Table 1.
Inhibitory effect of fargesin on eight major CYP enzyme activities in pooled human liver microsomes.
| CYP | Enzyme Activities | IC50 (µM) | Ki (µM) | |
|---|---|---|---|---|
| No Pre-Incubation | With Pre-Incubation * | (kinact, min−1 or Inhibition Mode) |
||
| 1A2 | Phenacetin O-deethylase | >100 | >100 | - |
| 2A6 | Coumarin 7-hydroxylase | >100 | >100 | - |
| 2B6 | Bupropion hydroxylase | >100 | >100 | - |
| 2C8 | Amodiaquine N-deethylase | 34.9 | 4.0 | 10.7 (kinact: 0.082) |
| 2C9 | Diclofenac 4′-hydroxylase | 30.8 | 16.4 | 16.3 (competitive) |
| 2C19 | (S)-Mephenytoin 4′-hydroxylase | 30.2 | 1.6 | 3.7 (kinact: 0.102) |
| 2D6 | Bufuralol 1′-hydroxylase | >100 | >100 | - |
| 3A4 | Midazolam 1′-hydroxylase | >100 | 17.9 | 23.0 (kinact: 0.050) |
* 30 min pre-incubation of fargesin with microsomes and NADPH before the addition of CYP substrates. The substrate cocktail concentrations for the measurement of the IC50 values were as following: 50 μM phenacetin, 2.5 μM coumarin, 2.0 μM amodiaquine, 10 μM diclofenac, 100 μM [S]-mephenytoin, 5.0 μM bufuralol, and 2.5 μM midazolam. Inhibition of CYP2B6 activity was determined separately using 50 μM bupropion. The data represent the average of three determinations.