title: Effects of CYP4F2 gene polymorphisms on warfarin clearance and sensitivity in Korean patients with mechanical cardiac valves.
abstract: BACKGROUND
  Recently, a single nucleotide polymorphism of CYP4F2 (rs2108622) was reported to have a significant relationship with the stable warfarin dose. However, the underlying mechanism of CYP4F2 effects on the stable warfarin dose has not been studied. This study aimed to examine the effects of cytochrome P450 (CYP) 4F2 gene on warfarin clearance and sensitivity in Korean patients with mechanical heart valves.
  
  
  METHODS
  One hundred ninety-one patients with mechanical heart valves who were on anticoagulation therapy with warfarin and maintained international normalized ratio levels of 2-3 for 3 consecutive times were followed up, retrospectively. Warfarin enantiomer concentrations were determined by a validated high-performance liquid chromatography method. Genotypes of vitamin K epoxide reductase complex subunit 1, CYP2C9, CYP2C19, CYP4F2, human microsomal epoxide hydroxylase, calumenin, and γ-glutamyl carboxylase were determined.
  
  
  RESULTS
  From multiple linear regression models, vitamin K epoxide reductase complex subunit 1, CYP2C9, CYP4F2, and age were found to have significant effects on warfarin stable dose. The stable warfarin daily doses of patients with the CC, CT, and TT genotypes in the CYP4F2 gene were 5.34 ± 2.04, 5.33 ± 1.64, and 6.55 ± 2.12 mg, respectively. The higher dose requirements in patients with TT alleles in CYP4F2 were attributable to a low warfarin sensitivity (international normalized ratio/warfarin plasma concentration); the warfarin sensitivity in CC, CT, and TT genotypes was 2.1 ± 1.2, 1.0 ± 0.4, and 0.8 ± 0.6, respectively. The similarity between the dose requirements of patients with CT and CC alleles was explained through the combined result of warfarin sensitivity and clearance outcomes. Apparent plasma (S)- and (R)-warfarin clearances were found to be 37.7% and 34.1% lower in CT genotype patients than in CC genotype patients, respectively.
  
  
  CONCLUSIONS
  The dose variability in CYP4F2 genotypes was attributable to both warfarin clearance and sensitivity differences.
authors.affiliation: College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
authors.forename: Kyung-Eun
authors.initials: KE
authors.lastname: Lee
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Chang
authors.forename: Han-Oll
authors.initials: HO
authors.lastname: Kim
authors.forename: In-Kyung
authors.initials: IK
authors.lastname: Yoon
authors.forename: Na-Ra
authors.initials: NR
authors.lastname: Lee
authors.forename: Hee-Yoon
authors.initials: HY
authors.lastname: Park
authors.forename: Hye-Sun
authors.initials: HS
authors.lastname: Gwak
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000208:ethnology / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006350:Heart Valve Prosthesis; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D056910:Republic of Korea / Q000208:ethnology; D014859:Warfarin / Q000378:metabolism*
chemical_list: D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human