CYP2C9*3 influences the metabolism and the drug-interaction of candesartan in vitro

Pharmacogenomics J. 2001;1(4):288-92. doi: 10.1038/sj.tpj.6500063.

Abstract

Candesartan cilexetil is an angiotensin II receptor antagonist, and candesartan, its active metabolite, is metabolized by CYP2C9. However, the effect of CYP2C9*3 on candesartan metabolism is not established. We characterized the kinetics of candesartan by CYP2C9*1/*1 and CYP2C9*1/*3 in human liver microsomes. The difference between the two was not significant. Subsequently, CYP2C9*1 and CYP2C9*3 (Leu359) were expressed in yeast, and the kinetics of candesartan were determined. The wild-type showed the lower Km (345 vs 439 microM; 3/4) and higher Vmax/Km (1/3) than the Leu359 variant. Also, we investigated potential interaction between candesartan and warfarin with both the wild-type and the Leu359 variant. Candesartan had no effect on S-warfarin 7-hydroxylation. In contrast, S-warfarin inhibited candesartan metabolism by the wild-type (K = 17microM) greater than by the Leu359 variant (Ki = 36 microM). These findings suggest that CYP2C9*3 may change not only the metabolic activity but also the inhibitory susceptibility compared with CYP2C9*1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Anticoagulants / metabolism
  • Anticoagulants / pharmacokinetics
  • Antihypertensive Agents / metabolism
  • Aryl Hydrocarbon Hydroxylases*
  • Benzimidazoles / metabolism*
  • Biphenyl Compounds
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Interactions / physiology
  • Humans
  • Leucine / genetics
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Recombinant Proteins / metabolism
  • Saccharomyces cerevisiae / genetics
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism*
  • Tetrazoles / metabolism*
  • Warfarin / metabolism
  • Warfarin / pharmacokinetics

Substances

  • Anticoagulants
  • Antihypertensive Agents
  • Benzimidazoles
  • Biphenyl Compounds
  • Recombinant Proteins
  • Tetrazoles
  • Warfarin
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Steroid 16-alpha-Hydroxylase
  • Leucine
  • candesartan