The anticoagulant drug warfarin occurs as a pair of enantiomers that are differentially metabolized by human cytochromes P450 (CYP). R-warfarin is metabolized primarily by CYP1A2 to 6- and 8-hydroxywarfarin, by CYP3A4 to 10-hydroxywarfarin, and by carbonyl reductases to diastereoisomeric alcohols. S-warfarin is metabolized primarily by CYP2C9 to 7-hydroxywarfarin. Potential warfarin-drug interactions could occur with any of a very wide range of drugs that are metabolized by these P450s, and a number of such interactions have been reported. The efficacy of warfarin is affected primarily when metabolism of S-warfarin is altered.
Metabolism of warfarin and vitamin K inhibition. Warfarin is supplied as a racemic mixture of R-warfarin and S-warfarin. S-warfarin is the more active of the two at inhibiting vitamin K reductase. The R isomer is metabolized by several CYP450 isoforms and the S isomer is metabolized primarily by CYP2C9. Abbreviations: CYP1A1 = cytochrome P450, family 1, subfamily A, polypeptide 1; CYP1A2 = cytochrome P450 1A2; CYP3A4 = cytochrome P450 3A4; CYP2C9 = cytochrome P450 2C9.
Warfarin itself is commercially supplied as a racemic mixture of R and S enantiomers. S-warfarin is responsible for 70% of the drug's activity because it has up to five-fold higher potency than R-warfarin. S-warfarin is metabolized primarily by CYP2C9 to 7-hydroxywarfarin (Figure 4).[45,46] Alterations in the activity of this enzyme were investigated to explain some of the variability in responses to warfarin. Numerous alleles of CYP2C9 have been reported that vary with ethnicity; however, the majority of clinical studies has involved two variant alleles, CYP2C9*2 and CYP2C9*3. The *2 allele is found in 11% of the Caucasian population and results in a 30% decrease in CYP2C9 activity compared with the *1 wild-type allele. The *3 allele is less common than the *2 allele, with an incidence of 7% in Caucasians; this variant results in an 80% decrease in enzyme activity....
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