Effects of the CYP2C9*13 allele on the pharmacokinetics of losartan in healthy male subjects

Xenobiotica. 2009 Oct;39(10):788-93. doi: 10.1080/00498250903134435.

Abstract

The aim of the study was to determine the pharmacokinetics of losartan in relation to the CYP2C9*13 allele. A single oral dose of 50 mg losartan was administrated to each of the 16 healthy male volunteers with a different genotype (CYP2C9*1/*1, n = 6; CYP2C9*1/*13, n = 4; and CYP2C9*1/*3, n = 6). Blood samples were collected from pre-dose up to 24 h after the drug administration. Plasma losartan and E3174 (an active metabolite of losartan) were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). All the subjects finished the study without adverse drug effects. In the present study, the frequencies of CYP2C9*13 and *13 alleles were 0.6% and 2.6% in Chinese healthy volunteers, respectively, and both alleles were in Hardy-Weinberg equilibrium. Compared with the subjects in the CYP2C9*1/*1 group, individuals carrying the CYP2C9*1/*13 genotype showed significantly a longer t(1/2) of losartan and E3174 and markedly increased the area under the curve (AUC) of losartan. Meanwhile, the CYP2C9*1/*3 genotype group had significant differences in t(1/2) and Cmax of E3174 compared with the CYP2C9*1/*1 group. The ratio of AUC(E3174)/AUC(losartan) after losartan administration in the CYP2C9*1/*13 and CYP2C9*1/*3 groups was also statistically different from that in the CYP2C9*1/*1 group. The data indicate that the presence of the CYP2C9*13 allele results in poor metabolism of losartan after a single oral dose.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Alleles
  • Antihypertensive Agents / administration & dosage
  • Antihypertensive Agents / pharmacokinetics*
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Asian People / genetics
  • Cytochrome P-450 CYP2C9
  • Gene Frequency
  • Humans
  • Imidazoles / pharmacokinetics*
  • Losartan / administration & dosage
  • Losartan / pharmacokinetics*
  • Male
  • Tetrazoles / pharmacokinetics*
  • Young Adult

Substances

  • Antihypertensive Agents
  • Imidazoles
  • Tetrazoles
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • losartan carboxylic acid
  • Losartan