Evaluation of laromustine as a direct-acting inhibitor of selected P450 enzymes in human liver microsomes
Enzyme | P450 Enzyme Reaction | Maximum Inhibition at 750 μM (%)a | Ki | Type of Inhibition |
|---|---|---|---|---|
| % | μM | |||
| CYP1A2 | Phenacetin O-dealkylation | 21 | >750 | Noncompetitive |
| CYP2B6 | Bupropion hydroxylation | 80 | 125 | Competitive |
| CYP2C8 | Amodiaquine N-dealkylation | 24 | >750 | Noncompetitive |
| CYP2C9 | Diclofenac 4′-hydroxylation | 14 | >750 | Noncompetitive |
| CYP2C19 | S-Mephenytoin 4′-hydroxylation | 55 | 349 | Mixed |
| CYP2D6 | Dextromethorphan O-demethylation | 16 | >750 | Noncompetitive |
| CYP3A4/5 | Testosterone 6β-hydroxylation | 26 | >750 | Competitive |
| CYP3A4/5 | Midazolam 1′-hydroxylation | 66 | 297 | Mixed |
↵ a Maximum inhibition is based on the highest concentration of laromustine evaluated (750 μM) with P450 marker substrates at concentrations approximately equal to Km.