title: Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects.
abstract: Genetic polymorphisms in CYP2C9 account for 10-20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions.
  
  
  
  The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance (CLS) among healthy subjects carrying different CYP2C9 genotypes.
  
  
  
  Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period.
  
  
  
  Compared with carriers of the wild-type CYP2C9*1/*1 genotype (n = 69), CLSwas reduced by 25, 39 and 47% among heterozygote for CYP2C9*2 (n = 41) CYP2C9*3 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001).
  
  
  
  The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision.
  
  
  
  Clinicaltrials.gov Identifier NCT00162474.
authors.affiliation: Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel.|Institute of Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
authors.forename: Chanan
authors.initials: C
authors.lastname: Shaul
authors.affiliation: Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel.
authors.forename: Simcha
authors.initials: S
authors.lastname: Blotnick
authors.affiliation: Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel.
authors.forename: Mordechai
authors.initials: M
authors.lastname: Muszkat
authors.affiliation: Institute of Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
authors.affiliation: Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel. caraco@hadassah.org.il.
authors.forename: Yoseph
authors.identifier: 0000-0002-7959-2517
authors.initials: Y
authors.lastname: Caraco
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005069:Evaluation Studies as Topic; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D014859:Warfarin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9