Warfarin analog inhibition of human CYP2C9-catalyzed S-warfarin 7-hydroxylation

Thrombosis Research
Z Y ZhangL S Kaminsky

Abstract

Human metabolism of the S-warfarin enantiomer is catalyzed primarily by cytochrome P4502C9 (CYP2C9), which, because of the enzyme's broad drug substrate specificity, leads to drug-S-warfarin interactions. Several warfarin analogs have been synthesized and used to determine whether they exhibit diminished interactions with CYP2C9. The kinetics of the warfarin analogs' inhibition of human liver microsomal CYP2C9 catalyzed metabolism of S-warfarin to S-7-hydroxywarfarin have been investigated. R- and S-7-fluorowarfarin were both predominantly competitive inhibitors, whereas racemic 6-fluorowarfarin and racemic 6,7,8-trifluorowarfarin were predominantly mixed inhibitors with some competitive inhibition. For the alcohols produced by reductive methylation of the side chain of R- and S-warfarin, the R-enantiomer did not inhibit S-warfarin metabolism, whereas the S-enantiomer was primarily a competitive inhibitor. The fluorine substituted warfarins and the S-warfarin alcohol apparently bind with high affinity to CYP2C9. Thus their use clinically (if efficacious) would not prevent CYP2C9 associated warfarin-drug interactions. The R-warfarin alcohol did not inhibit CYP2C9 catalyzed metabolism of S-warfarin and is less likely than warfari...Continue Reading

References

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Citations

Nov 15, 1997·Thrombosis Research·J S KerrP P Harlow
Jul 18, 2014·Drug Metabolism and Pharmacokinetics·Shuoye YangXijing Chen
Apr 23, 2016·Journal of Pharmaceutical Sciences·Abdul Naveed ShaikBarbara W LeDuc
Mar 23, 2007·Electrophoresis·Jiri KonecnýZdenek Glatz
Mar 4, 2005·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·M UferA Rane
May 1, 2010·Chemical Research in Toxicology·Drew R JonesGrover P Miller

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