Losartan and E3174 pharmacokinetics in cytochrome P450 2C9*1/*1, *1/*2, and *1/*3 individuals.
OBJECTIVE
To determine if differences in the pharmacokinetics of losartan and its pharmacologically active E3174 metabolite exist among individuals expressing the cytochrome P450 (CYP) 2C9*1/*1, *1/*2, and *1/*3 genotypes.


METHODS
Single-dose pharmacokinetic study.


METHODS
University general clinical research center.


METHODS
Fifteen healthy volunteers, five from each genotype: CYP2C9*1/*1, *1/*2, and *1/*3.


METHODS
A single oral dose of losartan 50 mg.


RESULTS
Plasma and urine samples were collected for 24 hours, and losartan and E3174 pharmacokinetic data were compared across the three genotypes. Orthostatic blood pressure was measured over 12 hours after dosing. No significant differences were observed among the three groups in losartan or E3174 area under the plasma concentration-time curve, losartan or E3174 elimination half-life, or losartan oral clearance. A significant association between CYP2C9 genotype and losartan to E3174 formation clearance was observed, such that 50% of the variability was accounted for by the genotype. No significant relationship between that genotype and blood pressure was observed at any time.


CONCLUSIONS
Differences in the pharmacokinetics of losartan and its active E3174 metabolite were not observed in healthy subjects with the genotype of CYP2C9*1/*2 and *1/*3 compared with those expressing *1/*1. Alterations in losartan dosing in CYP2C9*1/*2 and *1/*3 individuals does not appear necessary.
Lee
Craig R
CR
Division of Pharmacotherapy, University of North Carolina at Chapel Hill, 27599-7360, USA. craig_lee@unc.edu
Pieper
John A
JA
Hinderliter
Alan L
AL
Blaisdell
Joyce A
JA
Goldstein
Joyce A
JA
D000293:Adolescent; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008658:Inactivation, Metabolic / Q000235:genetics; D019808:Losartan / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D007093:Imidazoles; D013777:Tetrazoles; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C066026:losartan carboxylic acid; D019808:Losartan