title: Metabolism of R- and S-warfarin by CYP2C19 into four hydroxywarfarins.
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 de tailon 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 minormetabolite. Over all R-warfarin metabolism was slightly more efficient than that for S-warfarin. Metabolic pathways thatproduce R-6-, 7-, and 8-hydroxywarfarin in human liver microsomal reactions correlated strongly with CYP2C19 Smephenytoinhydroxylase 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 contributeto S-warfarin metabolism in patients, especially when CYP2C9 activity is compromised due to drug interactions orgenetic polymorphisms.
authors: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 516. Little Rock, AR 72205, USA.
authors: So-Young
authors: SY
authors: Kim
authors: Ji-Yeon
authors: JY
authors: Kang
authors: Jessica H
authors: JH
authors: Hartman
authors: Sun-Ha
authors: SH
authors: Park
authors: Drew R
authors: DR
authors: Jones
authors: Chul-Ho
authors: CH
authors: Yun
authors: Gunnar
authors: G
authors: Boysen
authors: Grover P
authors: GP
authors: Miller
mesh_terms: D000925:Anticoagulants / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010597:Pharmacogenetics; D013237:Stereoisomerism; D014859:Warfarin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000925:Anticoagulants; C101436:8-hydroxywarfarin; C059853:4'-hydroxywarfarin; D014859:Warfarin; C087837:7-hydroxywarfarin; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; C008091:6-hydroxywarfarin