Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CYP2C9 genotype.
OBJECTIVE
Losartan is metabolized by polymorphic CYP2C9 to E-3174. Our aim was to evaluate the pharmacokinetics of losartan and E-3174 in relation to the CYP2C9 genotype.


METHODS
A 50-mg oral dose of losartan was given to 22 Swedish volunteers with different CYP2C9 genotypes. Losartan and E-3174 were analyzed by HPLC in plasma and urine samples collected up to 24 hours after drug intake. Furthermore, losartan and E-3174 were analyzed in 8-hour urine samples collected from 17 Spanish subjects after a single oral dose of 25 mg losartan.


RESULTS
The maximum plasma concentration of E-3174 was significantly (P <.05) lower in the CYP2C9*1/*3 (n = 5) and CYP2C9*2/*3 (n = 4) groups compared with the CYP2C9*1/*1 (n = 6) and CYP2C9*1/*2 (n = 3) groups and extremely low in 1 subject with the CYP2C9*3/*3 genotype. The ratio of the total losartan area under the plasma concentration-time curve (AUC) to the total E-3174 AUC (AUC(losartan)/AUC(E-3174)) was higher in the subject with the CYP2C9*3/*3 genotype (30-fold) and also in the CYP2C9*1/*3 and *2/*3 groups (approximately 2- and 3-fold, respectively) compared with the CYP2C9*1/*1 group. The plasma ratios correlated significantly with the 0- to 8-hour urinary losartan/E-3174 ratios. Among the total of 39 subjects, the urinary ratio was significantly higher in subjects with the CYP2C9*1/*3 (n = 10) and *2/*3 (n = 4) genotypes than in those with the CYP2C9*1/*1 genotype (n = 11; P <.01) and approximately 40-fold higher in subjects with the CYP2C9*3/*3 genotype (n = 3).


CONCLUSIONS
The CYP2C9*3 allele was shown to be associated with decreased formation of E-3174 from losartan. The significant differences between genotypes in plasma and urine losartan/E-3174 ratios and the good correlation between the plasma and urine ratios suggest that the losartan/E-3174 ratio in 0- to 8-hour urine specimens may serve as a phenotyping assay for CYP2C9 activity. Further studies in larger populations will be required to establish this.
Yasar
Umit
U
Department of Medical Laboratory Sciences and Technology, Division of Clinical Pharmacology, Karolinska Institutet at Huddinge University Hospital, Stockholm.
Forslund-Bergengren
Cecilia
C
Tybring
Gunnel
G
Dorado
Pedro
P
Llerena
Adrián
A
Sjöqvist
Folke
F
Eliasson
Erik
E
Dahl
Marja-Liisa
ML
D000284:Administration, Oral; D000328:Adult; D000483:Alleles; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D019808:Losartan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D013030:Spain; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D013548:Sweden; D013777:Tetrazoles / Q000493:pharmacokinetics*
D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; C066026:losartan carboxylic acid; D019808:Losartan