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CYP2C9 Genotype‐Dependent Warfarin Pharmacokinetics: Impact of CYP2C9 Genotype on R‐ and S‐Warfarin and Their Oxidative Metabolites
Author(s) -
Flora Darcy R.,
Rettie Allan E.,
Brundage Richard C.,
Tracy Timothy S.
Publication year - 2017
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.813
Subject(s) - cyp2c9 , warfarin , pharmacology , pharmacokinetics , genotype , cytochrome p450 , pharmacogenetics , chemistry , metabolism , biology , medicine , biochemistry , atrial fibrillation , gene
Multiple factors can impact warfarin therapy, including genetic variations in the drug‐metabolizing enzyme cytochrome P450 2C9 (CYP2C9). Compared with individuals with the wild‐type allele, CYP2C9*1 , carriers of the common *3 variant have significantly impaired CYP2C9 metabolism. Genetic variations in CYP2C9, the primary enzyme governing the metabolic clearance of the more potent S‐enantiomer of the racemic anticoagulant warfarin, may impact warfarin–drug interactions. To establish a baseline for such studies, plasma and urine concentrations of R‐ and S‐warfarin and 10 warfarin metabolites were monitored for up to 360 hours following a 10‐mg warfarin dose in healthy subjects with 4 different CYP2C9 genotypes: CYP2C9*1/*1 (n = 8), CYP2C9*1/*3 (n = 9), CYP2C9*2/*3 (n = 3), and CYP2C9*3/*3 (n = 4). Plasma clearance of S‐warfarin, but not R‐warfarin, decreased multiexponentially and in a CYP2C9 gene‐dependent manner: 56%, 70%, and 75% for CYP2C9*1/*3 , CYP2C9*2/*3 , and CYP2C9*3/*3 genotypes, respectively, compared with CYP2C9*1/*1 , resulting in pronounced differences in the S:R ratio that identified warfarin‐sensitive genotypes. CYP2C9 was the primary P450 enzyme contributing to S‐warfarin metabolism and a minor contributor to R‐warfarin metabolism. In the presence of a defective CYP2C9 allele, switching of warfarin metabolism to other oxidative pathways and P450 enzymes for the metabolic elimination of S‐warfarin was not observed. The 10‐hydroxywarfarin metabolites, whose detailed pharmacokinetics are reported for the first time, exhibited a prolonged half‐life with no evidence of renal excretion and displayed elimination rate‐limited kinetics. Understanding the impact of CYP2C9 genetics on warfarin pharmacokinetics lays the foundation for future genotype‐dependent warfarin–drug interaction studies.