Generic placeholder image

Drug Metabolism Letters

Editor-in-Chief

ISSN (Print): 1872-3128
ISSN (Online): 1874-0758

Metabolism of R- and S-Warfarin by CYP2C19 into Four Hydroxywarfarins

Author(s): So-Young Kim, Ji-Yeon Kang, Jessica H. Hartman, Sun-Ha Park, Drew R. Jones, Chul-Ho Yun, Gunnar Boysen and Grover P. Miller

Volume 6, Issue 3, 2012

Page: [157 - 164] Pages: 8

DOI: 10.2174/1872312811206030002

Price: $65

Abstract

Coumadin (R/S-warfarin) is a highly efficacious and widely used anticoagulant; however, its highly variable metabolism remains an important contributor to uncertainties in therapeutic responses. Pharmacogenetic studies report conflicting findings on the clinical relevance of CYP2C19. A resolution to this controversy is impeded by a lack of detail on the potential role of CYP2C19 in warfarin metabolism. Consequently, we assessed the efficiency of CYP2C19 metabolism of R- and S-warfarin and explored possible contributions in the liver using in vitro methods. Recombinant CYP2C19 metabolized R- and S-warfarin mainly to 6-, 7-, and 8-hydroxywarfarin, while 4'-hydroxywarfarin was a minor metabolite. Overall R-warfarin metabolism was slightly more efficient than that for S-warfarin. Metabolic pathways that produce R-6-, 7-, and 8-hydroxywarfarin in human liver microsomal reactions correlated strongly with CYP2C19 Smephenytoin hydroxylase activity. Similarly, CYP1A2 activity toward phenacetin correlated with formation of R-6 and 7- hydroxywarfarin such that R-8-hydroxywarfarin seems unique to CYP2C19 and possibly a biomarker. In following, CYP2C19 likely impacts R-warfarin metabolism and patient response to therapy. Intriguingly, CYP2C19 may contribute to S-warfarin metabolism in patients, especially when CYP2C9 activity is compromised due to drug interactions or genetic polymorphisms.

Keywords: Warfarin, CYP2C19, cytochrome P450, metabolism, biomarker.


Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy