Inhibition of the P450 probe reactions, phenacetin O-deethylation (POD), diclofenac 4-hydroxylation (D4OH), S-mephenytoin 4-hydroxylation (SM4OH), bufuralol 1-hydroxylation (B1OH), and midazolam 1-hydroxylation (M1OH) by standard time-dependent inhibitors
Percentage TDI was calculated from the ratio of R + INADPH/R – INADPH and R + INO NADPH/R – INO NADPH as detailed under Results (eq. 2). Projected IC50 was calculated according to eq. 1 (Results). Inhibitor concentrations were as follows: Furafylline (FUR),10 μM; tienilic acid (TA), 0.5 μM; ticlopidine (TIC), 5 μM; MDMA, 5 μM; troleandomycin (TAO), 1.5 μM; mifepristone (MIF), 5 μM. Data are the mean of 30 experiments. For each inhibitor, the coefficient of variance (CV) was less than 5% for percentage TDI values and less than 20% for projected IC50 values.
Probe Reaction | Inhibitor | R + INADPH/R - INADPH | R + INO NADPH/R - INO NADPH | Percentage TDI | Projected IC50 |
|---|---|---|---|---|---|
| mean ± S.D. | μM | ||||
| POD | FUR | 0.16 | 0.75 | 79 ± 3 | 1.9 |
| TA | 0.87 | 0.98 | 6 ± 3 | ||
| TIC | 0.91 | 0.90 | 0 | ||
| MDMA | 0.95 | 0.92 | 0 | ||
| TAO | 0.93 | 1 | 6 ± 2 | ||
| MIF | 0.94 | 0.94 | 0 | ||
| D4OH | FUR | 0.91 | 0.87 | 0 | |
| TA | 0.32 | 0.8 | 66 ± 6 | 0.2 | |
| TIC | 0.94 | 0.93 | 0 | ||
| MDMA | 0.94 | 0.89 | 0 | ||
| TAO | 0.93 | 0.99 | 6 ± 1 | ||
| MIF | 0.81 | 0.83 | 3 ± 1 | ||
| SM4OH | FUR | 0.91 | 0.94 | 4 ± 2 | |
| TA | 0.96 | 1 | 8 ± 3 | ||
| TIC | 0.29 | 0.63 | 54 ± 9 | 3.9 | |
| MDMA | 0.99 | 0.99 | 0 | ||
| TAO | 0.91 | 0.96 | 6 ± 3 | ||
| MIF | 0.96 | 0.96 | 0 | ||
| B1OH | FUR | 0.96 | 0.89 | 0 | |
| TA | 0.98 | 0.96 | 0 | ||
| TIC | 0.96 | 0.94 | 0 | ||
| MDMA | 0.26 | 0.77 | 67 ± 2 | 1.9 | |
| TAO | 0.85 | 0.9 | 6 ± 1 | ||
| MIF | 0.89 | 0.87 | 0 | ||
| M1OH | FUR | 0.99 | 0.93 | 0 | |
| TA | 1.01 | 1.00 | 0 | ||
| TIC | 1.00 | 1.02 | 0 | ||
| MDMA | 1.01 | 0.94 | 0 | ||
| TAO | 0.28 | 0.9 | 69 ± 3 | 0.5 | |
|
| MIF | 0.33 | 0.71 | 53 ± 4 | 4.1 |