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

• Published in: Clinical pharmacology and therapeutics 2012-04, Vol.91 (4), p.660-665
• Main Authors: Liu, Y, Jeong, H, Takahashi, H, Drozda, K, Patel, S R, Shapiro, N L, Nutescu, E A, Cavallari, L H
• Format: Article
• Language: English
• Subjects: Adult; African Americans - genetics; Aged; Aryl Hydrocarbon Hydroxylases - genetics; Biological and medical sciences; Cytochrome P-450 CYP2C9; Female; Genetic Variation - genetics; Hep G2 Cells; Humans; Male; Medical sciences; Metabolic Clearance Rate - genetics; Middle Aged; Pharmacology. Drug treatments; Polymorphism, Genetic - genetics; Warfarin - pharmacokinetics
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/clpt.2011.269

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