Warfarin Analog Inhibition of Human CYP2C9-Catalyzed S-Warfarin 7-Hydroxylation
Section snippets
Materials
Optically pure R- and S-warfarin enantiomers (Fig. 1, I and II) were resolved from racemic warfarin (Sigma Chemical Co., St. Louis, MO) by the method of West et al. [27]to greater than 99% optical purity [28]. The metabolite 7-hydroxywarfarin was synthesized and characterized as previously described using published methods 29, 30, 31. HPLC grade acetic acid and acetonitrile were obtained from Mallinckrodt (Paris, KY). Pooled human liver microsomes were purchased from Human Biologics, Inc.
Results
Preliminary studies of the potential of the warfarin analogs to undergo human hepatic microsomal metabolism were undertaken using the assay systems for the analysis of warfarin metabolism. Such studies were required to determine whether the presence of the analogs or any of their metabolites would interfere with the HPLC analyses of S-warfarin metabolism in the microsomal system. Additionally, it was important to gauge whether any of the analogs would be substantially metabolized and thus
Discussion
The objective of this study—assessments of the potential for modifying drug-drug interactions of warfarin—has been addressed by using a series of analogs of warfarin (Fig. 1). Four of these analogs (Fig. 1, III to VI) have the coumarin moiety modified by the substitution of various hydrogens by fluorine. Hydrogen and fluorine have similar Van Der Waal's radii, 1.2 and 1.35Å, respectively, and substitution of hydrogen by fluorine on a substrate should not influence purely steric interactions of
Acknowledgements
This project has been funded in part by a grant from the National Institutes of Health, Public Health Service (P01 ESO4238).
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