title: Warfarin Metabolites in Patients Following Cardiac Valve Implantation: A Contribution of Clinical and Genetic Factors.
abstract: BACKGROUND
  Warfarin, a racemic mixture of S- and R-enantiomers, is the cornerstone of therapy in patients following cardiac valve replacement. S-warfarin is metabolized to 7-S-hydroxywarfarin by the cytochrome P450 isoform 2C9 encoded by CYP2C9 gene. R-warfarin is metabolized by multiple cytochromes P450. We sought to assess the impact of clinical and genetic factors on circulating warfarin metabolites following valve implantation.
  
  
  METHODS
  Venous blood was collected from 120 patients after 3 months since elective mitral and/or aortic valve replacement. Plasma S-warfarin, R-warfarin, S-7-hydroxywarfarin, and R-7-hydroxywarfarin were determined using high-performance liquid chromatography. The S-7-hydroxywarfarin/S-warfarin and S-warfarin/R-warfarin (S/R) ratios, along with warfarin sensitivity index (WSI), defined as INR/S-warfarin ratio, were calculated. Vitamin K epoxide reductase complex subunit 1 (VKORC1) c.-1639A, CYP2C9*3 and CYP2C9*2 alleles were determined using real-time polymerase chain reaction.
  
  
  RESULTS
  The S-warfarin was higher in former smokers (p = 0.047) and the VKORC1 c.-1639A allele carriers (p < 0.0001). The S-7-hydroxywarfarin was lower in carriers of the VKORC1 c.-1639A allele (p = 0.0005) and CYP2C9*3 (p = 0.047). The S-7-hydroxywarfarin/S-warfarin ratio was lower in the carriers of CYP2C9*3 (p = 0.008), but not in those with VKORC1 -c.1639A allele. The S/R ratio was higher in patients with hypertension (p = 0.01). The independent predictors of elevated S/R ratio defined as the upper quartile were diabetes (p = 0.045), CYP2C9*3 (p < 0.0001) and CYP2C9*2 (p = 0.0002). The independent predictors of elevated WSI were current smoking (p = 0.049), implantation of mechanical valve (p = 0.006) and VKORC1c.-1639A allele (p = 0.007).
  
  
  CONCLUSIONS
  We conclude that not only genetic, but also several clinical factors affect warfarin metabolites in patients following cardiac valve implantation.
authors.affiliation: Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202, Krakow, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Bryk
authors.forename: Ewa
authors.initials: E
authors.lastname: Wypasek
authors.forename: Magdalena
authors.initials: M
authors.lastname: Awsiuk
authors.forename: Dorota
authors.initials: D
authors.lastname: Maj
authors.forename: Anetta
authors.initials: A
authors.lastname: Undas
mesh_terms: D000483:Alleles; D001021:Aortic Valve / Q000637:transplantation*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008875:Middle Aged; D008943:Mitral Valve / Q000637:transplantation*; D064417:Vitamin K Epoxide Reductases / Q000235:genetics* / Q000378:metabolism; D014859:Warfarin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*
chemical_list: D014859:Warfarin; C087837:7-hydroxywarfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases