Warfarin is a 1:1 racemate; the enantiomers clear via different CYPs. S-warfarin (3-5× more potent at VKORC1) is metabolized primarily by CYP2C9 to 7-hydroxywarfarin — this is why CYP2C9 inhibitors (fluconazole, amiodarone) raise INR more than expected for a "weak inhibition" of total warfarin. R-warfarin (less active) is metabolized by CYP1A2 and CYP3A4. The asymmetry explains why DDIs with R- vs S-selective perpetrators produce qualitatively different INR effects.
Organ Systems
cardiovascular
immune-hematologic
Pathway Steps
warfarin → 7-hydroxywarfarin — via CYP2C9 — S-warfarin (primary path for active enantiomer). The potent S-enantiomer is cleared mainly by CYP2C9, so CYP2C9 loss-of-function (*2,*3) plus VKORC1 promoter variants together explain ~40% of dose variability (the basis of pharmacogenomic dosing). Many interactions (azoles, amiodarone, sulfamethoxazole) act by inhibiting CYP2C9.
warfarin → 6-hydroxywarfarin — via CYP1A2 + CYP3A4 — R-warfarin (less-active enantiomer). The less-active R-enantiomer is handled by CYP1A2/CYP3A4; since warfarin is dosed as a racemate this is the minor contributor to anticoagulant effect, though R-pathway interactions can still nudge the INR.
Known Modulators
fluconazole (inhibitor) — CYP2C9 (S-warfarin path). INR rises markedly because S-warfarin is the active enantiomer.