Metabolism of R- and S-warfarin by CYP2C19 into four hydroxywarfarins.

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Kim SY, Kang JY, Hartman JH, Park SH, Jones DR, Yun CH, Boysen G, Miller GP

Metabolism of R- and S-warfarin by CYP2C19 into four hydroxywarfarins.

Drug Metab Lett. 2012 Sep 1;6(3):157-64.

PubMed ID

23331088 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
(R)-warfarin	Cytochrome P450 1A2	Protein	Humans	Unknown	Substrate	Details
(R)-warfarin	Cytochrome P450 2C19	Protein	Humans	Unknown	Substrate	Details
(S)-Warfarin	Cytochrome P450 2C19	Protein	Humans	Unknown	Substrate	Details