanil MRs in subjects of different CYP2C19 genotypes, due possibly to variability in the activity of other enzymes contributing to the formation of cycloguanil.
Hoskins
J M
JM
Department of Clinical Pharmacology, Royal North Shore Hospital, St Leonards, NSW, Australia.
Shenfield
G M
GM
Gross
A S
AS
D000293:Adolescent; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D003915:Dextromethorphan / Q000493:pharmacokinetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D002727:Proguanil / Q000493:pharmacokinetics*; D013223:Statistics as Topic; D014227:Triazines / Q000378:metabolism*; D044465:White People / Q000235:genetics
D014227:Triazines; C026009:cycloguanil; D003915:Dextromethorphan; 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