CYP2C9 R150H variant and warfarin PK_clean_9_6_2011.pdf (266.48 kB)
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Decreased Warfarin Clearance with the CYP2C9 R150H (*8) Polymorphism

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posted on 12.11.2013 by Yong Liu, Hyun-Young Jeong, Harumi Takahashi, Katarzyna Drozda, Shitalben R. Patel, Nancy L. Shapiro, Edith A. Nutescu, Larisa H. Cavallari
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.

Funding

This work was supported an American Heart Association Midwest Affiliate Spring 2010 Grant-In-Aid (10GRNT3750024) .

History

Publisher Statement

This is a copy of an article published in the Clinical Pharmacology and Therapeutics © 2012 Nature Publishing Group. The final publication is available at http://www.nature.com/clpt/index.html doi: 10.1038/clpt.2011.269

Publisher

Nature Publishing Group

Language

en_US

issn

1532-6535

Issue date

01/04/2012

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