Decreased Warfarin Clearance Associated With the CYP2C9 R150H ( *8 ) Polymorphism

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. Clinical Pharmacology & Therapeutics (2012); 91 4, 660–665. doi: 10.1038/clpt.2011.269