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

Y Liu¹, H Jeong, H Takahashi

¹Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.

Clinical Pharmacology and Therapeutics

|March 2, 2012

Summary

The CYP2C9*8 allele, common in African Americans, is linked to lower warfarin doses. This study confirms the CYP2C9 R150H variant reduces S-warfarin clearance, explaining reduced dosage needs.

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Area of Science:

Pharmacogenomics
Drug Metabolism
Biochemistry

Background:

The cytochrome P450 (CYP) 2C9 R150H (*8) allele is prevalent in African Americans.
This allele is associated with reduced warfarin dose requirements.

Purpose of the Study:

To investigate the impact of the CYP2C9*8 allele on warfarin pharmacokinetics in African-American patients.
To determine the in vitro effect of the CYP2C9 R150H variant on S-warfarin metabolism.

Main Methods:

Conducted a pharmacokinetic study in African-American patients with CYP2C9*8 and CYP2C9*1 alleles.
Performed in vitro kinetic studies using complementary DNA (cDNA)-expressed CYP2C9 enzymes to assess S-warfarin 7-hydroxylation.

Main Results:

Patients with the CYP2C9*8 allele showed a 30% reduction in unbound oral clearance of S-warfarin.
A 25% lower R- to S-warfarin plasma concentration ratio was observed in CYP2C9*8 carriers.
In vitro studies revealed a 30% lower intrinsic clearance of S-warfarin with the R150H variant protein compared to wild-type.

Conclusions:

The CYP2C9 R150H variant protein, expressed by the CYP2C9*8 allele, is associated with decreased S-warfarin clearance.
This finding provides clinical and experimental validation for lower warfarin dose requirements in individuals carrying the CYP2C9*8 allele.