Decreased Warfarin Clearance with the CYP2C9 R150H (*8) Polymorphism
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Date
2012-04Author
Liu, Yong
Jeong, Hyun-Young
Takahashi, Harumi
Drozda, Katarzyna
Patel, Shitalben R.
Shapiro, Nancy L.
Nutescu, Edith A.
Cavallari, Larisa H.
Publisher
Nature Publishing GroupMetadata
Show full item recordAbstract
The cytochrome P450 (CYP) 2C9 R150H (*8) allele occurs commonly in African Americans and is associated with lower warfarin dose requirements. We examined whether the CYP2C9*8 allele impacts warfarin clearance through a pharmacokinetic study in warfarin-treated African American patients and an in vitro kinetic study of S-warfarin 7-hydroxylation using cDNA-expressed CYP2C9 enzymes. We observed a 30% reduction in the unbound oral clearance of S-warfarin and 25% lower R- to S-warfarin plasma concentration in patients with the CYP2C9*8 allele (n=12) 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 compared to the wild-type protein. These data show that the R150H variant of the CYP2C9*8 allele reduces S-warfarin clearance, thus providing clinical and experimental evidence to explain lower warfarin dose requirements with the CYP2C9*8 allele.
Subject
CYP2C9*8warfarin
Pharmacokinetics
polymorphism
metabolism