Effect of the single CYP2C9*3 allele on pharmacokinetics and pharmacodynamics of losartan in healthy Japanese subjects

Objective: Losartan is metabolized to the active carboxylic acid metabolite EXP3174 by CYP2C9. In this study, we determined the effects of the single CYP2C9*3 variant on the pharmacokinetics and pharmacodynamics of losartan. Methods: Seven healthy Japanese subjects (CYP2C9*1/*1, n = 4 and CYP2C9*1/*3, n = 3) were phenotyped with a single dose of losartan (25 mg). Blood and urine samples were collected and assayed for losartan and EXP3174. Blood pressure and pulse rate were also measured using a sphygmomanometer. Results: The maximum plasma concentration of EXP3174 was significantly (P < 0.05) lower in the CYP2C9*1/*3 (n = 3) group than in the CYP2C9*1/*1 (n = 4) group. Diastolic blood pressure in the CYP2C9*1/ *1 group, but not that in the CYP2C9*1/*3 group except for at 6 It and 8 h, was reduced from 1.5 h to 12 h compared with the baseline level. Systolic blood pressure in the CYP2C9*1/*1 group, but not that in the CYP2C9*1/*3 group, was reduced from 1 h to 12 h compared with the baseline level. The metabolic ratio (MR) of EXP3174 concentration to the losartan concentration in plasma at 6 h post-dosing and the 4-h to 8-h urinary EXP3174/losartan MR were significantly lower in the CYP2C9*1/*3 group than in the CYP2C9*1/*1 group. The plasma 6-h MR and the 4-h to 8-h urinary MR were significantly (P < 0.05) correlated with the plasma AUC ratio (AUC(EXP3174)/AUC(losartan)), with Spearman rank correlation coefficients of 0.75 and 0.89, respectively. Conclusion: The single CYP2C9*3 variant reduces the metabolism of losartan and its hypotensive effect. Plasma MR, as well as urine MR, may be useful for phenotyping assays of CYP2C9 activity.