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

So-Young      Kim; Ji-Yeon      Kang; Jessica   H.   Hartman; Sun-Ha      Park; Drew   R.   Jones; Chul-Ho      Yun; Gunnar      Boysen; Grover   P.   Miller

doi:10.2174/1872312811206030002

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.

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