title: Decreased warfarin clearance associated with the CYP2C9 R150H (*8) polymorphism.
abstract: The cytochrome P450 (CYP) 2C9 R150H (*8) allele occurs commonly in African Americans and is associated with lower warfarin dose requirements. We conducted a pharmacokinetic study to examine whether the CYP2C9*8 allele impacts warfarin clearance in African-American patients. We also conducted an in vitro kinetic study of S-warfarin 7-hydroxylation using complementary DNA (cDNA)-expressed CYP2C9 enzymes. We observed a 30% reduction in the unbound oral clearance of S-warfarin and a 25% lower R- to S-warfarin plasma concentration ratio in patients with the CYP2C9*8 allele (n = 12) as compared to CYP2C9*1 homozygotes (n = 26). Consistent with these findings, the in vitro intrinsic clearance of S-warfarin was 30% lower with the cDNA-expressed R150H protein as compared to the wild-type protein. These data show that the R150H variant protein expressed by the CYP2C9*8 allele is associated with lower S-warfarin clearance. This finding provides clinical and experimental evidence to explain the lower warfarin dose requirements in patients with the CYP2C9*8 allele.
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Jeong
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Drozda
authors.forename: S R
authors.initials: SR
authors.lastname: Patel
authors.forename: N L
authors.initials: NL
authors.lastname: Shapiro
authors.forename: E A
authors.initials: EA
authors.lastname: Nutescu
authors.forename: L H
authors.initials: LH
authors.lastname: Cavallari
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D014859:Warfarin / Q000493:pharmacokinetics*
chemical_list: D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases