title: Population differences in S-warfarin pharmacokinetics among African Americans, Asians and whites: their influence on pharmacogenetic dosing algorithms.
abstract: Using population pharmacokinetic analysis (PPK), we attempted to identify predictors of S-warfarin clearance (CL(S)) and to clarify population differences in S-warfarin pharmacokinetics among a cohort of 378 African American, Asian and white patients. Significant predictors of CL(S) included clinical (age, body weight and sex) and genotypic (CYP2C9*2,*3 and *8) factors, as well as African American ethnicity, the median CL(S) being 30% lower in the latter than in Asians and whites (170 versus 243 and 250 ml h-1, P<0.01). The plasma S-warfarin (Cp(S)) time courses following the genotype-based dosing algorithms simulated using the PPK estimates showed African Americans with CYP2C9*1/*1 and any of the VKORC1 genotypes would have an average Cp(S) at steady state 1.5-1.8 times higher than in Asians and whites. These results indicate warfarin dosing algorithms should be evaluated in each respective ethnic population. Further study of a large African American cohort will be necessary to confirm the present findings.
authors: Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
authors: K
authors: K
authors: Kubo
authors: Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
authors: M
authors: M
authors: Ohara
authors: Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
authors: M
authors: M
authors: Tachikawa
authors: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA.
authors: L H
authors: LH
authors: Cavallari
authors: Genomic Medicine Institute, Geisinger Health System, Danville, PA, USA.|Division of Epidemiology and Genetics, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: M T M
authors: MTM
authors: Lee
authors: Department of Internal Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors: M S
authors: MS
authors: Wen
authors: Department of Medical Sciences, Clinical Pharmacology, Uppsala University Hospital, Uppsala, Sweden.
authors: M G
authors: MG
authors: Scordo
authors: Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL, USA.
authors: E A
authors: EA
authors: Nutescu
authors: Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USA.
authors: M A
authors: MA
authors: Perera
authors: Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
authors: A
authors: A
authors: Miyajima
authors: Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
authors: N
authors: N
authors: Kaneko
authors: Department of Cardiothoracic and Vascular Sciences, University of Padova, Padova, Italy.
authors: V
authors: V
authors: Pengo
authors: Department of Medicine DIMED, University of Padova, Padova, Italy.
authors: R
authors: R
authors: Padrini
authors: Division of Epidemiology and Genetics, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: Y T
authors: YT
authors: Chen
authors: Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
authors: H
authors: H
authors: Takahashi
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood; D044466:Asian People / Q000235:genetics*; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D008875:Middle Aged; D008954:Models, Biological; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage / Q000097:blood; D044465:White People / Q000235:genetics*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases