Comparison of milnacipran and duloxetine as inhibitors of selected P450 enzymes with and without a 30-min preincubation with NADPH-fortified human liver microsomes
| Enzyme | P450 Activity | Direct Inhibition (0-Min Preincubation) | Time-Dependent Inhibition (30-Min Preincubation) | ||
|---|---|---|---|---|---|
| Milnacipran IC50 | Duloxetine IC50 | Milnacipran IC50 | Duloxetine IC50 | ||
| μM | |||||
| CYP1A2 | Phenacetin O-dealkylation | >100 | 50 | >100 | 18 |
| CYP2B6 | Bupropion hydroxylation | 98 | 15 | >100 | 4.7 |
| CYP2C8 | Amodiaquine N-dealkylation | >100 | 60 | >100 | 49 |
| CYP2C9 | Diclofenac 4′-hydroxylation | >100 | >100 | >100 | >100 |
| CYP2C19 | S-Mephenytoin 4′-hydroxylation | >100 | 27 | >100 | 8.6 |
| CYP2D6 | Dextromethorphan O-demethylation | >100 | 7.0 | >100 | 13 |
| CYP3A4/5 | Testosterone 6β-hydroxylation | >100a | 38 | >100 | 17 |
| CYP3A4/5 | Midazolam 1′-hydroxylation | 28 | 37 | 24 | 26 |
↵a The IC50 value calculated was 102 μM but is reported as >100 μM because concentrations beyond the concentration range studied should be considered estimates.