CYP2C9 Genotype-Dependent Warfarin Pharmacokinetics: Impact of CYP2C9 Genotype on R- and S-Warfarin and Their Oxidative Metabolites

Darcy R. Flora, Allan E. Rettie, Richard C. Brundage, Timothy S. Tracy

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)382-393
Number of pages12
JournalJournal of Clinical Pharmacology
Volume57
Issue number3
DOIs
StatePublished - Mar 2017

Bibliographical note

Funding Information:
This study was supported by the National Institutes of Health Institute of General Medical Sciences (GM069753 and GM032165). We acknowledge funding source P30ES07033 at the Center for Exposures, Diseases, Genomics and Environment (University of Washington). For his work on the development of the warfarin assay, we acknowledge James Fisher in the Clinical Pharmacology Analytical Services Laboratory at the University of Minnesota.

Publisher Copyright:
© 2016, The American College of Clinical Pharmacology

Keywords

  • CYP2C9
  • pharmacogenetics
  • pharmacokinetics
  • warfarin

Fingerprint

Dive into the research topics of 'CYP2C9 Genotype-Dependent Warfarin Pharmacokinetics: Impact of CYP2C9 Genotype on R- and S-Warfarin and Their Oxidative Metabolites'. Together they form a unique fingerprint.

Cite this