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 h 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.


CONCLUSIONS
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.
D000328:Adult; D000959:Antihypertensive Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D007564:Japan; D019808:Losartan / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D013777:Tetrazoles / Q000493:pharmacokinetics / Q000494:pharmacology
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