CYP2C9*3 allelic variant is associated with metabolism of irbesartan in Chinese population.
OBJECTIVE
There is considerable variability in the individual pharmaceutical dosages required to achieve optimal therapeutic effects, which may be due to environmental or genetic factors. The objective of this study was to test the presence of the CYP2C9*3 allelic variant in the Chinese population and to investigate the association of this variant with both metabolism and therapeutic efficacy of irbesartan on essential hypertension.


METHODS
In this study, we enrolled 711 subjects from Taihu County and 376 subjects from Dongzhi County in Anhui Province, China. All subjects received a single oral dose of 150 mg irbesartan daily for 28 days. The plasma concentration of irbesartan at 24 h after dosing on the 27th day and at 6 h after dosing on the 28th day was detected using fluorescence-high-performance liquid chromatography. CYP2C9 genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism.


RESULTS
No CYP2C9*2 allele was found in 235 Chinese samples and was removed from further study. The mean frequency of the CYP2C9*3 allele was 3.65%, while no CYP2C9*3/*3 genotype was detected. Multiple linear regression analyses revealed that the CYP2C9*3 allele carriers had significantly higher irbesartan concentrations in plasma at 6 h (Taihu: P < 0.0001; Dongzhi: P = 0.03) and 24 h (Taihu: P < 0.0001; Dongzhi: P = 0.00013) after dosing. No significant association was found between the CYP2C9*3 allelic variant and the therapeutic effect of irbesartan on essential hypertension.


CONCLUSIONS
Our study suggests that the CYP2C9*3 plays an important role in the metabolism of irbesartan and/or is in linkage disequilibrium with another potential CYP2C9 allele, both of which possibly modify the pharmacokinetics of irbesartan.
Hong
Xiumei
X
Life Science School, University of Science and Technology of China, Huangshan Road, Hefei City, Anhui Province, China.
Zhang
Shanchun
S
Mao
Guangyun
G
Jiang
Shanqun
S
Zhang
Yan
Y
Yu
Yunxian
Y
Tang
Genfu
G
Xing
Houxun
H
Xu
Xiping
X
D000284:Administration, Oral; D000328:Adult; D000483:Alleles; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology / Q000208:ethnology; D000077405:Irbesartan; D016014:Linear Models; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D013777:Tetrazoles; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000077405:Irbesartan