Effects of the CYP2C9*13 allele on the pharmacokinetics of losartan in healthy male subjects.
The aim of the study was to determine the pharmacokinetics of losartan in relation to the CYP2C9*13 allele. A single oral dose of 50 mg losartan was administrated to each of the 16 healthy male volunteers with a different genotype (CYP2C9*1/*1, n = 6; CYP2C9*1/*13, n = 4; and CYP2C9*1/*3, n = 6). Blood samples were collected from pre-dose up to 24 h after the drug administration. Plasma losartan and E3174 (an active metabolite of losartan) were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). All the subjects finished the study without adverse drug effects. In the present study, the frequencies of CYP2C9*13 and *13 alleles were 0.6% and 2.6% in Chinese healthy volunteers, respectively, and both alleles were in Hardy-Weinberg equilibrium. Compared with the subjects in the CYP2C9*1/*1 group, individuals carrying the CYP2C9*1/*13 genotype showed significantly a longer t(1/2) of losartan and E3174 and markedly increased the area under the curve (AUC) of losartan. Meanwhile, the CYP2C9*1/*3 genotype group had significant differences in t(1/2) and Cmax of E3174 compared with the CYP2C9*1/*1 group. The ratio of AUC(E3174)/AUC(losartan) after losartan administration in the CYP2C9*1/*13 and CYP2C9*1/*3 groups was also statistically different from that in the CYP2C9*1/*1 group. The data indicate that the presence of the CYP2C9*13 allele results in poor metabolism of losartan after a single oral dose.
Li
Z
Z
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, P. R. China.
Wang
G
G
Wang
L-S
LS
Zhang
W
W
Tan
Z-R
ZR
Fan
L
L
Chen
B-L
BL
Li
Q
Q
Liu
J
J
Tu
J-H
JH
Hu
D-L
DL
Liu
Z-Q
ZQ
Zhou
H-H
HH
D000284:Administration, Oral; D000483:Alleles; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D005787:Gene Frequency; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D019808:Losartan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D013777:Tetrazoles / Q000493:pharmacokinetics*; D055815:Young Adult
D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C066026:losartan carboxylic acid; D019808:Losartan