title: VKORC1 diplotype-derived dosing model to explain variability in warfarin dose requirements in Asian patients.
abstract: Warfarin-induced bleeding complications and high inter-patient variability are major hindrances to oral anticoagulant therapy. The present study identifies the influence of VKORC1 diplotypes, CYP2C9 and CYP2C19 variants on warfarin disposition and dose requirements in Chinese patients (n=107). The study subjects were genotyped for VKORC1, CYP2C9 and CYP2C19 polymorphic variants. Weekly warfarin dose requirements and S-warfarin clearance were stratified by VKORC1, CYP2C9 and CYP2C19 pharmacogenetics. The major VKORC1 diplotypes were H1-H1 (62%), H1-H7 (18%) and H1-H(*)(b) (10%). Warfarin dose requirements were significantly lower in patients with VKORC1 H1-H1 and H1-H(*)(a) diplotypes compared to patients harboring the H1-H7 and H1-H(*)(b) diplotypes (P<0.05). Hepatic tissues with H1-H1 diplotype had significantly lower expression of VKORC1 mRNA compared with liver tissues carrying the H1-H7 and H1-H(*)(b) diplotypes (P=0.006). The percent variability explained by VKORC1 diplotype status was 59.1% while the CYP2C9 genotype status accounted for 6.9% variability in warfarin dose requirements. Patient age and weight were significant covariates accounting for 29% and 8.6% of warfarin dose variability, respectively. The present study shows that VKORC1 diplotype status, CYP2C9 genotype, age and weight are significant covariates, accounting for 73.4% of interindividual variability in warfarin dose requirements among Chinese patients. Translation of these findings into clinical guidelines for warfarin dosing may be required to assess its impact on the safety and efficacy of warfarin.
authors.affiliation: Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Edwin
authors.initials: E
authors.lastname: Sandanaraj
authors.forename: Suman
authors.initials: S
authors.lastname: Lal
authors.forename: Yin Bun
authors.initials: YB
authors.lastname: Cheung
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Xiang
authors.forename: Ming Chai
authors.initials: MC
authors.lastname: Kong
authors.forename: Lai Heng
authors.initials: LH
authors.lastname: Lee
authors.forename: London Lucien
authors.initials: LL
authors.lastname: Ooi
authors.forename: Balram
authors.initials: B
authors.lastname: Chowbay
mesh_terms: D000925:Anticoagulants / Q000008:administration & dosage* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D018628:Gene Dosage; D005787:Gene Frequency; D006801:Humans; D008957:Models, Genetic; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D014859:Warfarin / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19