Effects of CYP2C9*1/*3 and *1/*13 on the pharmacokinetics of losartan and its active metabolite E-3174.
OBJECTIVE
The effects of CYP2C9*1/*3 and *1/*13 genotypes were evaluated on the pharmacokinetics of losartan and its active metabolite, E-3174, in Korean subjects.


METHODS
Losartan (50 mg) was administered in 43 Korean volunteers with different CYP2C9 genotypes (CYP2C9*1/*1, *1/*3 and *1/*13). Losartan and E-3174 levels in the plasma and urine were analyzed by HPLC using fluorescence.


RESULTS
The CYP2C9*1/*13 subjects showed lower oral clearance (p < 0.001) and greater AUC0-∞ (p < 0.01) of losartan and higher Cmax (p < 0.01) and longer half-life (p < 0.001) of E-3174 than the CYP2C9*1/*1 subjects, but AUC0-∞ of E-3174 was not different. The CYP2C9*1/*3 subjects showed lower oral clearance (p < 0.001) of losartan and higher Cmax (p < 0.01) and longer half-life (p < 0.01) of E-3174 than the CYP2C9*1/*1 subjects. However, AUC0-∞ of losartan was greater in CYP2C9*1/*3 subjects than in CYP2C9*1/*1, but these results were not significant (p < 0.05, but statistical power < 0.8). In addition, AUC0-∞ of E-3174 was not different. There were no significant differences in pharmacokinetic parameters between the CYP2C9*1/*13 and CYP2C9*1/*3 subjects.


CONCLUSIONS
These results suggest that CYP2C9*1/*3 and CYP2C9*1/*13 are similarly associated with decreased formation of E-3174 from losartan, but the clinical effects of losartan may not be reduced by CYP2C9*1/*3 and CYP2C9*1/*13.
College of Pharmacy, Keimyung University, Daegu, Korea.
Jung-Woo
JW
Bae
Chang-Ik
CI
Choi
Hye-In
HI
Lee
Yun-Jeong
YJ
Lee
Choon-Gon
CG
Jang
Seok-Yong
SY
Lee
D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9; D005838:Genotype; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019808:Losartan / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008657:Metabolic Clearance Rate; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D056910:Republic of Korea; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D055815:Young Adult
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D013777:Tetrazoles; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C066026:losartan carboxylic acid; D019808:Losartan