Effects of protein binding of warfarin enantiomers and metabolites on inhibition of VKORC1 activity
| Inhibitor . | fu plasma, % . | fu media, % . | [I]u/Kiu × 102 (relative %) . |
|---|---|---|---|
| 9S-warfarin | 0.4 | 31 | 135 (100) |
| 9R-warfarin | 0.4 | 25 | 25 (18.5) |
| 4′-OH warfarin | 2.1 | 50 | 1.4 (1.0) |
| 5-OH warfarin | 0.54 | 18 | 0.005 (<0.01) |
| 6-OH warfarin | 3.4 | 47 | 2.8 (2.1) |
| 7-OH warfarin | 2.2 | 34 | 1.2 (0.9) |
| 8-OH warfarin | 2.3 | 25 | 0.004 (<0.01) |
| 10-OH warfarin | 0.69 | 47 | 6.4 (4.7) |
| Warfarin alcohols | 0.97 | 37 | 19 (16.2) |
| Inhibitor . | fu plasma, % . | fu media, % . | [I]u/Kiu × 102 (relative %) . |
|---|---|---|---|
| 9S-warfarin | 0.4 | 31 | 135 (100) |
| 9R-warfarin | 0.4 | 25 | 25 (18.5) |
| 4′-OH warfarin | 2.1 | 50 | 1.4 (1.0) |
| 5-OH warfarin | 0.54 | 18 | 0.005 (<0.01) |
| 6-OH warfarin | 3.4 | 47 | 2.8 (2.1) |
| 7-OH warfarin | 2.2 | 34 | 1.2 (0.9) |
| 8-OH warfarin | 2.3 | 25 | 0.004 (<0.01) |
| 10-OH warfarin | 0.69 | 47 | 6.4 (4.7) |
| Warfarin alcohols | 0.97 | 37 | 19 (16.2) |
Unbound fraction of VKORC1 inhibitors in human plasma (fuplasma) and HEK-C3 culture media (fumedia) was measured. Unbound fractions were used to refine [I]/IC50 calculations (Table 1) for in vivo and in vitro protein binding and calculate ([I]u/Kiu) reflecting relative in vivo contributions of each drug to VKORC1 inhibition.