title: Mechanistic insights into the effect of CYP2C9*2 and CYP2C9*3 variants on the 7-hydroxylation of warfarin.
abstract: OBJECTIVE
  To evaluate the impact of CYP2C9*2 and CYP2C9*3 variants on binding and hydroxylation of warfarin.
  
  
  METHODS
  Multiple linear regression model of warfarin pharmacokinetics was developed from the dataset of patients (n = 199). Pymol based in silico models were developed for the genetic variants.
  
  
  RESULTS
  CYP2C9*2 and CYP2C9*3 variants exhibited high warfarin/7-hydroxywarfarin (multiple linear regression model), dose-dependent disruption of hydrogen bonds with warfarin, dose-dependent increase in the distance between C7 of S-warfarin and Fe-O of CYP2C9, dose-dependent decrease in the glide scores (in silico).
  
  
  CONCLUSIONS
  CYP2C9*2 and CYP2C9*3 variants result in disruption of hydrogen bonding interactions with warfarin and longer distance between C7 and Fe-O thus impairing warfarin 7-hydroxylation due to lower binding affinity of warfarin. Original submitted 7 May 2014; Revision submitted 30 October 2014.
authors.affiliation: Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, India.
authors.forename: Addepalli
authors.initials: A
authors.lastname: Pavani
authors.forename: Shaik Mohammad
authors.initials: SM
authors.lastname: Naushad
authors.forename: Balraj Alex
authors.initials: BA
authors.lastname: Stanley
authors.forename: Renganathan Gnanambal
authors.initials: RG
authors.lastname: Kamakshi
authors.forename: Krishnan
authors.initials: K
authors.lastname: Abinaya
authors.forename: Malempati
authors.initials: M
authors.lastname: Amaresh Rao
authors.forename: Addepally
authors.initials: A
authors.lastname: Uma
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Kutala
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065729:Cytochrome P-450 CYP2C9 / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006860:Hydrogen Bonding; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D014859:Warfarin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C087837:7-hydroxywarfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9
keywords: 7-hydroxy warfarin; CYP2C9*2; CYP2C9*3; multiple linear regression; warfarin