Warfarin analog inhibition of human CYP2C9-catalyzed S-warfarin 7-hydroxylation.
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 warfarin to participate in CYP2C9 associated warfarin-drug interactions.
Zhang
Z Y
ZY
Department of Environmental Health and Toxicology, University at Albany, State University of New York, USA.
Kerr
J
J
Wexler
R S
RS
Li
H Y
HY
Robinson
A J
AJ
Harlow
P P
PP
Kaminsky
L S
LS
D001189:Aryl Hydrocarbon Hydroxylases; D001667:Binding, Competitive; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism; D013237:Stereoisomerism; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014859:Warfarin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase