Decreased warfarin clearance associated with the CYP2C9 R150H (*8) polymorphism.

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Liu Y, Jeong H, Takahashi H, Drozda K, Patel SR, Shapiro NL, Nutescu EA, Cavallari LH

Decreased warfarin clearance associated with the CYP2C9 R150H (*8) polymorphism.

Clin Pharmacol Ther. 2012 Apr;91(4):660-5. doi: 10.1038/clpt.2011.269. Epub 2012 Feb 29.

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22378156 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Phenytoin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*8	Not Available	449G>A (rs7900194)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Celecoxib	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*8	Not Available	449G>A (rs7900194)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Warfarin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*8	Not Available	449G>A (rs7900194)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Clopidogrel	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*8	Not Available	449G>A (rs7900194)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for drug-drug interactions	Details
Acetylsalicylic acid	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*8	Not Available	449G>A (rs7900194)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Glipizide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*8	Not Available	449G>A (rs7900194)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Tolbutamide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*8	Not Available	449G>A (rs7900194)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Acenocoumarol	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*8	Not Available	449G>A (rs7900194)	Effect Inferred	Poor drug metabolizer, associated with lower dose requirement.	Details
Phenprocoumon	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*8	Not Available	449G>A (rs7900194)	ADR Inferred	Associated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation.	Details