CYP2C9 genetic variants and losartan oxidation in a Turkish population

Eur J Clin Pharmacol. 2004 Jul;60(5):337-42. doi: 10.1007/s00228-004-0785-5. Epub 2004 Jun 10.

Abstract

Objective: Cytochrome P(450) 2C9 (CYP2C9) is a polymorphic enzyme catalysing the metabolism of several important drugs. Losartan has recently been suggested as a selective probe for CYP2C9 metabolic activity. The aim of the study was to determine the activity of CYP2C9, using losartan as a probe drug, in relation to CYP2C9 genotype in healthy Turkish subjects.

Methods: A single oral dose of 25 mg losartan was given to 85 Turkish unrelated subjects. Concentrations of losartan and its carboxylic acid metabolite, E3174, were analysed by means of high-performance liquid chromatography in urine collected for 8 h. The CYP2C9 genotypes were determined in 85 subjects using polymerase chain reaction-based endonuclease digestion methods specific for CYP2C9*2 and *3. Losartan oxidation was also studied in vitro, using human CYP2C8 and CYP2C9 enzymes expressed in yeast.

Results: The frequencies of the allelic variants CYP2C9*2 and CYP2C9*3 were 0.100 and 0.088, respectively. The urinary losartan/E3174 ratio was significantly higher in subjects with CYP2C9*1/*3 genotype (median 2.35, n=12) than in subjects with CYP2C9*1/*1 (0.71, n=58) and *1/*2 (0.85, n=10) genotypes ( P<0.05). In contrast to CYP2C9, no E3174 was formed by CYP2C8 in vitro.

Conclusion: The urinary losartan to E3174 metabolic ratio after a 25-mg losartan dose was found to be a safe and useful phenotyping assay for CYP2C9 activity in vivo. CYP2C9*3 variant allele is a major determinant of the enzyme activity, and it decreases losartan metabolism significantly, while CYP2C9*2 allele has less impact on enzyme function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antihypertensive Agents / adverse effects
  • Antihypertensive Agents / metabolism*
  • Antihypertensive Agents / urine
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP2C9
  • Female
  • Genetics, Population*
  • Genotype
  • Humans
  • Losartan / adverse effects
  • Losartan / metabolism*
  • Losartan / urine
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Genetic
  • Turkey

Substances

  • Antihypertensive Agents
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Losartan