title: Effect of the single CYP2C9*3 allele on pharmacokinetics and pharmacodynamics of losartan in healthy Japanese subjects.
abstract: 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.
mesh_terms: 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
chemical_list: 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